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BACKGROUND: Treatment of burn shock according to empirical resuscitation formulas is still considered the gold standard, and the burn community does not advocate the use of invasive cardiorespiratory monitoring in general. As a consequence, data dealing with early postburn hemodynamics are sparse, and only few studies have paid attention to the topic of end-point burn shock resuscitation. However, recent studies have suggested that burn survival may be improved when invasive monitoring is used to guide fluid therapy during the shock phase. MATERIALS AND METHODS: In an observational study of 24 patients with severe burns, the transpulmonary double indicator dilution technique was used for semi-invasive hemodynamic monitoring. The clinical utility of the intrathoracic blood volume (ITBV) as an end-point variable for fluid resuscitation was evaluated, comparing correlation of filling pressure obtained by a pulmonary artery catheter and intrathoracic blood volume to cardiac index and oxygen delivery. In addition fluid volume predicted by the Parkland burn formula was compared with the actual fluid volume given when ITBV was used as end point for resuscitation. RESULTS: ITBV-guided resuscitation was associated with restoration of preload and peripheral delivery of oxygen within 24 hours in the majority of patients. Augmentation of ITBV was significantly correlated with changes in cardiac index and oxygen transport rate. No such correlation could be demonstrated for the conventional preload parameters such as central venous pressure and pulmonary capillary wedge pressure. Thus, ITBV seemed in burned, hypovolemic patients a better indicator of the preload component of the cardiac output than the conventional preload parameters obtained with the pulmonary artery catheter. Significantly larger volumes of crystalloids than predicted by the Parkland formula were administered when ITBV was used as end point for resuscitation. The extravascular lung water remained normal during this extraordinary high volume load. CONCLUSION: ITBV may be a reliable preload indicator to guide volume therapy in life-threatening burns, and end-point-fixed resuscitation to this parameter seems to be associated with significantly higher fluid administration than calculated compared with traditional burn formulas. The effects of burn resuscitation to fixed end points on survival and multiple organ failure should be evaluated in future randomly assigned trials.

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Resuscitation from shock based on invasive hemodynamic monitoring has been widely used in trauma and surgical patients, but has been only sparsely evaluated in thermally injured patients, probably due to fear of invasive monitoring in this group of patients. However, end-point resuscitation to fixed circulatory and oxygen transport values has been proposed to be associated with an improved survival rate following trauma and high-risk surgery. Furthermore, the early circulatory response to resuscitation has been shown to be predictive of survival in these patients. In this study the early hemodynamic and oxygen transport profile following thermal injury was analysed with the aim to detect possible differences in the response of survivors and non-survivors. The transpulmonary thermodilution technique was used for hemodynamic monitoring of 21 patients, who were admitted to our burn unit with severe burns. Six patients died and 15 patients survived to leave the intensive care unit. Survivors were found to have a significantly higher cardiac index and oxygen delivery rate during the early postburn period than non-survivors. Furthermore, initial serum lactate levels as well as the ability to clear elevated lactate were found to be significantly associated with survival. Blood pressure and heart rate were not significantly different between the two groups of patients. All patients received significantly higher volumes of crystalloids during the first 24 h than predicted from the Baxter formula, independent of outcome. We concluded that standard vital signs such as blood pressure and heart rate may be invalid as outcome related resuscitation goals, and too insensitive to ensure appropriate fluid replacement. The response to fluid therapy may be significantly associated with outcome; survivors responding with an augmentation of cardiac output and oxygen delivery not seen in non-survivors. Lactate levels seem to correlate with organ failure and death and appear a suitable end-point for resuscitation of severely burned patients.

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Although burn-related shock resuscitation based on invasive hemodynamic monitoring has been reported at an increased rate, little is known about appropriate hemodynamic end points. Shock resuscitation based on oxygen transport criteria has been widely used for patients with trauma and patients who undergo surgery, and supranormal values of oxygen delivery (DO2) have been reported in association with an improved survival rate. This improved survival rate has been attributed to a shifting of the critical threshold of DO2 to higher values in these patients. In patients with thermal injuries, the effects of the manipulation of hemodynamics to optimize oxygen transport have not been proven. It is still unclear whether these patients exhibit delivery-dependent oxygen consumption (VO2) during the shock phase. The goal of this study was to evaluate the existence of oxygen supply dependency and to determine critical levels of DO2 in patients with burns. In a prospective study that included 16 patients with serious thermal injuries, we studied the effects of volume loading on DO2 and VO2. A transpulmonary double dilution technique was used for hemodynamic monitoring, and resuscitation end points included a normalization of preload and cardiac output parameters within 24 hours of the thermal injury. Fluid loading with crystalloids and colloids, according to our resuscitation protocol, was used to augment cardiac output and DO2. Of the 16 patients with a mean of 46% total body surface area burned (range, 22%-80%), 8 patients survived and 8 patients died. With the use of progressive fluid loading, cardiac index was restored within 24 hours of admission in all of the patients. Successful resuscitation was associated with increased levels of DO2 and VO2 and with declining serum lactate levels. VO2 appeared to be dependent on DO2 during the resuscitation period (r = 0.596), and the correlation was significantly stronger in the patients who survived (r = 0.744) than in the patients who died (r = 0.368; P < .05). A critical threshold of oxygen supply could not be identified. We concluded that increasing DO2 by fluid resuscitation increases VO2 during hypovolemic shock after a severe burn injury.

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Acute renal failure (ARF) is a well known complication of severe burns and is an important factor leading to an increase in mortality. In order to analyze possible pathogenetic and prognostic factors associated with ARF in burned patients we reviewed in a retrospective study the files of 328 patients with burns > 10% body surface area (BSA), admitted to our burn unit between 01.01.94 and 01.05.98. We found 48 patients with acute renal failure corresponding with an incidence of 14.6%. Patients with ARF had a mean burned surface area of 48% (13-95) and an abbreviated burn severity index score (ABSI) of 9.8 (4-15). Thirty eight (79%) of these patients had an inhalation injury diagnosed. Renal insufficiency was divided in a late and an early form depending on its time of onset and we found 15 (31%) patients with ARF occurring within the first 5 days of the hospital stay and 33 (69%) patients with ARF developing >5 days following the thermal injury. The incidence of myoglobinuria and hypotension during the resuscitation phase was significantly higher in the group with early ARF, whereas patients with late ARF presented sepsis more frequently than patients with early occurring renal failure. Accordingly, potential nephrotoxic antibiotics were administered more often in patients with late ARF. Patients with ARF were treated by continuous arteriovenous hemofiltration (CAVH) for a mean period of 10.5 days (1-47) and CAVH was associated with a complication rate of 10%. Most of the complications were associated with the vascular access in the femoral artery. The mortality rate in patients with ARF was 85% and death was due to multiple organ failure in 83% of the cases. Only burned BSA and inhalation injury proved to be significantly correlated with the development of ARF, whereas age, third degree burn or electric injury were not significantly different between the two groups. Neither age, TBSA, day of onset of ARF nor duration of the renal replacement therapy proved to be significantly different comparing survivors with non-survivors, and thus predictive for the survival rate.

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OBJECTIVE: To obtain further insight into the constitutional, phenotype-dependent changes of T-helper-1 and T-helper-2 signature lymphokine synthesis after trauma. DESIGN: Prospective, descriptive study. SETTING: Intensive care unit of a burn center in a community hospital. PATIENTS: Ten patients 1, 3, 5, and 7 days after major burn injury and 15 healthy individuals. INTERVENTIONS: Peripheral blood mononuclear cells were separated and incubated (5 hrs) for cytokine production induced by the accessory cell-independent stimulus of ionomycin and phorbol 12-myristate 13-acetate. After fixation and permeabilization, cell samples were immunofluorescently stained for cell surface antigens (CD4 and CD8), intracellular interferon (IFN)-gamma, and interleukin (IL)-4 synthesis. Results were correlated with corresponding enzyme-linked immunosorbent assay measurements of the culture supernatants. MEASUREMENTS AND MAIN RESULTS: The phenotypic analysis of the composition of the helper (CD4) and suppressor/cytotoxic (CD8) T-cell subset demonstrated that patients suffering from major burns and healthy controls express these antigens in similar percentages. The ratio of CD4 positive to CD8 positive/CD16 negative T-cell subsets showed no significant changes after trauma compared with controls. The production of IL-4 was excessively up-regulated while the release of IFN-gamma was only slightly increased. The predominant cell source of IL-4 after burn trauma was the CD8+ cell with nearly five-fold increased production on day 5 (7.2+/-2.6%) vs. 1.5+/-0.4% in controls. While CD8+ cells are also capable of enhancing their IFN-gamma synthesis under stress by about 60% due to the significant participation of the naive CD45RA+ subset, the CD4+ IFN-gamma release remained largely unchanged. With this study, we demonstrated that in nonsurvivors the number of CD8+ IL-4-producing cells was significantly higher compared with controls; also, the number of IFN-gamma-releasing memory/effector CD45RO+ cells was lower compared with survivors. CONCLUSIONS: In previous experiments, we show that a shift to T(H)2 dominated phenotypes increases the risk for postburn infection. The current study confirms that major burns induce a significant shift of cytokine response in the T(H)2 direction and demonstrates that the CD8+, rather than the CD4+ phenotype, is present. Increased IL-4 production is associated with the T(H)2 lymphocyte. These diagnostic tests may help to differentiate patients with compensatory anti-inflammatory response syndrome and immunosuppression from those patients in the proinflammatory state associated with the systemic inflammatory response syndrome. The profile described in this article is associated with immunosuppression and may contraindicate attempts at anti-inflammatory therapy for sepsis.

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BACKGROUND: Impairment of T-helper cell function and polarization toward T-helper 2-type cytokine synthesis have been postulated to represent a major cause for posttraumatic immunodeficiency. With a recently developed technology for intracellular cytokine measurement, a new diagnostic tool has become available to discriminate, within hours, a shift of functionality in T-cell subsets via their individual cytokine profiles. Thus, it was the objective of this study to obtain further insight into the constitutional, phenotype-dependent changes of T-helper 1 (TH1) and T-helper 2 (TH2), respectively, signature lymphokine synthesis under traumatic stress. METHODS: Peripheral blood mononuclear cells from 10 patients with major burn injury on day 1, 3, 5, and 7 after injury and from 15 healthy individuals were separated and incubated (5 hours) for cytokine production induced with the accessory cell-independent stimulus of ionomycin and phorbol 12-myristate 13-acetate. After fixation and permeabilization, cell samples were immunofluorescently stained for cell surface antigens (CD4 and CD8) as well as for intracellular interferon (IFN)-gamma and interleukin (IL)-4 synthesis. Results were correlated with corresponding enzyme-linked immunosorbent assay measurements of the culture supernatants. RESULTS: Phenotypic assessment of peripheral blood mononuclear cells showed a continuously diminished percentage of CD8+ cells during the immediate posttraumatic course compared with controls, whereas the number of CD4+ cells was found to be within the range of the control group. The production of IL-4, the index cytokine of TH2 cells, was excessively up-regulated (from 437.8 +/- 137.0 pg/mL on day 1 to 1,333.6 +/- 532.7 pg/mL on day 7 burns vs. 82.3 +/- 15.8 pg/mL controls), whereas the release of IFN-gamma, the index cytokine of TH1 cells, however, was only slightly increased. The predominant cellular source of IL-4 after burn trauma has been shown to be the CD8+ cell with a nearly fivefold elevated production on day 5 (7.2 +/- 2.6%) versus 1.5 +/- 0.4% in controls. Although CD8+ cells are also capable of enhancing their IFN-gamma synthesis under stress by about 60%, the CD4+ IFN-gamma release remained largely unchanged. CONCLUSION: Our data corroborate that major burn trauma will induce a significant shift of cytokine response toward the TH2 direction and demonstrate that the CD8+ rather than the CD4+ phenotype is the crucial cell for the polarization toward a TH2-driven immune response.

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OBJECTIVES: To determine the potential of interleukin-13 (IL-13) to modify in vitro lipopolysaccharide-induced monocyte-macrophage (MO) activity in human cells from individuals who had sustained either major mechanical or burn injury and to investigate whether the effect of IL-13 is different on MOs that have been preactivated under traumatic stress than on monocytic cells from healthy volunteers. DESIGN: Peripheral MOs from 20 controls and 16 patients after major burn or mechanical trauma were separated on days 1, 3, 5, and 7 after injury and incubated with lipopolysaccharide (1 microgram/mL) in the presence or absence of IL-13 (10 ng/mL) for 4 hours and for 20 hours. Thereafter, the following measures were determined from the culture supernatants: neopterin, nitric oxide, tumor necrosis factor alpha, IL-1 beta, IL-6, and IL-8. RESULTS: Ex vivo lipopolysaccharide-activated MOs, compared with control cells, displayed considerably enhanced inflammatory activity during the immediate posttraumatic course, with a substantial and consistent elevation of levels of tumor necrosis factor alpha and IL-6. The addition of human recombinant IL-13 to the MO cultures resulted in an effective down-regulation of the synthesis of tumor necrosis factor alpha, IL-1 beta, and IL-6 as well as IL-8, showing an average reduction of mediator production to two thirds of the value found in corresponding sole lipopolysaccharide-stimulated cultures. The impact of human recombinant IL-13 on control MOs was almost identical for IL-6 and IL-1 beta, slightly lower for IL-8, and nonexistent for tumor necrosis factor alpha. CONCLUSION: From this study and preexisting findings, we conclude that, based on its biologic properties, IL-13 should be tested as a biologic response modifier for acute states of trauma-induced host defense deficiency.

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In patients with extensive deep burns and scarce donor sites autogenic cultured epithelial grafts (auto-CEG) have become a real alternative. In deep burns the 'take' rate of auto-CEG applied directly on subcutaneous fat, fascia or muscle is unreliable and frequently disappointing. The auto-CEG seems to need a dermal base. Improved results have been reported when auto-CEG were applied to the dermal base of a viable cryopreserved donor skin. We extended this principle by using the dermal layer of non-viable glycerol-preserved donor skin (GPDS). We report on two patients with deep burns of 55 and 80 per cent TBSA in whom we used the composite grafting of auto-CEG on non-viable allogeneic dermis from GPDS. The estimated 'take' rates were 70 and 77 per cent. The grafted areas remained stable for 4 and 8 months respectively. The two-layer skin substitute gave a permanent cover for full thickness burn wounds of higher quality and better 'take' rate than previous results, where the auto-CEG had been grafted directly onto the debrided wounds.

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The study was performed to further elucidate the mechanisms of dysfunctional T-cell activation following extensive burn and mechanical injuries. The major regulatory level of interleukin-2 (IL-2) release under stressful conditions was determined via parallel analysis of IL-2 messenger RNA (mRNA) expression and IL-2 protein synthesis in mitogen-stimulated peripheral blood mononuclear cell (PBMCs) cultures on consecutive days postinjury. Furthermore, we wanted to scrutinize if inadequate lymphokine production after trauma is possibly a result of defective transduction of extracellular signals to the T-cell nucleus. Fourteen patients (11 men, 3 women, average age 38 +/- 6 years, Injury Severity Score 34 +/- 2) were included in the study. The PBMCs were isolated on days 1, 3, 5, 7, and 10 and stimulated either with the mitogen phytohemagglutinin (PHA) alone or in combination with the protein kinase C (PKC) activator phorbol myristate acetate (PMA). The protein release was examined via bioassay (human con-A blasts) from the supernatants, and the cellular RNA was indicated by radioactive hybridization with the specific complementary DNA (cDNA) after Northern blotting. The IL-2 protein synthesis generated in PHA-stimulated PBMC cultures following trauma, compared with that in controls (0.62 +/- 0.04 U/mL) was persistently and significantly depressed during the observation time with a 57% inhibition on day 10-identical with that on day 1. The Northern blot analysis of IL-2 mRNA expression in the lysates of PHA-stimulated cell cultures after trauma could not detect any mRNA signal for IL-2, in contrast to the control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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