Measuring gastric residual volumes in critically ill burn patients - A systematic review.

PURPOSE: Measuring gastric residual volumes (GRV) is common in intensive care units (ICU) in patients receiving enteral nutrition (EN) and are a common source of feeding interruptions. Interruptions in EN yield adverse outcomes and are an area of improvement in burn care. The objectives of this study are to summarize the literature's ICU GRV practices and offer practical suggestions to GRV management in the burn patient. METHODS: PubMed, SCOPUS, and OvidSP Medline were systematically reviewed using the keywords: burns; thermal injury; gastric residual volume; enteral feeding; tube feeding; enteral nutrition; gastric intolerance; ICU; critical illness. Reviews, case reports, and consensus and opinion papers were excluded. RESULTS: 26 articles were identified. Six burn-specific studies were identified. GRV practices vary widely and are a common cause of EN interruption. Elevated GRVs do not equate to gastrointestinal intolerance and do not always reflect aspiration risk. CONCLUSIONS: We advocate a GRV threshold of 500mL should be used to optimize the benefits of EN in burn ICUs. A single incident of elevated GRVs should not mandate immediate EN rate reduction or cessation but should prompt a thoughtful examination of secondary causes of gastrointestinal intolerance. Randomized controlled trials are needed to define the ideal GRV threshold and re-evaluate its role in burn care.

How long are burn patients really NPO in the perioperative period and can we effectively correct the caloric deficit using an enteral feeding "Catch-up" protocol?

OBJECTIVE: "NPO at midnight" is a standard preoperative practice intended to reduce aspiration risk but can result in prolonged feeding interruptions in critically ill burn patients. Postoperative hyperalimentation in the form of a "catch-up" tube feeding protocol is routine. A retrospective review of our perioperative fasting practices and "catch-up" enteral feeding protocols was performed. METHODS: Patients admitted to the Burn ICU from July 1st, 2015 to August 31st, 2016 were reviewed. Patients who had a protected airway in place, prescribed enteral nutrition, and underwent surgery were included. The time from NPO to surgical start (NPO-SS), NPO to feeding restart (NPO-FR), and calories received/prescribed were quantified. The efficacy of a postoperative catch-up feeding protocol was analyzed. RESULTS: There were 41 patients that fit inclusion criteria with some undergoing multiple surgeries, yielding 109 surgeries/discrete perioperative events. The average total body surface area burn (38.1±23.6%), age (38.8±20.1years), ICU days (45.0±37.3 days), and ventilator days (35.1±33.8 days) were calculated. Average fasting durations of NPO-SS and NPO-FR were 9.3±3.1 and 14.2±4.1h, respectively. The average caloric deficit to prescribed calories ratio during the NPO-SS and NPO-FR periods were 1154±629/3534±851kcal and 1765±928/3534±851kcal, respectively. A post-operative catch-up protocol completely compensated for perioperative caloric deficits 68.8% (22/32) of the time. CONCLUSIONS: In critically ill burn patients, a preoperative fast resulted in an average loss of greater than 50% of prescribed calories on the day of surgery. Clinicians should re-evaluate the standard practice of making preoperative patients "NPO at midnight". An effective catch-up protocol can adequately reduce caloric deficits.

Transforming growth factor-beta - and tumor necrosis factor-alpha -mediated induction and proteolytic activation of MMP-9 in human skin.

Both cytokines and matrix metalloproteinases (MMPs) are active during physiologic and pathologic processes such as cancer metastasis and wound repair. We have systematically studied cytokine-mediated MMP regulation. Cytokine-mediated proteinase induction and activation were initially investigated in organ-cultured human skin followed by determination of underlying cellular and molecular mechanisms using isolated skin cells. In this report we demonstrate that tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) synergistically induce pro-MMP-9 in human skin as well as isolated dermal fibroblasts and epidermal keratinocytes. Furthermore, TNF-alpha promotes proteolytic activation of pro-MMP-9 by conversion of the 92-kDa pro-MMP-9 to the 82-kDa active enzyme. This activation occurred only in skin organ culture and not by either isolated fibroblasts or keratinocyte, although the pro-MMP-9 activation could be measured in a cell-free system derived from TNF-alpha-activated skin. The cytokine-mediated induction of pro-MMP-9 in dermal fibroblasts was evident by increased mRNA. At the transcription level, we examined the cytokine-mediated transactivation of the 5'-region promoter of the human MMP-9 in dermal fibroblasts. The results demonstrated that TNF-alpha and TGF-beta could independently stimulate the 5'-flanking 670-base pair promoter. A TGF-beta-response element (-474) and an NF-kappaB-binding site (-601) were identified to be the cis-elements for TGF-beta or TNF-alpha activation, respectively. Taken together, these findings suggest a specific mechanism whereby multiple cytokines can regulate MMP-9 expression/activation in the cells of human skin. These results imply roles for these cytokines in the regulation of MMP-9 in physiologic and pathologic tissue remodeling.

The use of 5% mafenide acetate solution in the postgraft treatment of necrotizing fasciitis.

Twenty-nine patients with necrotizing fasciitis who were treated with 5% mafenide acetate solution (MAS) as an adjunct after grafting were compared with 45 patients treated without MAS. Statistical analysis of differences was obtained through P values by chi2 testing. The MAS+ (M) and MAS- (C) groups were similar in percent skin deficit (M = 7.5%; C = 9.8%), with the extremity being the most common area of infection. Streptococcus was the most common single organism but polymicrobial infections were the most prevalent (M = 48%; C = 58%). Patients with necrotizing fasciitis treated with MAS had fewer debridements per patient (M = 3.7; C = 5.4), fewer closure procedures (average per patient: M = 1.2; C = 1.73) and a higher percent of first-time closures (83 vs 59%; chi2 = 4.26; P = 0.039). There is a trend toward a lower mortality rate (3.4 vs 13%; chi2 = 2.00; P = 0.158). We conclude that MAS is a useful adjunct in necrotizing fasciitis wound care protocols.

TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP.

Tumor necrosis factor-alpha (TNF-(alpha)) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-(alpha) are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-(alpha) stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-(alpha) mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-(alpha) induced I(kappa)B to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-(kappa)B activation. Lastly, a consensus binding site for p65 NF-(kappa)B (TGGAGCTTCC) was found in the 5'-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-(alpha) activation of MMP-2 in human skin. Activation of NF(kappa)B signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-(alpha) may affect matrix remodeling during wound healing and other physiological and pathological processes.

Memory of past exposure to the chemokine IL-8 inhibits the contraction of fibroblast-populated collagen lattices.

The inflammatory cytokine makeup of healing wounds helps delineate the phases of the repair process. As an example, during the lag phase (inflammatory phase) of repair, elevated levels of IL-8, a chemokine, participate in the activation and chemotaxis of neutrophils. During the normal proliferative and remodeling phases of repair, IL-8 levels are minimal. Healing burn wounds often have small, open, slow-to-heal areas, which have been shown to contain elevated levels of IL-8. Does a limited exposure of IL-8 to fibroblasts in vitro at the concentrations measured in these unhealed sites cause altered cell behavior? To study this possibility the fibroblast-populated collagen lattice (FPCL) model, an in vitro model of wound contraction, was used to investigate fibroblast response to IL-8. As previously reported, the chronic exposure of fibroblasts to IL-8 at 30 ng/ml within FPCLs significantly inhibited FPCL contraction. Fibroblasts in monolayer culture were incubated with IL-8 for 3 days. In the absence of IL-8, FPCLs were manufactured with these preexposed cells and it was found that FPCL contraction was inhibited. Fibroblasts retained their reduced capacity of reorganizing collagen fibrils when previously exposed to IL-8. Treating fibroblasts in monolayer with IL-8 for only 1 h prior to their incorporation into collagen lattices caused inhibition of FPCL contraction. The speculation is that in vivo open areas in reepithelialized healed burns are the consequence of the local population of fibroblasts having been exposed to elevated levels of IL-8. Such an earlier exposure triggers a memory in this population of fibroblasts that alters their capacity to lay down an extracellular matrix that optimizes the migration of epidermal cells.

Interleukin-8 levels and activity in delayed-healing human thermal wounds.

There are numerous causes for slow or delayed wound healing. Because slowly healing wounds are often inflamed, we quantitated the inflammatory chemokine, interleukin-8, produced by slowly healing human burn wounds and compared this to interleukin-8 from healed wounds and normal intact skin. Interleukin-8 levels were increased significantly in unhealed wounds (19.7 ng/ml) compared to healed wounds (7.7 ng/ml) or normal skin (5.7 ng/ml). Interleukin-8 in these ranges was added to adult human keratinocytes and fibroblasts. Interleukin-8 significantly decreased keratinocyte replication but had no effect on fibroblast replication. The rate or final degree of fibroblast populated collagen lattice contraction was inhibited at interleukin-8 concentrations between 10 and 30 ng/ml, but not altered at concentrations below 10 ng/ml and above 100 ng/ml. The concurrent application of indomethacin at 10 microg/ml reversed this interleukin-8 induced inhibition. Interleukin-8 inhibited myosin ATPase activity, apparently by reducing the phosphorylation of nonmuscle myosin light chain. We conclude that elevated levels of interleukin-8 may be found during delayed healing, and these elevated interleukin-8 levels may directly contribute to retarded wound closure.

Acute burns.

Burn injuries are complex cutaneous traumas cared for by many plastic surgeons. Care is stratified by burn size, depth, and associated injuries. Advances in surgical technique, wound care, and bioengineered skin have resulted in excellent outcomes for most burn survivors. Moderate burn injuries can be treated effectively by an interested and experienced plastic surgeon.

Management of chemical injuries to the upper extremity.

Chemical burns are interesting and challenging to treat. When the practitioner is comfortable with the pathophysiology of chemical injury and treatment based on these principles, most patients can be treated effectively with good outcome (Fig. 2). Early treatment with water irrigation, followed by diligent wound care, will allow our patients to benefit to the maximum from our medical skills.

Determination of fluoxetine and norfluoxetine concentrations in cadaveric allograft skin.

Fluoxetine hydrochloride is the sixth most prescribed drug in the United States and is administered to treat major depression. A cadaveric skin donation was obtained from a 46-year-old woman who died as a result of a fluoxetine overdose. Due to the potential penetration of the drug and its major metabolite, norfluoxetine, into skin, the safety of using the skin as an allograft was questioned. Our evaluation showed that mean concentrations in skin were 2304+/-175 and 1353+/-102 ng/g of skin, respectively. The skin:plasma ratio was 0.41. Clinically, the amount of fluoxetine that can be transferred to an allograft recipient depends on many factors. Based on penetration of drug and metabolite into skin, one would have to evaluate carefully the risk:benefit ratio of using allografts from a donor who died from a fluoxetine overdose.

Epidermal regulation of dermal fibroblast activity.

Although the association between delayed burn wound healing and subsequent hypertrophic scar formation is well-established, the mechanism for this relationship is unknown. Unhealed burn wounds lack an epidermis, suggesting a possible regulatory role for the epidermis in controlling dermal fibroblast matrix synthesis. Therefore, we examined the effect of epidermal cells and media conditioned by epidermal cells on fibroblast collagen synthesis and replication. Purified fibroblast and keratinocyte cell strains were developed from discarded normal adult human skin. Conditioned media were created by incubation of cytokine-free and serum-free medium with either confluent fibroblast or keratinocyte cultures for 18 hours (n = 3). Nearly confluent fibroblast cultures were exposed for 48 hours to graded concentrations of either unconditioned medium (control), conditioned medium, or varying numbers of keratinocytes. Replication was quantified by the incorporation of 3H-thymidine. Collagen synthesis was measured by the incorporation of 3H-proline into collagenase-sensitive protein. Data were compared using analysis of variance (ANOVA) and linear regression. Keratinocyte conditioned medium induced a significant increase in replication (n = 3) (p = 0.004) and a decrease in collagen synthesis (n = 6) (p < 0.001). In contrast, neither fibroblast conditioned medium nor control medium had an effect on fibroblast replication or collagen synthesis. Co-culture of fibroblast with a graded number of keratinocytes similarly decreased collagen synthesis (n = 6) (p < 0.001). Dermal fibroblast collagen synthesis appears to be regulated by a soluble keratinocyte product. This result suggests a mechanism for the clinical observation that unhealed burn wounds, which lack the epidermis, demonstrate excess collagen production and scar. Clinical strategies to decrease hypertrophic scar should include an attempt at early wound closure with skin grafting or the application of cultured epithelial autografts.

Local reactions after injection of iodinated contrast material: detection, management, and outcome.

RATIONALE AND OBJECTIVES: The authors assessed the frequency, sequelae, and risk factors of extravasation of intravenously administered iodinated contrast media. MATERIALS AND METHODS: All patients with local reactions after intravenous injection of contrast media between November 1994 and December 1996 were studied. Comparison was made with data obtained from a control group of 100 patients with no local reactions who underwent contrast material-enhanced computed tomography (CT). RESULTS: Local reactions were reported in 56 (0.25%) of 22,254 patients who received intravenous injections of iodinated contrast media. Fifty-one patients experienced extravasation, and five patients experienced local irritation in the absence of clinically detectable extravasation. Extravasation occurred during CT (n = 46), urography (n = 4), and venography (n = 1). Contrast material was nonionic in 37 cases and conventional ionic in 14 cases of extravasation. Extravasated volumes exceeded 30 mL in 22 patients and 100 mL in six patients. Forty-five (80%) of 56 patients with local reactions had complete resolution of symptoms within 24 hours. Only four patients had symptoms for more than 48 hours. No surgery was required. Compared with the control group, patients with extravasation were significantly more likely to have been injected with small-bore catheters (21 or 22 gauge) and to have been injected at low or high rates. CONCLUSION: Symptoms of contrast medium extravasation usually resolve quickly. In patients with extravasation, injections are more likely to have been performed with techniques that vary from normal practice.

Biomechanical alterations in normal skin and hypertrophic scar after thermal injury.

Functional recovery after burn injury can be significantly limited by scar contraction and contracture. Mechanisms to explain these problems are not well described. Surface (shear) waves were generated in normal skin and hypertrophic burn scar with a newly described device. The velocity of propagation was used to examine biomechanical changes after burn injury. Shear wave velocity was markedly higher in scar and slightly higher in injured tissue without obvious scarring, verifying increased skin stiffness. Normal skin anisotrophy was exaggerated in scar tissue and not seen in the uninjured skin adjacent to hypertrophic scar. This result suggests the reorganization of normal tissue attempts to compensate for scar contraction. Measurements of shear wave velocity objectively document changes in skin properties that affect the recovery from thermal injury. Use of this or alternate technologies may increase understanding of postburn skin dysfunction, improving our ability to treat such patients.

The effect of essential fatty acid supplementation on keratinocyte replication.

Epidermal cell growth in culture, using the low calcium, low serum technique described by Boyce, is thought to induce rapid expansion by inducing an essential fatty acid (EFA) deficiency state. To determine the mechanisms whereby EFA deficiency induces increased epidermal cell growth, keratinocytes were passaged into medium without or with the addition of EFAs, 18:2(n-6), 20:4(n-6). The resulting populations were assayed for replication rate, differentiation, and plating efficiency. Supplemental EFAs significantly decrease keratinocyte culture expansion. This is evidenced by an increase in generation time, a decrease in thymidine incorporation, and a decrease in modeled replication rate. EFA supplementation also increased the expression of cornified cell envelopes. Serum-free medium induces EFA deficient keratinocytes that demonstrate increased replication and decreased differentiation. Restoration of EFAs reverses these changes. It may be possible to manipulate keratinocyte physiology using fatty acid modifications.

Hypertrophic scar fibroblasts accelerate collagen gel contraction.

Excessive contraction of hypertrophic scar and subsequent contracture formation are a formidable problem after thermal injury. A comparison between fibroblasts from hypertrophic scar and normal skin was made with the use of fibroblast-populated collagen lattices as a measure of cellular generated contractile forces. Hypertrophic scar and normal skin fibroblasts were mixed with soluble tendon collagen and Dulbecco's modified Eagle medium supplemented with 10% serum, and contraction was measured by serial area measurements. Parallel experiments in the presence of transforming growth factor-beta or anti-transforming growth factor-beta antibody examined the role of this cytokine on lattice contraction. Transforming growth factor-beta activity was measured in an additional set of 10 biopsy specimens. Hypertrophic scar fibroblasts contract lattices at a significantly faster rate than do normal skin fibroblasts. Exogenous transforming growth factor-beta increased lattice contraction by normal skin fibroblasts but had little effect on hypertrophic scar cell-populated lattices. The addition of anti-transforming growth factor-beta antibody decreased lattice contraction by both cell types. Transforming growth factor-beta activity was significantly increased in the hypertrophic scar biopsy specimens. Excessive scar contraction and post-burn scar contracture result from increased contraction forces generated by hypertrophic scar cells. This increased contractility appears to be mediated by increased endogenous presence of transforming growth factor-beta.

Excessive scarring as a consequence of healing.

Synthesis and degradation of collagen is an essential component of wound healing. In most persons, this deposition of collagen results in the formation of a fine line scar which restores much of the tensile strength to the injured tissue and is cosmetically acceptable. However, in certain individuals, the result of wound healing is the excessive accumulation of collagen, resulting in a hypertrophic scar or keloid. The precise origin of this abnormal collagen deposition is unknown, but recent studies have begun to identify potential mechanisms for these disfiguring and painful lesions. This article will review the clinical and laboratory findings pertinent to understanding the origin and treatment of excessive scarring.