Activated protein C to heal pressure ulcers.

Pressure ulcers present a major clinical challenge, are physically debilitating and place the patient at risk of serious comorbidities such as septic shock. Recombinant human activated protein C (APC) is an anticoagulant with anti-inflammatory, cytoprotective and angiogenic effects that promote rapid wound healing. Topical negative pressure wound therapy (TNP) has become widely used as a treatment modality in wounds although its efficacy has not been proven through randomised controlled trials. The aim of this study was to determine the preliminary efficacy and safety of treatment with APC for severe chronic pressure sores with and without TNP. This case presentation describes the history, management and outcome of two patients each with a severe chronic non-healing pressure ulcer that had failed to respond to conventional therapy. TNP was added to conservative management of both ulcers with no improvement seen. Then local application of small doses of APC was added to TNP and with conservative management, resulted in significant clinical improvement and rapid healing of both ulcers, displaying rapid growth of vascular granulation tissue with subsequent epithelialisation. Patients tolerated the treatment well and improvements suggested by long-term follow-up were provided. Randomised placebo-controlled double blind trials are needed to quantify the efficacy, safety, cost-effectiveness, optimal dose and quality of life changes seen from treatment with APC.

Management strategies for perioperative anaemia in the severely burn-injured Jehovah's Witness patients who decline a blood transfusion: A systematic review with illustrative case reports.

BACKGROUND: The management of severe burn-injured Jehovah's Witness patients who decline a blood transfusion poses unique challenges. The literature is scant for guiding perioperative anaemia management in these patients. We present a systematic review of this patient group, along with illustrative, consecutive case reports of our experience. METHODS: A systematic review was performed on Embase, MEDLINE and PubMed databases on articles discussing the treatment of burn-injured Jehovah's Witness patients. Articles were excluded if discussing isolated inhalation injury, or if blood transfusions were permitted. RESULTS: Nine articles including a total of 11 patients revealed consistent themes. A multimodal medical and surgical approach is suggested. Medical strategies are directed at reducing blood loss and optimising haematopoiesis and include rationalising blood collection, reversing coagulopathy, administering tranexamic acid and regular erythropoietin. Surgical strategies include staged aggressive debridement, tumescent adrenaline infiltration and limb tourniquets. We found that the argon beam coagulator was an effective haemostatic adjunct not previously described in literature. DISCUSSION: Management of anaemia in severely burn-injured Jehovah's Witness patients is challenging. This systematic review presents a summary of strategies directed at minimising blood loss, and optimising haematopoiesis. Careful preoperative planning, meticulous surgical technique, and postoperative physiological support are caveats to success.

Early protein C activation is reflective of burn injury severity and plays a critical role in inflammatory burden and patient outcomes.

BACKGROUND: Navigating the complexities of a severe burn injury is a challenging endeavour where the natural course of some patients can be difficult to predict. Straddling both the coagulation and inflammatory cascades that feature strongly in the burns systemic pathophysiology, we propose the pleiotropic protein C (PC) system may produce a viable biomarker to assist traditional evaluation methods for diagnostic and prognostic purposes. METHODS: We enrolled 86 patients in a prospective observational cohort study. Over three weeks, serial blood samples were taken and measured for PC, activated (A)PC, their receptor endothelial protein C receptor (EPCR), and a panel of inflammatory cytokines including C-reactive protein (CRP), tumour necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-8, and IL-17. Their temporal trends were analysed alongside clinical factors including burn size, burn depth, presence of inhalational injury, and a composite outcome of requiring increased support. RESULTS: (i) APC increased from a nadir on Day 3 (2.3±2.1ng/mL vs 4.1±2.5ng/mL by Day 18, p<0.0005), only becoming appropriately correlated to PC from Day 6 onwards (r=0.412-0.721, p<0.05 for all Days 6-21). (ii) This early disturbance in the PC system was amplified in the more severe burns (≥30% total body surface area, predominantly full thickness, or with inhalational injury), which were characterised by a marked fall in PC activation (approximated by APC/PC ratio) and APC levels during Days 0-3 with low unchanged PC levels. Critically low levels of this cytoprotective agent was associated with greater inflammatory burden, as reflected by significantly elevated CRP, IL-6, and IL-8 levels in the more severe compared to less severe burns, and by negative correlations between both PC and APC with most inflammatory cytokines. (iii) Alongside clinical markers of severity at admission (burn size, burn depth, and presence of inhalational injury), only Day 0 APC/PC ratio (OR 1.048 (1.014-1.083), p=0.006), APC (OR 1.364 (1.032-1.803), p=0.029), PC (OR 0.899 (0.849-0.953), p<0.0005), and not any inflammatory cytokines were predictive markers of requiring increased support. Uniquely, decreased Day 0 PC was further individually associated with each increased total length of stay, ICU length of stay, intravenous fluid resuscitation, and total surgeries, as well as possibly mortality. CONCLUSION: An early functional depletion of the cytoprotective PC system provides a physiological link between severe burns and the cytokine storm, likely contributing to worse outcomes. Our findings on the changes in APC, PC and PC activation during this pathological state support APC and PC as early diagnostic and prognostic biomarkers, and provides a basis for their therapeutic potential in severe burn injuries.

A Critical Update of the Assessment and Acute Management of Patients with Severe Burns.

Significance: Burns are debilitating, life threatening, and difficult to assess and manage. Recent advances in assessment and management have occurred since a comprehensive review of the care of patients with severe burns was last published, which may influence research and clinical practice. Recent Advances: Recent advances have occurred in the understanding of burn pathophysiology, which has led to the identification of potential biomarkers of burn severity, such as protein C. There is new evidence about the potential superiority of natural colloids over crystalloids during fluid resuscitation, and new evidence about components of initial and perioperative management, including an improved understanding of pain following burns. Critical Issues: The limitations of the clinical examination highlight the need for imaging and biomarkers to assist in estimations of burn severity. Fluid resuscitation reduces mortality, although there is conjecture over the ideal method. The subsequent perioperative period is associated with significant morbidity and the evidence for preventing and treating pain, infection, and fluid overload while maximizing wound healing potential is described. Future Directions: Promising developments are ongoing in imaging technology, histopathology, biomarkers, and wound healing adjuncts such as hyperbaric oxygen therapy, topical negative pressure therapy, stem cell treatments, and skin substitutes. The greatest benefit from further research on management of patients with burns would most likely be derived from the elucidation of optimal fluid resuscitation protocols, pain management protocols, and surgical techniques from randomized controlled trials.

Plasma protein C levels are directly associated with better outcomes in patients with severe burns.

Protein C circulates in human plasma to regulate inflammation and coagulation. It has shown a crucial role in wound healing in animals, and low plasma levels predict the presence of a wound in diabetic patients. However, no detailed study has measured protein C levels in patients with severe burns over the course of a hospital admission. A severe burn is associated with dysfunction of inflammation and coagulation as well as a significant risk of morbidity and mortality. The current methods of burn assessment have shortcomings in reliability and have limited prognostic value. The discovery of a biomarker that estimates burn severity and predicts clinical events with greater accuracy than current methods may improve management, resource allocation and patient counseling. This is the first study to assess the potential role of protein C as a biomarker of burn severity. We measured the plasma protein C levels of 86 patients immediately following a severe burn, then every three days over the first three weeks of a hospital admission. We also analysed the relationships between burn characteristics, blood test results including plasma protein C levels and clinical events. We used a primary composite outcome of increased support utilisation defined as: a mean intravenous fluid administration volume of five litres or more per day over the first 72 h of admission, a length of stay in the intensive care unit of more than four days, or greater than four surgical procedures during admission. The hypothesis was that low protein C levels would be negatively associated with increased support utilisation. At presentation to hospital after a severe burn, the mean plasma protein C level was 76 ± 20% with a range of 34-130% compared to the normal range of 70-180%. The initial low can be plausibly explained by impaired synthesis, increased degradation and excessive consumption of protein C following a burn. Levels increased gradually over six days then remained at a steady-state until the end of the inpatient study period, day 21. A multivariable regression model (Nagelkerke's R2 = 0.83) showed that the plasma protein C level on admission contributed the most to the ability of the model to predict increased support utilisation (OR = 0.825 (95% CI = 0.698-0.977), P = 0.025), followed by burn size (OR = 1.252 (95% CI = 1.025-1.530), P = 0.027), burn depth (partial thickness was used as the reference, full thickness OR = 80.499 (1.569-4129.248), P = 0.029), and neutrophil count on admission (OR = 1.532 (95% CI = 0.950-2.473), P = 0.08). Together, these four variables predicted increased support utilisation with 93.2% accuracy, 83.3% sensitivity and 97.6% specificity. However if protein C values were disregarded, only 49.5% of the variance was explained, with 82% accuracy, 63% sensitivity and 91.5% specificity. Thus, protein C may be a useful biomarker of burn severity and study replication will enable validation of these novel findings.

Self-inflicted burns: a case series.

Self-inflicted burns are regularly admitted to burns units worldwide. Most of these patients are referred to psychiatric services and are successfully treated however some return to hospital with recurrent self-inflicted burns. The aim of this study is to explore the characteristics of the recurrent self-inflicted burn patients admitted to the Royal North Shore Hospital during 2004-2011. Burn patients were drawn from a computerized database and recurrent self-inflicted burn patients were identified. Of the total of 1442 burn patients, 40 (2.8%) were identified as self-inflicted burns. Of these patients, 5 (0.4%) were identified to have sustained previous self-inflicted burns and were interviewed by a psychiatrist. Each patient had been diagnosed with a borderline personality disorder and had suffered other forms of deliberate self-harm. Self-inflicted burns were utilized to relieve or help regulate psychological distress, rather than to commit suicide. Most patients had a history of emotional neglect, physical and/or sexual abuse during their early life experience. Following discharge from hospital, the patients described varying levels of psychiatric follow-up, from a post-discharge review at a local community mental health centre to twice-weekly psychotherapy. The patients who engaged in regular psychotherapy described feeling more in control of their emotions and reported having a longer period of abstinence from self-inflicted burn. Although these patients represent a small proportion of all burns, the repeat nature of their injuries led to a significant use of clinical resources. A coordinated and consistent treatment pathway involving surgical and psychiatric services for recurrent self-inflicted burns may assist in the management of these challenging patients.

A split forehead flap for the treatment of resistant bilateral upper and lower eyelid ectropion postburn injury.

OBJECTIVE: The aim of this surgical procedure was to definitively correct severe recurrent upper and lower bilateral eyelid ectropion after 2 attempts with full-thickness skin grafts. It was necessary to repair all 4 eyelids with forehead skin. Middle lamella support was required. METHODS: Bilateral median forehead flaps, which were well vascularized by the supratrochlear vessels, were chosen for this procedure to utilize the readily available forehead tissue. The median forehead flap can be easily positioned to cover the entire eyelid. Furthermore, the flap could be split in half, without the risk of vascular compromise. Middle lamella support was provided with a cartilage graft from the nasal septum. RESULTS: At 4 months, the patient no longer suffered from exposure keratopathy and both forehead flaps had healed well. At 12 months, the functional and cosmetic outcomes of this procedure were acceptable. CONCLUSIONS: This method of surgery can be effective in the young, in whom the Mustarde cheek advancement fails, or when there is little available unburnt tissue. It can be used as an alternative to a forehead flap when both upper and lower eyelids are damaged bilaterally. The split forehead flap definitively corrected the ectropion in this case.

Combination of activated protein C and topical negative pressure rapidly regenerates granulation tissue over exposed bone to heal recalcitrant orthopedic wounds.

Chronic wounds arising from orthopedic surgery present a major clinical challenge. Osteomyelitis may develop from polymicrobial infection, which can be unresponsive to treatment and lead to amputation. Topical negative pressure (TNP) is an effective treatment in wound management and is now used worldwide. Activated protein C (APC) is an anticoagulant with cytoprotective and healing properties. The aim of this study was to determine whether combined treatment of TNP and APC was tolerated and was efficacious for treatment of difficult-to-treat wounds. Four patients who presented to Royal North Shore Hospital with wounds that were not responsive to conventional therapy were studied. All cases showed a marked reduction in wound size and depth within 1 week of starting treatment and progressively improved over time. There was a remarkable increase in the volume of granulation tissue. After treatment, wounds either completely closed or provided sufficient granulation tissue to allow split-thickness skin grafting. The treatment was well tolerated, and the patients were able to be managed on out-patient basis. Long-term follow-up suggested that this treatment prevented osteomyelitis. This innovative treatment is very promising and may significantly increase quality of care for patients with recalcitrant orthopedic wounds. A randomized, placebo-controlled double blind trial is required to further determine the efficacy of APC plus TNP.