The skin is the most sensitive organ of the body through which various communicable diseases and allergic chemical substances transmits. Examiner observes visual signs and symptoms to analyze skin lesions. In pathology, skin lesions are sings of chronic diseases manifested by various pathogens like bacteria, virus and fungus. Any physical injury to body leading to cutting, tearing, puncturing or abrasion of skin is an open wound. Damage to underlying skin tissues and muscles resulting from trauma, allergy, improper recovery or surgery is a closed wound. Closed wounds generally, tend to accumulate infected cells locally, resulting in development of a chronic disease. Blood clots, venous occlusion, pain and numbness in affected areas are some common signs of a closed wound. Clean or sterile wounds heal themselves within few days but contaminated wounds resulting from accident or injury needs therapeutic procedure. Moulds, bacteria and microorganisms can spread infection over wound to produce pus, pain, redness and crust. Therefore, it is essential to have proper sterile dressings and first aid for contaminated wounds to prevent further harm.
Natural immunogenic response has an important function in wound healing process. People with good immunity are likely to heal quickly, and suffer less with chronic disease. Therapeutic settings in treatment of contaminated wounds lead to compromise of natural immune system where inflammatory responses are suppressed against macrophages. Primary goal of therapeutic settings in medicine is to reduce inflammation to repair quickly the damaged tissues. In severe accidental case or prevalence of chronic disease, microorganisms get colonized in an infected wounds. Colonization of gram-positive and gram-negative bacteria results in formation of internal blood clots and tissue infection, which becomes difficult to heal. Structural and morphological changes in cellular composition are important indicators of disease, which depends upon the extent of microbial invasion in neighboring tissues. There is no direct measure to determine the extent of damage caused by the wound, rather analyzed by therapeutic means for eradication of signs and symptoms. During natural repair, or healing process macrophages create inflammatory responses to clear cell debris and fight infection prevailing in RBCs. Accumulation of unessential devitalized microbial film or unrepaired tissue components re-initiate clotting of newly generated blood vessels and capillaries. People with poor immunity lack natural defenses; and untreated infection from past injury prevailing their blood vessels hinder growth of newly generated cells, resulting in a chronic wound or chronic disease.
Systemic infection
Systemic inflammatory response syndrome (SIRS) or systemic infection or septicemia or sepsis characterize early response to the injury, which may be infective or non-infective during initial stages. Systemic infection is a combined result of gram-positive or gram-negative bacteria and dysregulated immune function of the patient. Clinical indications of sepsis are hemodynamic instability, mental confusion and tachypnea. Hemodynamic instability may or may not associate bacteriemia i.e. presence of bacteria in the blood stream of the patient. There is a greater incidence of bacteriemia in nosocomial or community-acquired infections. Septic shock is commonly associated with severe form of sepsis in patients suffering from severe combined immunodeficiency syndrome (SCID) or Autoimmune diseases. Septic shock diagnosis in SCID patients includes altered mental status, fever, profound hypotension, acidosis and hypoxia. Septic shock may also associate acute respiratory distress syndrome (ARDS), Acute renal failure and Intravascular coagulation. Most common site of secondary infection in SIRS is the lower respiratory tract and abdomen through which chronic disease manifests, and metastasize to other organs. The extent of metastasis depends upon the severity of infection. Gram-negative bacteria causing septicemia are Escherichia coli, Klebsiella and Pseudomonas aeruginosaI and gram-positive bacteria includes Staphylococcus aureus (including methicillin-resistant S. aureus), Styphalococcus epidermidis, Streptococcus pneumoniae and Enterococci. In gram-negative sepsis, the prime initiator is a lipopolysaccharide bacterial cell wall component (i.e., an endotoxin). Gram-positive bacteria do not have lipopolysaccharide in their cell wall, but peptidoglycan and lipoteichoic acids can have similar effects. In addition, some gram-positive bacteria produce endotoxins (eg, Staphylococcus toxic shock toxin). Bacterial components recognize Toll-like receptors on cell surfaces. Macrophages and other cells of the immune system are stimulated by these receptors adhered to antigenic components, which produce cytokines such as tumor necrosis factor (TNF) and interleukin-1. Important physiological changes takes place in diseased cell that lead to activation of neutrophils and other blood factors responsible for blood clotting. Activated neutrophils adhere to each other and to the vascular endothelium, and contribute to vascular and tissue injury. Among the many other mediators activated are the coagulation cascade and vascular mediators such as complement, the arachidonic acid pathway and nitric oxide.
Process of wound healing
Wound healing refers to repair of damaged cells, tissues, organs of biological system to resume its normal functioning. Healing (literally meaning to make whole) is the process of the restoration of health to an unbalanced, diseased or damaged organism. Wound healing is an immunological process where organism’s defense system activates to fight infection, repair and regenerate necrotic cells or tissues. This process of wound healing must be assisted with sterile dressings and proper medication to promote body’s natural immunity in fighting infected pathogens and aid in regeneration. Visible signs of damaged skin or skin lesions change during the healing process with reduction in pain and the area of infection or damage. Casting of new epidermal cells occurs at much faster rate than normal process in wound healing; and sometimes a thick crust is formed over the infected area with constant scarring. Psychic healing refers to mental healing with reduction in pain, feeling of being overwhelmed and enhanced spiritual experience.
Tissue repair is interplay of cellular macrophages and other enzymes (proteases) along with essential growth factors. Repair of tissues do not commence until complete removal of microbial casts through our lymphatic system. Chronic infection develops in nearby cells and invades neighboring body parts. Lethal infections metastasize to other organs and tissues of the body to an extent of invasion of lymph nodes. Function of macrohages is to carry debris components to lymph nodes, where they are removed by monocytes reducing burden at the damaged site. Growth of chronic infections at the damaged site results in neurologic damages with incomplete repair of tissues or growth of mutated tissues that spread to nearby organs and lymph nodes. Inflammation lasts as long as infection causing microbial film or cellular debris is present. As inflammation fades, few inflammatory factors are secreted and existing ones are broken down to reduce macrophages at the wound site. Structural and morphological changes indicate reduction of inflammatory compounds at the wounded side.
Low oxygen environment and lactic acid in cells stimulate macrophages to form endothelial cells. Endothelial cells along with granulation tissues and zinc metalloproteases make collagenase to degrade clots and regenerate new tissues. Aerobic environment and perfusion of cells in absence of lactic acid inhibit formation of endothelial cells. Presence of oxygen or absence of lactic acid eventually leads to apoptosis of nearby blood vessels. Collagenous cells and Fibroblasts are required for cellular regeneration because collagen framework made from fibroblasts and basilar membranes are resistant to ischemia and most toxins. Basal keratinocytes from wounded edges and dermal appendages such as hair follicles, sweat glands and sebaceous glands cause epithelial cells to grow and mature resulting in complete healing of the wound or infection. Various systemic factors affect the formation of epithelial cells and maturation of wound.
Healing must happen by repair in the case of injury to cells that are unable to regenerate (e.g. cardiac muscle or neurons). Cellular DNA contains genetic information of repair mechanism. Healing by repair mechanism is activated during infarction, total collapse or damage to the collagen network (e.g. by enzymes or physical destruction). In response to an incision or wound, a wound healing cascade is unleashed. This cascade takes place in four phases: Clot formation (Recall phase), Inflammation (Resolution phase), Cellular Proliferation (Regeneration phase), and Cell Maturation (Repair phase). Hemostasis or clot formation is a natural process of immune function to prevent blood loss and reduce growth of microorganisms, which may cause infection. The speed of wound healing depends on bloodstream levels of platelets, fibrin, and hormones such as oxytocin. Neutrophils of WBCs invade the clot area to induce mitosis of epithelial cells within 3 to 24 hours with the help of pro-inflammatory eicosanoids or signaling molecules. Macrophages and Monocytes of Leukocytes (WBCs) kill bacteria and clear cellular debris, and release chemical factors such as growth hormones that encourage fibroblasts, epithelial cells and endothelial cells to make new capillaries and blood vessels. Mature erythrocytes proliferates regenerating lost cells and tissues. Some cells such as neurons and smooth myofibrils are slow to recover. Angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction characterize the proliferative phase. A plump of active fibroblasts forms immature granulation and quickly produce Type III collagen to fill the defect left by open wound. Mature granulation tissue are removed by apoptosis and Type I collagen formed is cross-linked to align with tension lines. Maturation phase is long lived with anti-inflammatory factors lipoxins, epi-lipoxins and resolvins cause release of growth hormone. Small number of fibroblasts still invade proliferative erythrocytes. Repair process is fragile and susceptible to interruption and failure due to formation of non-healing chronic wounds. Many factors like diabetes, venous or arterial disease and metabolic inefficiencies of old age interrupt repair mechanism and cross linking of Type I collagen framework with tension lines. There is a subtle distinction between 'repair' and ‘regeneration’. Repair means complete regeneration, whereas incomplete regeneration refers to the physiologic adaptation of an organ after injury in an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue. Repair restores lost morphology and function of tissue and organs that resulted from injury. Skin tissues generally restore their lost morphology whereas connective tissues to nerve tissues mostly restore their lost functionality.
Management
Many factors control efficacy, speed, and manner of wound healing. Local factors include: Mechanical factors, edema or swelling, ischemia, cellular necrosis, foreign body invasion and low oxygen tension. Some of the systemic factors affecting wound healing process are inadequate perfusion, inflammation, diabetes, nutrients, metabolic diseases, immunosuppression, connective tissue disorders, alcohol and smoking. A reasonable therapeutic means for management of infectious wounds is antibiotic therapy, sterile dressings, suturing and nursing. Sterile dressing is an adjunct adhering to damaged skin that promotes wound healing and prevents further harm. Dressing materials are various medicated bandages, exudates, plasters, latex, topical ointments and biodegradable materials. Sterile dressing is essential as they come into direct contact with the wound, and sterility is required to fulfill the 'protection from infection' or control rapid multiplication of pathogens. An "ideal" wound dressing is the one, which is sterile, breathable, and conducive for a moist healing environment to reduce risk of infection, help in speedy recovery, and reduce scarring. Moist environment proliferates microorganisms thus it becomes essential to control bleeding of moist wounds, maintain pH and temperature to encourage healing. Studies have shown a direct link between the prompt administration of antibiotics and reduced mortality. Ideally, treatment should start within 5 minutes of presentation, and antibiotics should never be delayed while awaiting the results of laboratory tests. No single antibiotic regimen can be recommended for all patients. The probable site of origin of sepsis is often apparent, and knowledge of likely microbial flora can help in choice of appropriate antibiotics. The constantly changing pattern of antimicrobial resistance with broad-spectrum agents have reduced the use of reference laboratory tests unless specific culture results become available for blood infections.
During prevalence of hemodynamic shock cardiac index or volumetric flow of arterial blood increases from a normal level of 2.8 to 3.6 but there is a marked decrease in vascular resistance, oxygen delivery and oxygen consumption with respect to their normal levels thereby leading to apoptosis of blood vessels and capillaries. Septic shocks can be managed through proper airway and ventilation to provide adequate oxygenation for arterial blood. Fluid replacement can be used with the aim of optimizing cardiac output without increasing the risk of pulmonary edema. Drugs such as dopamine are often used to sustain blood pressure. Therefore, dopamine, 5 - 25 microgram/kg/min, can be titrated against blood pressure of the patient. If the patient remains hypotensive, nor-adrenaline (nor-epinephrine) is added, typically at 0.01 – 0.5 microgram/kg/min. It is important to note that these drugs do not cure septic shock; at most, they provide support during a critical period. Adjuvant therapy includes high-dose corticosteroids in treatment of septic shock. Some investigators have suggested that lower-dose physiological replacement of corticosteroids (hydrocortisone 100 mg 6-hourly for 5 days, then tapering to day 11, with or without fludrocortisones) may be beneficial, but studies that are more recent did not confirm those findings. Sepsis patients are at risk of developing stress-associated gastric ulceration. H-2 blockers or sucralfate are used, particularly in patients receiving mechanical ventilation. There is considerable dysregulation of metabolic control in sepsis. Coagulation is disturbed in sepsis, and much evidence suggests that occlusion of small blood vessels leading to inadequate tissue perfusion is a major cause of organ failure. Protein C is a natural anticoagulant consumed by septic patients. Large randomized controlled trial has shown that replacement of protein C (as drotrecogin alfa (activated)) significantly reduces mortality, most notable in patients with moderate-to-severe disease. In the UK, the national institute of health and clinical excellence (NICE) has endorsed use of this drug for adult patients who have severe sepsis that has resulted in multiple-organ failure (two or more major organs are not working properly) and are being given the most appropriate intensive care support for their condition. International consensus guidelines on the management of severe sepsis are a useful source of more detailed information. Wound care and nursing is encouraged to reduce inflammation and stop the growth of chronic wounds. In some cases, abrasions or exudates and needle ablation to drain infectious wounds become necessary. Tissue grafts and other debridement procedures have proven to become successful in many cases of fractures, burns, severe lacerations and pressure ulcers.
(The author is MD of VMG Biotech Consultants, New Delhi, a premier biotechnology consultancy and CRO).