Purulent Diseases of Soft Tissues and Bones: diagnosis and treatment in the Outpatient Department of Family Doctor, bleeding, hemorrhage, transient and terminal blood arrest. Wounds and Wound Process. Prevention of infection development in the wound. Treatment of clear wounds. Patient’s referral arrangement. Principles of antibiotic therapy in prevention and management of surgical infection. Medical and Labour Expert Examination (MLEE)..

Soft tissue infections

Introduction

Soft tissue infections are classified by anatomic extent and pathophysiologic process. Thus, they may be focal or diffuse; the most severe have associated tissue necrosis; and when this is combined with systemic toxic effects the results are devastating. But most cases are easily diagnosed and treated.

Figure 1 Schema of approach to soft tissue infection.

Awareness of the harbingers of necrotizing infection and knowledge of the complicating factors in toxic infections are essential to avoid loss of limb and life. Although most treatment has been empirical, strategies for diagnosis and treatment are emerging, that yield improved results (fig. 1).

Presentation and pathogenesis

Simple focal infections

These infections arise in the skin or in the adenexal skin structures, particularly the follicles. The commonest examples are impetigo contagiosa and folliculitis. Impetigo contagiosa is an infection of minor skin abrasions on the face or limbs of children caused by S. aureus or Strep. pyogenes. In folliculitis staphylococcal pyodermas of the hair follicles may extend to form furuncles or coalesce to form carbuncles.

Necrotizing focal infections

Focal necrotizing infections occur far less commonly. The best examples are Meleney's Progressive bacterial Synergistic Gangrene and Fournier's Idiopathic Scrotal Gangrene. Progressive synergistic gangrene is characterized by three concentric zones of erythema, cyanosis, and necrosis at sites of synergistic infection of operative wounds or pressure sores by a microaerophilic nonhemolytic streptococcus and a hemolytic S. aureus or gram-negative bacillus. Idiopathic scrotal gangrene as described by Fournier is caused by anaerobic streptococci and differs from the perineal form of Gram-negative bacterial synergistic gangrene commonly given this name today. The onset is dramatic and progression to gangrene of the scrotum occurs within 24 hours.

Toxic non-necrotizing focal infections

These infections occur still less often and include the Staphylococcal scalded skin syndrome (SSSS) and toxic shock syndrome (TSS). SSSS occurs most frequently in young children and sometimes in neonates (pemphigus neonatorum). It presents as a diffuse rash that follows a staphylococcal infection, and progresses to generalized bullae that break and slough. An exfoliative toxin has been identified that splits the epidermis so that the bullae develop. In TSS fever and a generalized macular rash develops in a patient with vaginitis associated with menstruation and the use of superabsorbent tampons. Enterotoxin F produced by group I phage strains of S. aureus is responsible for this constellation of symptoms and for the multiple organ failure that commonly ensues.

Diffuse non-necrotizing infection: cellulitis

Cellulitis is a diffuse infection of the skin and subcutaneous tissues characterized by local spreading erythema, warmth, tenderness and swelling. Most infections are mild and are caused by S. aureus or group A streptococci. Systemic signs such as fever, chills, and leucocytosis indicate severe cellulitis that usually requires intravenous antibiotic therapy. Patients should be investigated for underlying diseases including diabetes mellitus and peripheral arterial occlusive disease that worsen the prognosis.

Infections at some sites are regarded as high risk cellulitis because they are prone to serious complications. These include facial and orbital cellulitis, post adenectomy and postvenectomy cellulitis of the extremities, and infected animal and human bites of the hands. Facial cellulitis that originates in the teeth or gums is odontogenic. It occurs typically in the lower face of older children. Most facial cellulitis is non-odontogenic and occurs in the upper face of infants and younger children. Typical examples are erysipelas and Haemophilus influenzae type B (HIB) cellulitis. The peau d'orange cellulitis of erysipelas follows streptococcal upper respiratory infection that invades the dermis and lymphatics of the cheek. Similar infection by Haemophilus influenzae type B results in the characteristic “bruised cheek” appearance of HIB cellulitis now uncommon with the use of H. influenzee vaccine.

Postadenectomy and postvenectomy cellulitis are caused by lymphedema that is secondarily infected by non-group A streptococci. High risk hand infections include erysipeloid and infected human and animal bites. Erysipeloid is diagnosed when a spreading violaceous wound appears at the site of a minor wound on the hand of a worker handling fish, meat, or poultry. The infection is caused by the gram positive bacillus Erysipelothrix rhusiopathae. Animal and human bites are dangerous when secondary infection occurs and tenosynovitis develops in deep tendons. Pasteurella multocida in cat bites, and Eikenella corrodens in human bites are common pathogens. Delay in seeking treatment and anaerobic conditions in deep hand infections favor tissue necrosis and rapid progression.

The spread of infection in cellulitis is associated with toxins and enzymes produced by the offending organisms. Further, a disparity has been noted between the low frequency of positive culture of deep aspirates of these wounds and the marked inflammation observed. This has recently been attributed to cytokines such as interleukin-1 and tumor necrosis factor produced by specific dendritic cells of Langerhans in the stratum spinosum of the skin when they are exposed to bacterial components. The inflammatory response may therefore persist even when the bacteria have been killed by antibiotics.

Diffuse necrotizing cellulitis

These conditions are described fully in the chapter that follows. In general, they include necrotizing infections in which inflammatory cells are absent or sparse on biopsy, particularly clostridial myonecrosis, and those conditions in which inflammatory cells are abundant on histologic examination or Gram's stain of deep aspirates. Meleney's streptococcal gangrene, clostridial cellulitis, necrotizing fasciitis as described by Wilson and gram-negative bacterial synergistic necrotizing cellulitis are all encompassed by the latter group. A high index of suspicion is essential for early recognition and treatment of diffuse necrotizing cellulitis. Key markers of the disease include subcutaneous edema out of proportion to erythema progressing to skin vesicles and later skin anesthesia, discoloration, and patchy necrosis, and gas in the subcutaneous tissues identified on plain radiographs or as clinical crepitus. Necrotizing soft tissue infections owe their rapid progression to impaired host resistance, anaerobic conditions and bacterial synergy in the wound, and to lytic enzymes and toxins produced by the organisms involved. In the recently described variant, streptococcal necrotizing fasciitis with toxic shock syndrome (STSS), the explosive nature of the “flesh-eating disease” is related to pyrogenic exotoxins produced by group A streptococci that stimulate mononuclear cells and lymphocytes to produce cytokines that cause fever, shock and tissue injury. They also act as superantigens that interact with T-lymphocytes by methods that are more rapid and universal than those employed by conventional antigens, so that massive activation occurs and the damaging cytokines are poured out in abundance to exert their dramatic effect.

Diagnosis

A systematic approach to diagnosis that includes, needle aspiration, blood sampling for risk assessment, aerobic and anaerobic culture and diagnostic imaging is employed except in the simplest and most obvious cases.

Needle aspiration

Needle aspiration for sampling of tissue fluid or collections is preferable to superficial culture. It supplies the best information for improving on empirical therapy with semisynthetic penicillins.

Blood sampling

Blood sampling aids in assessment of the risk of the infection to the patient, and is an important reminder of the importance on outcome of conditions affecting the immune state of the patient . Diabetes, severe malnutrition and organ failure are all important.

Culture

Culture of the tissue aspirate is positive for organisms in only 20 to 30% of patients, but allows revision of antibiotic therapy in difficult cases. Blood culture was formerly done routinely, but is seldom positive, and should only be obtained by specific indication.

Diagnostic imaging

Plain roentgenographs of the affected site should be obtained except in mild disease. They may provide the only evidence of gas in the tissues, complicating deep infection such as osteomyelitis, or of a retained foreign body. Isotope imaging performed with technetium (^99mTc) pyrophosphate detects areas of increased blood flow or newbone formation. Gallium citrate and indium chloride indicate sequestered polymorphonuclears cells and macrophages in areas of inflammation. By combining the two or using phased ^99mTc pyrophosphate scans one may distinguish between soft tissue and bome inflammation. But the best method of identifying osteomyelitis complicating soft tissue infection of the extremities is by use of magnetic resonance imaging (MRI) with gadolinium contrast. MRI with also differentiates necrotizing from non-necrotizing soft tissue infection by failure of the necrotic fascia to enhance with gadolinium.

Treatment

Strategies for optimal treatment follow naturally from the schema suggested in figure 1. Simple focal lesions are readily treated with oral or topical antibiotics, such as mupirocin 2% ointment applied three times per day, and cloxacillin 250 or 500 mg every 6 hours for 7 days, local cleansing of the wounds, and attention to hygiene. On the other hand, focal necrotizing disease and focal lesions with toxic symptoms require intravenous fluid resuscitation and combined antibiotics such as amoxycillin 1 to 2 g every six hours and gentamicin 1.5 mg/kg every 8 hours or monotherapy such as ticarcillin disodium/clavulanate potassium 3 × 1 g every six hours. In TSS the culprit vaginal tampon must be removed, and wide debridement is best in progressive synergistic gangrene and idiopathic scrotal gangrene. Among the diffuse infections, mild cellulitis responds well to oral antibiotics and local care; but severe and high risk cellulitis require intravenous antibiotics. Current strategies using long acting intravenous antibiotics such as ceftriaxone and antibiotics e.g. quinolones that are equally effective by oral or intravenous route allow rapid conversion to out-patient intravenous or oral antibiotics. Certain types of high risk cellulitis require specific antibiotics - cefuroxime for HIB cellulitis, cloxacillin (not erythromycin) for human bites, and amoxicillin-clavulanic acid for dog and cat bites. The diffuse necrotizing infections also demand aggressive surgical debridement. The antibiotics and need for further debridement should both be reviewed after 36 to 48 hours. In STSS intravenous clindamycin has also been recommended to slow the M protein synthesis essential for exotoxin production; and human immunoglobulin 2 g with or without subsequent booster doses is given to neutralize existing exotoxin.

Necrotizing soft-tissue infections

Necrotizing soft-tissue infections (NSTI) encompass a diverse disease process characterized by extensive, rapidly progressive soft tissue inflammation and necrosis. NSTIs are increasingly more common, and continue to be associated with a fulminant course and high mortality rates. These infections comprise a spectrum of diseases ranging from necrosis of the skin to life-threatening infections involving the fascia and muscle with systemic toxicity. They vary in predisposing and causative factors, anatomic location, offending bacteria, and tissue level of involvement.

The nomenclature of NSTI can be confusing with many terms used to describe the variable presentations. The original description of “hospital gangrene” was made by Joseph Jones in 1871 following his experience during the U.S. Civil War. Additional terms used in the past included Fournier gangrene, acute hemolytic streptococcus gangrene, and gas gangrene (clostridial myonecrosis). The term “necrotizing fasciitis” was popularized by Wilson in 1952, and remains in use today.

The terminology of NSTI is of secondary concern when surgeons are challenged by a patient with this aggressive illness. Primary emphasis must be focused on rapid recognition and appropriate aggressive treatment. A high index of suspicion leading to early diagnosis, aggressive surgical intervention and appropriate antimicrobial therapy is essential to reducing the mortality of NSTIs.

Presentation and diagnosis

The presentation of NSTI is highly variable and can range from early sepsis with obvious skin involvement to minimal cutaneous manifestations with a disproportionate (even alarming) underlying necrotizing fasciitis. The usual clinical presentation begins with localized pain and a deceptively benign appearance. Clinical “clues” which may assist in establishing an early diagnosis are: edema beyond the area of erythema, small skin vesicles, crepitus and the absence of lymphangitis. Additional local signs suggesting deep infection may include cyanosis or bronzing of the skin, induration, dermal thrombosis, epidermolysis or dermal gangrene. Classic signs of fever, diffuse crepitus, and shock are late signs. Once large blisters and gangrene develop, the infectious process is already at an advanced stage.

Early recognition is the sine qua non for the assessment of risk factors. Multiple risk factors increase the probability of a life-threatening infection. These co-morbid conditions include diabetes mellitus, peripheral vascular disease, malnutrition, malignancy, immunocompromised states (AIDS, steroid therapy), obesity, chronic alcohol or intravenous drug abuse. In the urban setting, intravenous and subcutaneous injection of illicit substances has become a more prevalent risk factor and should raise one's suspicion. Our recent experience with NSTIs (1990–1995) revealed that 67% of patients were actively practicing parental drug use.

The etiologies for NSTI are not always obvious, and often the initiating event is surprisingly minor. The most common etiologies include postoperative wound complications, penetrating and blunt trauma, cutaneous infections, intravenous or subcutaneous illicit substance injection, peri-rectal abscesses, strangulated hernias, and idiopathic causes.

Establishing an early diagnosis depends on a high index of suspicion and a willingness to proceed with appropriate treatment. Plain x-rays may demonstrate subcutaneous air or a foreign body but are usually not necessary. Interest in the use of MRI scanning and frozen section biopsy to aid in diagnosis has been reported. Early and aggressive surgical intervention should not be delayed by these ancillary studies. At exploration, the diagnosis can be confirmed by the presence of necrotic fascia, the absence of gross pus and easy finger dissection along the fascial planes.

Bacteriology

The bacteriology of NSTI is well recognized, and the infectious process is independent of specific bacteria . Most NSTI are polymicrobial, involving organisms behaving synergistically. In our series of patients treated 78% of cases were polymicrobial, and 2.8 organisms were recovered per patient. Anaerobes, skin flora, and gram negative rods are commonly encountered.

Table I Bacteriologic findings in patients with necrotizing soft-tissue infections

Organism	No of patients
Anaerobes
Mixed anaerobes	16
Clostridium species^a	8
Diphtheroids	3
Bacteroides fragilis	2
Bacteroides buccae	2
Peptostreptococcus sp	1
Total	32
Gram-positive cocci
Streptococcus viridans	8
Hemolytic group A streptococci	7
Enterococcus faecalis	6
Total	21
Gram-negative rods
Mixed gram-negative rods	6
Proteus mirabilis	4
Escherichia coli	3
Eikenella corrodens	3
Enterobacter sp	1
Serratia marcescens	1
Total	18
Skin flora
Staphylococcus coagulase negative	14
Staphylococcus aureus	14
Mixed skin flora	4
Total	12

A Includes C perfringens, C septicum, C sordellii, C tetani, and C botulinum.

Monomicrobial infections are usually caused by hemolytic group A streptococcus, Staphylococcus aureus, or clostridial species. Group A streptococcal NSTI not uncommonly involve younger patients, the extremities, and are associated with a streptococcal toxic shock-like syndrome. There has been a recent rise in cases of necrotizing fasciitis caused by group B streptococcus. Marine vibrio species have also been associated with NSTI.

The sharp increase in NSTI caused by parental drug abuse is at least in part attributable to Black Tar Heroin. This substance is manufactured in Mexico using crude processing methods, which result in low purity and a high water content. This may support bacterial growth and explain the high incidence of necrotizing fasciitis with subcutaneous black tar heroin use.

Treatment

The treatment of NSTI must be aggressive and rapid. All infections should be treated as potentially life-threatening emergencies. Previous studies have documented the efficacy of a unified approach to successful treatment. The essential elements of treatment are resuscitation, antimicrobial therapy, surgical debridement, and supportive care. Aggressive resuscitative measures are required early with invasive monitoring to achieve fluid, electrolyte, and hemodynamic stability. Massive volumes of fluid are often required secondary to third spacing and sepsis.

Antimicrobial therapy consists of broad-spectrum antibiotics. Empiric coverage with high dose penicillin G, an aminoglycoside, and clindamycin or metronidazole is recommended. Single agent coverage with imipenem-cilastin is an alternative choice. Antibiotics can be adjusted once cultures are reported. The tetanus status of the patient must be addressed.

Surgical debridement is paramount, and must be performed early and aggressively. It should not be delayed if the patient is in septic shock. Debridement is best performed under general anesthesia and all necrotic tissue must be excised. Debridement is considered adequate when finger dissection no longer easily separates the subcutaneous tissue from the fascia. The deep muscle should be inspected. Parallel counter incisions may be made if indicated to exclude additional spread of infection. Amputation may be necessary for massive involvement of an extremity. The wound is packed open and kept moist with saline or 0.25% Dakin's solution. Patients should undergo re-exploration and debridement every 24 hours (or earlier if indicated) until progression of the necrosis has been halted.

Post-operatively, patients are monitored in the intensive care unit until deemed stable. Early nutritional support is initiated, and physical therapy can be started once sepsis has resolved. Coverage of the wound should be delayed until the infection has clinically resolved and healthy granulation tissue is present. Split-thickness skin grafts usually provide coverage, although more extensive wounds may require a flap procedure.

Controversy surrounds the routine use of hyperbaric oxygen (HBO) in treating NSTI. Supporters claim a decrease in mortality when infections involve anaerobic bacteria, specifically the clostridial species. However, no survival benefit has been demonstrated by a prospective, randomized trial for HBO in treating nonclostridial NSTI. Its use should not delay appropriate and adequate surgical debridement. For these reasons, HBO should be considered as an adjunctive therapy and in no way should diminish the importance of proper surgical management.

Mortality

Despite advances in intensive medical care, mortality rates for NSTI remain substantial. Recent large series continue to demonstrate rates in excess of 20%. The number of risk factors present, extent of infection, delay in first debridement, and degree of organ system dysfunction at admission have been shown to be predictors of outcome. Retrospective reviews have clearly demonstrated that a delay in presentation, debridement, or both contribute to the high mortality rates. Time is a critical element in successful management of NSTI, and delays must be avoided.

Wound healing is an integral step to the restoration of tissue after injury. Surface wounds are often the only external evidence of surgical intervention and as such are the patients' visual link to their procedures. The major`ity of wounds heal without difficulty. However, wound complications such as infection, disruption, or delayed closure can be devastating.

Phases of normal healing

Although wound healing is a dynamic cascade of events initiated by injury and extending well beyond the restoration of tissue continuity, it may be divided into distinct phases as characterized by both the predominant cellular population and cellular function.

Tissue disruption causes bleeding and initiates the coagulation cascade. Platelet activation, in the form of degranulation and adhesion, leads to hemostasis and chemotaxis of inflammatory cells. These are the hallmarks of the initial phase of healing. The inflammatory phase of healing (injury to 5 days) is defined by neutrophil infiltration with subsequent replacement by macrophages and lymphocytes. Each population of cells acts in response to specific cytokines that are temporally released as the normal healing process progresses. Neutrophils function primarily to clean the wound environment by production of superoxides that kill bacteria and by phagocytosis of necrotic material. Although optimal healing requires that all different populations of cells be present, only macrophages are an absolute necessity. The fibroplastic phase is the second phase of wound healing (days 4 through 12). Macrophages produce growth factors and other cytokines which then promote fibroblast migration, proliferation and collagen synthesis. It is during this phase that tissue continuity is restored; angiogenesis and epithelialization are also achieved. The maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by reorganization of the previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs) and net collagen in the wound is the result of a balance between collagenolysis and collagen synthesis.

Role of growth factors in normal healing

Growth factors are polypeptide substances which function to stimulate cellular migration, proliferation and function. They are often named for the cells from which they were first derived (i.e. platelet-derived growth factor, PDGF) or for their initially identified function (i.e. fibroblast growth factor, FGF). These names are at times misleading because growth factors have multiple functions (and their functions continue to be defined). Most growth factors are extremely potent and produce their effects naturally in nanomolar concentrations. They may act in an autocrine manner (where the growth factor acts on the cell producing it), a paracrine manner (by release into the extracellular environment where it acts on the immediately neighboring cells) or in an endocrine manner (where the effect of the substance is distant to the site of release and the substance is carried to the effector site through the blood). Temporal release of growth factors may be as important as concentration in determining effect. As these polypeptides exert their effects by cell-surface receptor binding, the appropriate receptor on the responding cells must be present at the time of release in order that the effect occur.

Table Origin and action of growth factors

Growth factor	Wound cell origin	Noted pre-clinical cellular effects
Platelet-derived growth factor (PDGF)	platelets, macrophages, monocytes, smooth muscle cells, endothelial cells	· chemotaxis: fibroblasts, smooth muscle, monocytes, neutrophils · mitogenesis: fibroblasts, smooth muscle cells · stimulation of angiogenesis · stimulation of collagen synthesis
Fibroblast growth factor (FGF)	fibroblasts, endothelial cells, smooth muscle cells, endothelial cells	· stimulation of angiogenesis (by stimulation of endothelial cell proliferation and migration) · mitogenesis: mesoderm and neuroectoderm · stimulate fibroblasts, keratinocytes, chondrocytes, myoblasts
Keratinocyte growth factor (KGF)	fibroblasts	· significant homology with FGF; stimulates keratinocytes
Epidermal growth factor (EGF)	platelet, macrophages, monocytes (also identified in salivary glands, duodenal glands, kidney and lacrimal glands)	· stimulates proliferation and migration of all epithelial cell types
Transforming growth factor alpha (TGF-α)	keratinocytes, platelets, macrophages	· homology with EGF; binds to EGF receptor · mitogenic and chemotactic for epidermal and endothelial cells
Transforming growth factor beta (TGF-β)	platelets, T-lymphocytes, macrophages, monocytes, neutrophils	· three isoforms: β1, β2, β3 · stimulates angiogenesis · TGF-β1 stimulates wound matrix production (fibronectin, collagen glycosaminoglycans); regulation of inflammation · TGF-β3 inhibits scar formation
Insulin-like growth factors (IGF-1, IGF-2)	platelets (IGF-1 in high concentrations in liver; IGF-2 in high concentrations in fetal growth)	· likely the effector of growth hormone action promotes protein/extra-cellular matrix synthesis · increase membrane glucose transport
Platelet-derived wound healing formula (PD-WHF)	platelets	· growth factor “soup”; assessed in clinical scenarios
Vascular endothelial growth factor (VEGF)	macrophages, fibroblasts, keratinocytes	· similar to PDGF · mitogen for endothelial cells (not fibroblasts) · stimulates angiogenesis
GM-CSF	macrophage/monocyte, endothelial cell, fibroblast	· stimulates macrophage differentiation/proliferation

Impaired healing in sepsis

The global physiologic changes characteristic of sepsis or septic inflammatory response are governed by a heightened production and release of inflammatory cytokines with their concomitant dysregulation. This extended production of acute phase proteins may be likened to a light switch stuck in the on position. Frequently the most readily identifiable cause is a focal infection (or septic source), but the hyper-dynamic state of inflammatory response may be the result of overwhelming injury as well. Excessive inflammatory mediators are responsible, either directly or indirectly, for fever, hypotension, elevated cardiac output, depressed tissue perfusion and continued protein catabolism.

There are several ways in which wound healing is impaired during sepsis. The key to survival following severe traumatic or infectious insult is the maintenance of blood flow to essential organs. This occurs at the expense of non-essential structures such as viscera, skeletal muscle and cutaneous tissue. Prolonged insult results in impaired cellular oxygen perfusion (tissue hypoxia) in the setting of an increased metabolic state; ultimately there is progression to multiple organ failure. Locally, hypoxia is exacerbated by the edema which results from leaky capillaries. Hypoxia itself is a powerful stimulant of the healing response. The accumulation of toxic metabolites and excessive inflammatory cytokines are a direct result. Macrophages activated by the hypoxic stimulus produce pro-inflammatory cytokines (such as TNF-α; and IL-1β). These then lead to altered of MMP synthesis with increased collagenolysis and decreased collagen synthesis; the resultant decreased wound collagen content physically weakens the wound leading to acute wound failure. Hypoxia also impairs leukocyte killing of bacteria, angiogenesis, collagen synthesis and thus contributing to depression of healing. It is important to recognize that growth factors influence normal cellular function, but do not correct deficits caused by inadequate oxygen delivery.

As wound healing is a restorative process, tissue repair is anabolic and requires an adequate nutrient supply. Sepsis induces an overwhelmingly catabolic state where nutrient allocation is detrimental to healing tissues. Additionally, poor nutritional status significantly impairs immune response, which in itself is closely linked to the wound healing cascade.

It is still unclear the degree to which local or systemically produced inflammatory cytokines result in wound impairment. Excessive or prolonged inflammation enhances scarring; conversely, anti-inflammatory therapy (such as steroids and NSAIDs) adversely effect wound healing. There are no studies examining the effects of inflammatory cytokine modulation and clinical wound outcomes in humans. Nor are there consistent data to support modulation of the inflammatory responses seen in septic syndromes by monokine (or anti-monokine) therapy that correlate with positive outcome.

Dietary enhancement with immunomodulators such as arginine, nucleic acids and omega-3 fatty acids have demonstrated some benefit in decreasing ICU stay and total ventilator days, but does not appear to benefit mortality. Its role in wound healing or failure has not been examined. Supplemental dietary arginine, which is known to both qualitatively enhance wound collagen deposition and T-cell reactivity in normal and physiologically stressed humans, has not been assessed for affect on clinical wound outcome.

Optimization of oxygen delivery, providing adequate nutrition and treating proven infected sources are the therapeutic mainstays for the septic patients. They are also appropriate for reducing the effect of sepsis on the healing wound. At present, the greatest benefit to wound healing during sepsis is to eliminate the sepsis. Concerns about wound healing in septic or inflammatory states are directed most frequently towards the acute post-surgical wound. Wound failures in these patients (i.e. abdominal dehiscence or anastomotic disruption) are devastating and frequently fatal occurrences. Unfortunately it is difficult to predict which wounds will become clinically significant prior to the event.

Surgical site infection

Surgical site infection inhibits healing by maintaining an inflammatory state in the healing tissues. Additionally, the inflammatory response may be especially damaging secondary to excessive neutrophil accumulation, superoxide and protease release, tissue necrosis and pus formation. This also contributes to acute wound failure. Appropriate wound care consisting of debridement of necrotic tissues and drainage of purulent collection combined with systemic antibiotic therapy remain the most important therapies for surgical site infection.

Antibiotic prophylaxis

Epidemiology

Approximately 1 million patients suffer from wound infections each year in the United States. Wound infections are responsible for extension of hospital stay on an average of 1 week and for increase in hospital costs by 20%_.

Pathogenesis

The development of wound infection requires a local inoculum which is sufficient to overcome the local host defense. The development of wound infection depends on microbial virulence factors, the local environment, systemic factors, e.g., comorbidity, and surgical technique. Antibiotic prophylaxis plays an important part in prevention of wound infections. The efficacy of antibiotic prophylaxis has been demonstrated to be significant; however, antibiotic prophylaxis cannot be a substitute for any other preventive measure. The scientific basis for the perioperative use of antibiotics was established by Burke.Polk and Stone have confirmed the hypothesis in clinical studies and laid the ground for antibiotic prophylaxis in surgery.

Classification and Risk factors

It has been demonstrated in large clinical studies that the classification of operative wounds, e.g., clean, clean-contaminated, contaminated, and dirty, is associated with a different risk for the occurence of wound infections. The classification of postoperative wounds is based on a definition of the National Academy of Sciences, National Research Council (NRC), Division of Medicine, Ad Hoc Committee on Trauma. The risk of wound infections in trauma patients is considered to be similar to equivalent classes of elective operations. There is a widely accepted agreement that antibiotic prophylaxis in clean-contaminated, contaminated and dirty wounds is warranted.

Table I Classification of operative wounds and risk of infection

Classification	Criteria	Risk (%)
Clean	Elective, not emergency, nontraumatic, primarily closed; no acute inflammation; no breka in technique; respiratory, gastrointestinal, biliary and genitourinary tracts not entered	< 2
Clean-contaminated	Urgent or emergency case that is otherwise clean; elective opening of respiratory, gastrointestinal, biliary or genitourinary tract with minimal spillage (e.g., appendectomy) not encountering infected urine or bile; minor technique break	<10
Contaminated	Nonpurulent inflammation; gross spillage from gastrointestinal tract; entry into biliary or genitourinary tract in the presence of infected bile or urine; major break in technique; penetrating trauma < 4 hours old; chronic open wounds to be grafted or covered	Approx. 20
Dirty	Purulent inflammation(e.g., abscess); preoperative perforation of respiratory, gastrointestinal, biliary or genitourinary tract; penetratinbg trauma > 4 hours old	Approx. 40

Controversy exists about the necessity of antibiotic prophylaxis in clean operations. The argument against the prophylaxis is the low wound infection rate of 2% and less. However, it is well recognized that 40% of wound infections occur after clean operations. and in some clean operations the effect of wound infection may be devastating for the patient. We have observed in clean operation, e.g. hyperthermic perfusion of melanoma patients, an infection rate of 13% which was mainly due to a prolonged operation time and the use of immunosupressive agents. There is evidence that the infection rate in clean operations may be reduced by antibiotic prophylaxis by 17%.

Risk factors associated with increased risk of infection may be systemic or local factors. Systemic factors include diabetes, corticosteroid use, obesity, age, malnutrition, recent surgery, massive transfusion, comorbidity (more than three diagnoses), and American Society of Anaesthesiologists (ASA) class 3, 4 or 5. Local factors are considered to be foreign body, electrocautery, injection with epinephrine, wound drains, hair removal with razor, previous irradion. Remote infection, the length of operation (> 2 hours), and three comorbid diagnoses were identified to be independent risk factors. However, meticulous surgical technique remains the mainstay of infection control.

Prevention and management of wound infection

Guidance from WHO’s Department of Violence and Injury Prevention and Disability and the Department of Essential Health Technologies

Introduction

Open injuries have a potential for serious bacterial wound infections, including gas gangrene and tetanus, and these in turn may lead to long term disabilities, chronic wound or bone infection, and death. Wound infection is particularly of concern when injured patients present late for definitive care, or in disasters where large numbers of injured survivors exceed available trauma care capacity. Appropriate management of injuries is important to reduce the likelihood of wound infections. The following core principles and protocols provide guidance for appropriate prevention and management of infected wounds.

Core Principles

• Never close infected wounds Systematically perform wound toilet and surgical debridement (described in Protocol 1 given below). Continue the cycle of surgical debridement and saline irrigation until the wound is completely clean.

• Do not close contaminated wounds and clean wounds that are more than six hours old. Manage these with surgical toilet, leave open and then close 48 hours later. This is known as delayed primary closure.

• To prevent wound infection: Restore breathing and blood circulation as soon as possible after injury. Warm the victim and at the earliest opportunity provide high-energy nutrition and pain relief.

Do not use tourniquets.

Perform wound toilet and debridement as soon as possible (within 8 hours if possible). Respect universal precautions to avoid transmission of infection.

Give antibiotic prophylaxis to victims with deep wounds and other indications (described in Protocol 3).

• Antibiotics do not reach the source of the wound infection. Antibiotics only reach the area around the wound; they are necessary but not sufficient and need to be combined with appropriate debridement and wound toilet as described above.

• Use of topical antibiotics and washing wounds with antibiotic solutions are not recommended.

1. An infected wound is a wound with pus present.

2. A contaminated wound is a wound containing foreign or infected material.

Department of Violence and Injury Prevention and Disability

World Health Organization

Protocols

Protocol 1: Wound toilet and surgical debridement

Apply one of these two antiseptics to the wound:

o Polyvidone-iodine 10% solution apply undiluted twice daily.

The application to large open wounds may produce systemic adverse effects.

o Cetrimide 15% + chlorhexidine gluconate 1.5%

Note: The freshly prepared aqueous solution (0.05%) of Chlorhexidine gluconate 5% is not recommended in emergency situations (risk of flakes according to water quality)

1. Wash the wound with large quantities of soap and boiled water for 10 minutes, and then irrigate the wound with saline.

2. Debridement: mechanically remove dirt particles and other foreign matter from the wound and use surgical techniques to cut away damaged and dead tissue. Dead tissue does not bleed when cut. Irrigate the wound again. If a local anaesthetic is needed, use 1% lidocaine without epinephrine.

3. Leave the wound open. Pack it lightly with damp saline disinfected or clean gauze and cover the packed wound with dry dressing. Change the packing and dressing at least daily.

Protocol 2: Management of tetanus-prone wounds

1. Wounds are considered to be tetanus-prone if they are sustained either more than 6 hours before surgical treatment of the wound or at any interval after injury and show one or more of the following: a puncture-type wound, a significant degree of devitalized tissue, clinical evidence of sepsis, contamination with soil/manure likely to contain tetanus organisms, burns, frostbite, and high velocity missile injuries.

2. For patients with tetanus-prone injuries, WHO recommends TT or Td and TIG.

3. When tetanus vaccine and tetanus immunoglobulin are administered at the same time, they should be administered using separate syringes and separates sites.

Tetanus vaccine

ADULT and CHILDREN over 10 years:

• Active immunization with tetanus toxoid (TT) or with tetanus and diphtheria vaccine (Td) 1 dose (0.5 ml) by intramuscular or deep subcutaneous injection. Follow up: 6weeks, 6 months.

CHILDREN under 10 years:

Diphtheria and tetanus vaccine (DT) 0.5 ml by intramuscular or deep subcutaneous injection. Follow up at least 4 weeks and 8 weeks.

Tetanus immune globulin (TIG)

In addition to wound toilet and absorbed tetanus vaccine. Also consider if antibacterial prophylaxis

(Protocol 3 below) is indicated.

ADULT and CHILD

• Tetanus immunoglobulin (human) 500 units/vial

250 units by intramuscular injection, increased to 500 units if any of the following conditions apply: wound older than 12 hours; presence, or risk of, heavy contamination; or if patient weights more than 90 kg.

Note: national recommendations may vary

Protocol 3: Antibiotic prophylaxis and treatment

Antibiotic prophylaxis

Antibiotic prophylaxis is indicated in situations or wounds at high risk to become infected such as:

contaminated wounds, penetrating wounds, abdominal trauma, compound fractures, lacerations greater than 5 cm, wounds with devitalized tissue, high risk anatomical sites such as hand or foot. etc. These indications apply for injuries which may or may not require surgical intervention. For injuries requiring surgical intervention, antibiotic prophylaxis is also indicated and should be administered prior to surgery, within the 2 hour period before the skin is cut. Recommended prophylaxis consists of penicillin G and metronidazole given once (more than once if the surgical procedure is > 6 hours).

• Penicillin G ADULT: IV 8-12 million IU once. CHILD: IV 200,000 IU/kg once.

• Metronidazole ADULT: IV 1,500 mg once (infused over 30 min). CHILD: IV 20 mg/kg once.

Antibiotic treatment

If infection is present or likely, administer antibiotics via intravenous and not intramuscular route.

Penicillin G and metronidazole for 5-7 days provide good coverage.

• Penicillin G ADULT: IV 1 - 5 MIU every 6 hours. After 2 days it is possible to use oral Penicillin: Penicillin V 2 tablets every 6 hours.

CHILD: IV 100mg/kg daily divided doses (with higher doses in severe infections),

In case of known allergy to penicillin use erythromycin.

In case of sudden allergy reaction (seldom):

IM adrenaline 0.5 - 1.0 mg to adults. 0.1 mg/ 10 kg body weight to children.

• Metronidazole ADULT: IV 500 mg every 8 hours (infused over 20 minutes).

CHILD: IV 7.5 mg/kg every 8 hours.

Selection of antibiotics

Antibiotics used for prophylaxis should be active against the most likely infecting organism with relevant tissue penetration. Antibiotics may be applied topical, systemical or enteral. They should show a low toxicity, a low incidence of allergy, and should be involved in the selection of virulent organisms.

The antibiotic should be administered ideally 30 minutes before incision in order to achieve relevant tissue concentration. In operations lasting longer than three hours a second dosage is recommended. There is no evidence to support a prolongation of antibiotic administration to 24 or 48 hours in most instances. Single dose is cheaper and does not increase the risk of the developement of bacterial resistance. The most commonly administered drug in the United States is cefazolin (Ancef, Kefzol).Gram-negative and anaerobic pathogens are likely to influence wound infections in operations of the alimentary tract or the hepatobiliary system and should be covered by antibiotic prophylaxis. Cefotetan, cefoxitin, ceftizoxime with or without metronidazole are possible options in these operations. Quinolones have been mentioned by some authors; however, there is no evidence to support the use of these compounds in antibiotic prophylaxis.

Recommendation for specific procedures

Table Antibiotic prophylaxis in specific procedures

Specific operations	Expected organism	Antibiotic of choice	Dosage in adults
Esophagus	S. aureus, streptococci	Cefazolin	1-2 g i.v.
		Amoxycillin + clavulanate
Thoracic	S. aureus. S. epidermidis	Cefazolin	1-2 g i.v.
Gastroduodenal	Gram-positive cocci, enteric gram-negative bacilli	Cefazolin	1-2 g i.v.
Colorectal	Enteric gram-negative bacilli, anaerobes	Oral: neomycin and erythromycin base	1g orally (3 times daily)
		Parenteral: cefotetan or cefoxitin	1-2 g i.v.
		Amoxycillin+clavulanate
Appendectomy	Enteric gram-negative bacilli, anaerobes	Cefotetan or cefoxitin	1-2 g i.v.
Biliary	Enteric gram-negative bacilli	Cefazolin	1-2 g i.v.
		Amoxycillin + clavulanate
Vascular	S. aureus, S. epidermidis, enteric gram-negative bacilli	Cefazolin	1-2 g i.v.
Breast and hernia	S. aureus, S. epidermidis	Cefazolin	1-2 g i.v.

According to : Woods RK and Dellinger EP 1998 based on recommendations of the Surgical Infection Society of North America (1991)

• Cutaneous and soft tissue procedures

There is no general recommendation for antibiotic prophylaxis in soft tissue or cutaneous procedures available.

• Head and neck procedures

In case of operations of the esophagus antibiotic prophylaxis is recommended. Cefazolin is commonly used.

• General thoracic procedures

Antibiotic prophylaxis is routinely used in most institutions, preferably with cefazolin. The evidence is based mostly on studies of pulmonary resection for lung cancer. The rationale for antibiotic prophylaxis in thoracic procedures is not yet clear.

• Gastrointestinal tract procedures

Prophylaxis is recommended for most operations in the gastrointestinal tract. The increasing number of pathogens in the lower gastrointestinal tract is a strong argument for antibiotic coverage. However, despite low microbial count in the stomach, duodenum or small bowel, antibiotic prophylaxis may be indicated when there is a situation with decreased gastric acidity, previous use of antacids, histamine blockers or proton pump inhibitors, stasis, upper gastrointestinal bleeding, morbid obesity or advanced malignancy. The levels of intragastric flora were increased in patients in whom gastric pH was increased or gastric motility impaired. These patients had postoperative infection rates of greater than 20%. Several studies have confirmed that antibiotic prophylaxis in high risk patients may reduce the infection rate from 35% to 0–5%. Cefazolin may be recommended for operations of the upper gastrointestinal tract which is associated with one of the afore mentioned factors.

In colorectal operation there is an increased risk of wound infection due to the large number of pathogens. It has been demonstrated that antibiotic prophylaxis covering gram-negative aerobes and anaerobic bacteria may reduce the incidence of wound infections from 50% to less than 9%. Antibiotic prophylaxis may be given either orally or parentally. However, preoperative mechanical bowel preparation with purgatives, e.g., polyethylene glycol, mannitol or magnesium citrate, and enemas are a cornerstone of the infection prophylaxis. In general, the addition of oral antibiotics may reduce the risk of infection to approximately 9% which is similar to the risk of infection when parenteral antibiotics are given alone.

In the United States it is common practice to use both oral and parenteral antibiotic prophylaxis. For intraluminal prophylaxis erythromycin base or metronidazole and neomycin or kanamycin (3 times 1g per dose per day) are given the day before the operation. Second generation cephalosporins, e.g., cefotetan and cefoxitin, are administered parenterally 30 minutes before incision.

In appendectomy cefotetan or cefoxitin may be the antibiotic of choice for prophylaxis. Single dose is equally effective as multiple doses. In combined topical and systemic antibiotic prophylaxis the wound infection rate was reduced to 5% which is equal to wound infection rate after systemic antibiotic prophylaxis. The use of topical povidone-iodine alone is not recommended. Preincisional or intraincisional administration of metronidazole was able to reduce the wound infection rate. Single dose cefamandole is as effective as cefamandole plus carbenicillin to reduce the rate of wound infections. Bauer et al. were able to show a significant reduction in wound infections after normal appendectomy, acutely inflammed appendix and gangrenous appendix by cefoxtin antibiotic prophylaxis. Lau et al. have studied the effect of bacteriology on septic complications in appendicitis. The most effective agent against anaerobes was metronidazole, the most effective agent against aerobes aminoglycosides and cephalosporins. Moxalactam was considered to be the best single agent against aerobes and anaerobes.

Some authors accept metronidazole combined with an aminoglycoside or a quinolone for prophylaxis. In a recent systematic review of randomised controlled trials for antimicrobial prophylaxis in colorectal surgery it was again confirmed that prophylactic antibiotics reduce the wound infection rate, however it was impossible to say which antibiotic is the best. Certain regimens appear to be inadequate, e.g., metronidazole alone, doxycycline alone, piperacillin alone, oral neomycin plus erythromycin alone). There is no convincing evidence that new-generation cephalosporins are more effective than first-generation cephalosporins. The authors found infection rates for the same antibiotic to be as low as 2% and as high as 30%. There is evidence that bowel prep, decontamination by oral nonabsorbable antibiotics and systemic antibiotic prophylaxis covering aerobic and anaerobic pathogens is the best regimen for prevention of wound infections. Most studies favour prophylaxis in appendectomy and gastroduodenal surgery when bacterial growth may be likely (Grade A/B).

• Biliary tract procedures

Antibiotic prophylaxis for biliary tract operations is considered optional by some authors and depends largely on the identification of risk factors, e.g., advanced age, common duct disease, cholecystitis, jaundice, previous biliary tract surgery. Cefazolin is accepted as effective antibiotic prophylaxis. The addition of mezlocillin may be useful in selected cases. The clinical success rate in the 1g cefotetan, 2g cefotetan and 2g cefoxitin group was 97%, 98% and 97%, respectively. Topical cefamandole achieved similar results as systemic antibiotic prophylaxis. The authors concluded that the application of topical cefamandole is sufficient prophylaxis in biliary surgery. In a comparison of 1g cefotaxime to 4 doses of 2g cefoxitin cefotaxime was superior to cefoxitin. Hjortrup et al. found no difference in wound infection rate after single dose ceftriaxone and 2 doses of cefuroxime. The wound infection rate after cefazolin and ceftizoxime in elective biliary surgery was comparable (7% versus 8%) Kellum et al. found no difference in clinical success between first generation cephalosporins and third generation cephalosporins (51).One dose of ceftriaxone achieved similar results than one perioperative and three postoperative doses of cefazolin. Cefamandole and ampicillin prophylaxis achieved similar results in biliary surgery (wound infection rate 1.8% and 3.2%, respectively). Sarr et al. compared systemic and topical antibiotic regimens. There was no difference in the wound infection rate when topical antibiotics were given alone, combined with cefoxtin or combined with penicillin, tobramycin and clindamycin. In a meta-analysis Meijer et al. compared all available clinical trials from 1965 to 1988. Wound infection rates in controls ranged from 3% to 47%. The overall difference in infection rate was 9% in favour of antibiotic prophylaxis (95% CI 7–11%). There was no difference between first and third generation cephalosporins nor single versus multiple doses. There is evidence that antibiotic prophylaxis in biliary surgery reduces the wound infection rate. In general, the administration of systemic antibiotics is acepted. (Grade A/B)

• Vascular procedures

Antibiotic prophylaxis is recommended in incisions of the groin, in procedures using synthetic material, and in procedures affecting the aorta. Cefazolin is the appropriate antibiotic as in most instances S. aureus and S. epidermidis are isolated. Single-shot may be accepted although there is evidence that two doses may be superior. There was no difference detected in patients who received topical (incisional) cephradine, systemic cephradine or both. Hasselgren et al. have compared the effect of cefuroxime 1.5g every 8 hours at the day of operation, three days versus placebo and found a reduction in wound infection rate from 16.7% in the placebo group to 3.8% in the day 1 only group and 4.3% in the three day group. Controversy exists whether multiple-dose antibiotic prophylaxis produces better results. Hall et al. have shown that multiple-dose regimen with ticarcillin 3.0g/clavulanate 0.1g (Timentin) was superior to single dose. In a retrospective review of a randomized trial of two antibiotics (cephalothin sodium versus oxacillin sodium) there was no difference in wound infection rate. In summary, there is evidence that antibiotic prophylaxis in vascular surgery is relevant for the reduction in wound infection. It is not yet decided that multiple dose of antibiotics are superior to single dose. (Grade A/B)

• Breast and hernia procedures

It has been demonstrated in several studies that antibiotic prophylaxis in groin or breast surgery may lead to a reduction in wound infection despite the intrinsically low risk. The application of synthetic mesh in hernia surgery may be alleviated by the administration of prophylactic antibiotics. The efect of antibiotic prophylaxis may not be visible in other clean operations. A reduction of complications was seen only in axillary lymph node dissection whereas after inguinal lymph node dissection the complication rate was 69% in the antibiotic group and 62% in the placebo group.

• Laparoscopic procedures

The role of antibiotic prophylaxis in laparoscopic procedures needs to be determined. In a retrospective study incisional infections were discovered in 11 of 556 cases, of whom 10 had received prophylactic antibiotics. In a prospective randomized study in 53 patients no incisional infection was discovered. In 150 patients undergoing elective laparoscopic cholecystectomy there was no difference in the infection rate in the cefotetan group, the cefazolin group and the intravenous placebo group. The overall infection rate was 2.4%. Cefotaxime was given randomly as antibiotic prophylaxis.The wound infection rate in the treatment group was 7%, in the placebo group 10% (not significant). In a prospective open study in 253 patients cefuroxime was administered as antibiotic prophylaxis; 2 of 253 patients suffered from wound infection. In summary, there is no evidence to support the antibiotic prophylaxis in laparoscopic cholecystectomy (Grade A/B).

• Trauma surgery

In trauma patients a major problem is the morbidity due to infections. Single-antibiotic use may suffice for prophylaxis in penetrating abdominal trauma. 12 hours of antibiotic prophylaxis were comparable to fiveday antibiotic treatment in the prevention of postoperative infections. The decision for short term prophylaxis may depend on the operative findings, e.g., colonic injury. There is an increased risk when the following factors are present: injury to the liver, pancreas, or colon; abdominal trauma index > 25, and/or prolonged surgery). A revised Trauma Index value above 20 and a colon injury represent an increased risk for intra-abdominal infection. Griswold et al. compared the efficacy of three different antibiotics (cefoxitin, ceftizoxime, mezlocillin) in patients with a trauma index of 8.8 and an infection rate of 10.3% to patients with a trauma index of 28.2 and an infection rate of 42.3%. Only in patients with ceftizoxime there was no increase in the infection rate observed. Cefoxitin prophylaxis is as safe and effective in preventing infections as a triple drug treatment. The overall infection rate was 14.5% in the cefoxitin treated patients versus 18.0% in the triple drug treated patients. Cefoxitin is as effective as clindamycin/tobramycin and superior to cefamandole. However, an improved coverage of enterococcal and Bacteroides by ampicillin/sulbactam may lower the abdominal surgical wound infection rate when compared to cefoxitin. Harlan Stone has demonstrated the efficacy of antibiotic prophylaxis to reduce infections in closed tube thoracostomy. The incidence of posttraumatic empyema ranges between 0 and 18%. Administration of antibiotics for longer than 24 hours did not reduce the risk compared with a shorter duration. A clear management guideline for prophylactic use in penetrating abdominal trauma was rececently published by the AAST.Single preoperative dose of antibiotics with coverage of aerobic and anaerobic pathogens is the standard for treating trauma patients with penetrating abdominal trauma. In the presence of injury to hollow viscus a continuation of antibiotics is recommended for 24 hours only. Aminoglycosides have suboptimal activity in patients with serious injury and should not be used. The use of cephalosporins may avoid serious side effects). (Grade A and B).

OSTEOMYELITIS

Osteomyelitis is a bone infection caused by bacteria or other germs.

A.D.A.M.

• Osteomyelitis is an infection of the bone
• Many species of organisms have been implicated in the etiology of osteomyelitis, with Staphylococcus aureus being the most commonly isolated organism
• Patients with osteomyelitis typically present with localized pain and swelling accompanied by nonspecific symptoms, including chills, fever, and malaise
• Several diagnostic modalities are used to determine the presence of osteomyelitis, including laboratory tests, radiographic imaging, radionuclide studies, and cross-sectional imaging. The gold standard for diagnosing osteomyelitis is bone biopsy and culture
• Treatment of osteomyelitis involves both antimicrobial therapy, with administration of antibiotics for at least 4 to 6 weeks, and surgical intervention, which involves debridement, dead space management, and bone stabilization
• Complications of osteomyelitis include abscess formation, sepsis, bone deformity, limited range of movement, and motor and sensory deficits
• Approximately 20% to 30% of patients with osteomyelitis experience recurrence within 2 years, even with appropriate medical and surgical treatment

Description

• Osteomyelitis is an inflammation or infection of the bone and may include the marrow, cortex, and periosteum; surrounding soft tissues are often involved as well
• The condition may arise from trauma, bacteremia, surgery, or orthopedic implants that disrupt the integrity of the bone, as well as from overlying infections, such as those associated with diabetic foot ulcerations
• There are two major systems for classifying osteomyelitis. The Waldvogel classification system is based on the pathogenesis of the infection, whereas the Cierny-Mader staging and classification system categorizes the disease according to the extent of involvement and the patient's physiologic status, which is valuable in determining treatment and prognosis.

Pathogenesis

The primary septic focus is often a septic skin lesion such as scabies, a septic tooth or other lesion. The child is often undernourished and the disease is often associated with poverty. There may be a history of minor trauma, the organisms seed to the metaphysis and form a small abscess, perhaps in the pre-existing haematoma. The pus builds up in the metaphysis and later escapes under the periosteum.

Pathogenesis of acute osteitis, showing how the pus escapes from the bone

By this time there is a general septicemia and the child is toxically ill.In some areas such as the hip and knee the metaphysis is partially intra capsular and escape of this pus can cause a septic arthritis to complicate the original osteomyelitis. The growth plate acts as a barrier and the pus cannot cross it directly into the joint.

Acute Osteomyelitis is a disease of children. In adults only the vertebrae can be infected. In children all long bones can be affected especially the proximal femur and about the knee. The pelvis and vertebrae are also often affected in children.

The septicemia can seed organisms to other bones and other systemic complications such as meningitis, bronchopneumonia and pericarditis are common. The child may present primarily to the paediatric casualty with these complaints and the bone infection can be overlooked.

The causative organism in 95% of cases is Staphylococcus aureus. Haemophyllis influenza is common under 2 years of age. In the immune suppressed, virtually any organism can be the cause.

The first X Ray signs of osteomyelitis
begin at about day 10,
when a periosteal reaction
will be seen

Early Osteomyelitis
The right hip joint space is widened due to septic arthritis.
In the hip, pus can cross from the metaphysis into the joint
space, as the synovial space partially crosses over the metaphysis.
The metaphyseal area is osteopaenic and three drill holes are noted
from a surgical drainage.

Osteomyelitis is classified according to the mechanism of infection (hematogenous or contiguous) and the presence of vascular insufficiency:

• Hematogenous osteomyelitis
• Occurs when bone tissue is seeded by pathogenic organisms during the course of bacteremia
• Accounts for 20% of cases of osteomyelitis in adults
• The vertebrae are the most common site of hematogenous infection in adults, but the long bones, pelvis, and clavicle may also be affected
• Vertebral osteomyelitis is divided into the following two categories:
• Pyogenic infections, which are most commonly caused by S. aureus (40%-45% of all cases)
• Nonpyogenic (granulomatous) infections, which are most commonly caused by Mycobacterium tuberculosis
• Vertebral osteomyelitis occurs most commonly in men between 60 and 70 years of age and involves the lumbar spine
• Osteomyelitis secondary to a contiguous focus of infection
• Occurs after a traumatic bone injury or as a result of the spread of infection from a nearby source (eg, soft tissue infection)
• Common associated factors include a history of surgical reduction and internal fixation of fractures, prosthetic devices, open fractures, and chronic soft tissue infections; decubitus ulcer; burn; or regional soft tissue infection
• More common in older patients, who generally develop infections following cellulitis or arthroplasties; infection in younger patients usually occurs as a result of trauma or surgery
• Most often affects the tibia and femur
• Osteomyelitis associated with vascular insufficiency
• Caused by impaired blood supply to susceptible tissues
• Usually occurs in older patients and in patients with diabetes mellitus or severe atherosclerosis
• In patients with diabetes, the small bones of the feet are most often involved; neuropathy may also be present
• The risk of developing osteomyelitis is greater in patients with large (>2 cm in diameter) and deep (>3 mm) diabetic ulcers and if the bone is exposed

Osteomyelitis may be classified as acute, subacute, or chronic, depending on the time to clinical presentation relative to the introduction of infection.

• Acute osteomyelitis is characterized as a suppurative infection presenting with edema, small vessel thrombosis, and vascular congestion within 2 weeks of onset
• Subacute osteomyelitis may be more indolent, presenting 1 to several months after infection
• Chronic osteomyelitis is the result of longstanding infection, which may take months or years to develop or which has been suppressed by the host ('remission') or partially treated so that it remains relatively dormant for long periods before becoming clinically apparent. Chronic osteomyelitis is characterized by the presence of necrotic bone (sequestrum); new bone formation; drainage or sinus tracts; and the presence of leukocytes, lymphocytes, and histiocytes. It can be recognized in patients with a history of osteomyelitis who experience a recurrence of pain, erythema, and swelling, along with a draining sinus

Cierny-Mader staging and classification system

Osteomyelitis is categorized according to the portion of bone affected; the physiologic status of the patient; and risk factors that affect immunity, metabolism, and vascularity. The first part of the system categorizes osteomyelitis according to anatomic type, as follows:

• Stage 1: medullary osteomyelitis
• Limited to the medullary cavity
• Often caused by a solitary organism
• Causes include hematogenous spread and infections from orthopedic devices (intramedullary rods)
• Stage 2: superficial osteomyelitis
• Involves the cortex
• Often caused by an adjacent soft tissue infection
• Exposed, infected outer necrotic surface of bone is observed at the base of a soft tissue wound
• Local ischemia is seen
• Stage 3: localized osteomyelitis
• May involve both the medulla and cortex, but the bone generally remains stable, as the infection does not involve its entire diameter
• Stage 4: diffuse osteomyelitis
• Extensive disease
• May occur on both sides of a nonunion or a joint
• Involves the entire thickness of the bone, with loss of stability

The second part of the system describes the patient's physiologic status, as deficiencies of leukocyte recruitment, phagocytosis, or vascular supplies may promote osteomyelitis and contribute to its chronicity. The physiologic class of the infected patient is often more important than the anatomic type because the state of the host is the strongest predictor of treatment failure.

• Class A: normal host
• Normal physiologic, metabolic, and immune functions
• Associated with a much better prognosis
• Class B: host factors limit normal immune response and healing
• Immunocompromised, either locally (Bl), systemically (Bs), or both (Bls)
• Local factors include problems of perfusion (peripheral vascular disease, vasculitis, venous stasis, lymphedema)
• Systemic factors include hypoxemia, illnesses associated with impaired immune function (chronic renal or hepatic insufficiency, malignancy, diabetes), or use of immunosuppressive medication (steroids)
• The goal of treatment is to remove the factors that lead to the development of osteomyelitis
• Class C: health of host does not allow full treatment
• Treatment poses a greater risk than the infection itself
• Surgery may not be possible because of the patient's debilitated or immunocompromised status

Epidemiology

• There are several recent trends in the epidemiology of osteomyelitis. Acute hematogenous osteomyelitis is decreasing in incidence, whereas the incidence of osteomyelitis due to direct inoculation or contiguous focus of infection is increasing. This is attributed to the increase in both trauma (due to motor vehicle accidents) and orthopedic surgical procedures
• Osteomyelitis secondary to open fractures occurs in 3% to 25% of cases, usually in young men in their twenties and thirties
• Foot ulcers occur in 2% of patients with diabetes every year, 15% of whom will develop osteomyelitis. Recurrent infection occurs in up to 36% of patients with diabetes
• Vertebral osteomyelitis is responsible for 2% to 4% of all cases of osteomyelitis, with an annual incidence of 5.3 cases per million persons. Men are more commonly affected than women, with a mean age at presentation of 61 years

Causes and risk factors

Causes:

• The focus for hematogenous osteomyelitis may vary from a mild skin infection to bacterial endocarditis; it is also a complication among intravenous drug users
• Osteomyelitis secondary to a contiguous focus of infection may be caused by the direct inoculation of bacteria through trauma, from spread of adjacent soft tissue infection, or introduction of infection during preoperative or intraoperative procedures. Predisposing factors include surgical reduction and internal fixation of fractures, prosthetic devices, open fractures, and chronic soft tissue infections
• Osteomyelitis secondary to vascular insufficiency is often associated with diabetes mellitus. Infection often results from minor trauma to the feet, such as infected nail beds or skin ulceration. Inadequate tissue perfusion limits local tissue response to injury
• Multiple organisms are responsible for osteomyelitis in different populations. The causative organism is related to the age, clinical history, and immune status of the patient (see Table 1). S. aureus is the most common cause in all cases

Table Organisms Commonly Implicated in Osteomyelitis in Different Patient Populations

Category of Osteomyelitis	Population	Causative Organism(s)
Hematogenous osteomyelitis	Patients of all ages	S. aureus
	Neonates	Enterobacteriaceae, group B streptococci
	Infants and children	Haemophilus influenzae type B
	Intravenous drug users	S. aureus, Pseudomonas aeruginosa, Candida species
	Patients with sickle cell disease	Streptococcus pneumoniae, Salmonella species
	HIV-infected patients	Bartonella henselae
	Patients with nosocomial infections	S. aureus, Enterobacteriaceae, Candida species, Aspergillus (in immunocompromised patients)
Vertebral osteomyelitis (hematogenous and contiguous focus)	Adults (most commonly)	S. aureus
	Patients with urinary tract infections	Aerobic gram-negative bacilli, Enterococcus species
	Intravenous drug users	S. aureus, P. aeruginosa
	Patients undergoing spinal surgery	Coagulase-negative staphylococci, S. aureus, aerobic gram-negative bacilli
	Patients with infections of intravascular devices	Candida species, staphylococci
	Patients living in endemic regions	M. tuberculosis, Brucella species, regional fungi (coccidioidomycosis, blastomycosis, histoplasmosis), Coxiella burnetii (Q fever)
Contiguous-focus osteomyelitis	Patients exposed to contaminated soil	Clostridium species, Bacillus species, Stenotrophomonas maltophilia, Nocardia species, atypical mycobacteria, Aspergillus species, Rhizopus species, Mucor species
	Patients with orthopedic devices	S. aureus, coagulase-negative staphylococci, Propionibacterium species
	Patients with decubitus ulcers	Enterobacteriaceae, P. aeruginosa, enterococci, anaerobes, Candida species
	Patients with a history of cat bites	Pasteurella multocida
	Patients with a history of human bites (including clenched-fist injury)	Eikenella corrodens, Moraxella species
	Patients with puncture injuries on the foot	P. aeruginosa
	Patients with periodontal infection	Actinomyces species
Osteomyelitis associated with vascular insufficiency	Patients with diabetes	Polymicrobial: S. aureus, β-hemolytic streptococci, Enterococcus faecalis, aerobic gram-negative bacilli

HIV = human immunodeficiency virus

Risk factors:

• Diabetes mellitus
• Immunocompromise
• Neuropathy
• Vascular insufficiency
• Intravenous drug use
• Open fractures
• Local trauma
• Orthopedic hardware (including prosthetic joints)
• Hemodialysis
• Sickle cell disease
• Dental infections
• Urinary tract infections
• Catheter-related bloodstream infection

Associated disorders

• Occurs more frequently in patients with diabetes mellitus, vascular insufficiency, or immunosuppression
• Recent history of surgical procedure or joint or bone trauma

Screening

Not applicable.

Primary prevention

Summary approach

• Patients with diabetes should have a complete examination of the lower extremities annually and inspection of the feet for wounds at interim routine follow-up visits. Measures to prevent diabetic foot ulcers should be emphasized. A high index of suspicion should be maintained for the contiguous spread of local diabetic foot infections to the bone, with continuous evaluation for signs and symptoms of the development of osteomyelitis
• Patients with open fractures who are able to receive antibiotics within 6 hours of injury and prompt surgical treatment have a reduced risk of developing osteomyelitis
• The use of prophylactic antibiotics prior to bone surgery has been shown to prevent wound infections
• Scrupulous care should be taken to avoid health care–associated osteomyelitis, with careful attention to intravascular and urinary catheters, surgical incisions, and other wounds

Population at risk

• Patients with diabetes mellitus
• Patients undergoing orthopedic surgery, including placement of prostheses and other clean surgery and management of open fractures

Preventive measures

In patients with diabetes mellitus:

• Measures to prevent diabetic foot include excellent foot hygiene, glycemic control, and use of protective footwear
• Patients should be instructed to examine their feet daily and to seek prompt medical care for new wounds or other injuries to the feet
• A complete evaluation of the lower extremities should be done annually, and the feet should be inspected for wounds at periodic follow-up visits in the interim
• Patients with Charcot joints or other abnormalities that result in friction with shoes may require specially adapted shoes
• In patients undergoing foot surgery or amputation, the use of protective footwear postoperatively is helpful in preventing subsequent ulceration and infection

In patients with open fractures:

• Administration of antibiotics within 6 hours of injury and prompt surgical treatment are associated with a reduced risk of developing osteomyelitis
• A continued 24-hour regimen of penicillin or first-generation or second-generation cephalosporins is also beneficial

In patients undergoing bone surgery:

• Administration of prophylactic antibiotics has proven to be successful in the prevention of infection following surgery, particularly in patients with noncompound hip fractures and those receiving total hip and knee prostheses
• In patients undergoing clean bone surgery, intravenous antibiotics are administered 30 minutes before skin incision and up to 24 hours following the procedure. A first-generation or second-generation cephalosporin is appropriate in many cases; vancomycin may be used in patients who are allergic to cephalosporin and in settings with a high prevalence of methicillin-resistant staphylococci
• In patients undergoing surgery for closed fractures, the use of penicillin, first-generation cephalosporins (eg, cefazolin), or second-generation cephalosporins (eg, cefamandole, cefuroxime) has led to a reduction in postsurgical infection
• Standard preoperative procedures, such as the use of antimicrobial shower, shaving, and topical disinfectants, should be followed. Observation of such procedures, together with the use of surgical rooms with laminar airflow and prophylactic antibiotic therapy, has led to a reduction in the postsurgical rate of infection to 0.5% to 2%, depending on the type of joint replacement

BLEEDING

Bleeding is the name commonly used to describe blood loss. It can refer to blood loss inside the body (internal bleeding) or blood loss outside of the body (external bleeding).

Blood loss can occur in almost any area of the body. Typically, internal bleeding occurs when blood leaks out through damage to a blood vessel or organ. External bleeding occurs either when blood exits through a break in the skin, or when blood exits through a natural opening in the body, such as the mouth, vagina, or rectum.

Bleeding is the loss of blood. Bleeding may be:

• Inside the body (internally) 
• Outside the body (externally)

Bleeding may occur:

• Inside the body when blood leaks from blood vessels or organs
• Outside the body when blood flows through a natural opening (such as the vagina, mouth, or rectum)
• Outside the body when blood moves through a break in the skin

Considerations

Get emergency medical help for severe bleeding. This is very important if you think there is internal bleeding.  Internal bleeding can very quickly become life threatening. Immediate medical care is needed.

Serious injuries don't cause heavy bleeding. Sometimes, relatively minor injuries can bleed a lot. An example is a scalp wound.

You may bleed a lot if you take blood-thinning medication or have a bleeding disorder such as hemophilia. Bleeding in such people requires immediate medical attention.

The most important step for external bleeding is to apply direct pressure. This will stop most external bleeding.

Always wash your hands before (if possible) and after giving first aid to someone who is bleeding. This helps prevent infection.

Try to use latex gloves when treating someone who is bleeding. Latex gloves should be in every first aid kit. People allergic to latex can use a nonlatex glove. You can catch viral hepatitis if you touch infected blood. HIV can be spread if infected blood gets into an open wound, even a small one.

Although puncture wounds usually don't bleed very much, they carry a high risk of infection. Seek medical care to prevent tetanus or other infection.

Abdominal and chest wounds can be very serious because of the possibility of severe internal bleeding. They may not look very serious, but can result in shock.

• Seek immediate medical care for any abdominal or chest wound.
•  If organs are showing through the wound, do not try to push them back into place.
• Cover the injury with a moistened cloth or bandage.
• Apply only very gentle pressure to stop the bleeding.

Blood loss can cause blood to collect under the skin, turning it black and blue (bruised). Apply a cool compress to the area as soon as possible to reduce swelling. Wrap the ice in a towel and place the towel over the injury. Do not place ice directly on the skin.

Causes

Bleeding can be caused by injuries or may be spontaneous. Spontaneous bleeding is most commonly caused by problems with the joints, or gastrointestinal or urogenital tracts.

Symptoms

• Blood coming from an open wound
• Bruising
• Shock, which may cause any of the following symptoms:
• Confusion or decreasing alertness
• Clammy skin
• Dizziness or light-headedness after an injury
• Low blood pressure
• Paleness (pallor)
• Rapid pulse, increased heart rate
• Shortness of breath
• Weakness

Symptoms of internal bleeding may also include:

• Abdominal pain and swelling
• Chest pain
• External bleeding through a natural opening
• Blood in the stool (appears black, maroon, or bright red)
• Blood in the urine (appears red, pink, or tea-colored)
• Blood in the vomit (looks bright red, or brown like coffee-grounds)
• Vaginal bleeding (heavier than usual or after menopause)
• Skin color changes that occur several days after an injury (skin may black, blue, purple, yellowish green)

First Aid

First aid is appropriate for external bleeding. If bleeding is severe, or if you think there is internal bleeding or the person is in shock, get emergency help.

1. Calm and reassure the person. The sight of blood can be very frightening.

2. If the wound affects just the top layers of skin (superficial), wash it with soap and warm water and pat dry. Bleeding from superficial wounds or scrapes is often described as "oozing," because it is slow.

3. Lay the person down. This reduces the chances of fainting by increasing blood flow to the brain. When possible, raise up the part of the body that is bleeding.

4. Remove any loose debris or dirt that you can see from a wound.

5. Do NOT remove an object such as a knife, stick, or arrow that is stuck in the body. Doing so may cause more damage and bleeding. Place pads and bandages around the object and tape the object in place.

6. Put pressure directly on an outer wound with a sterile bandage, clean cloth, or even a piece of clothing. If nothing else is available, use your hand. Direct pressure is best for external bleeding, except for an eye injury.

7. Maintain pressure until the bleeding stops. When it has stopped, tightly wrap the wound dressing with adhesive tape or a piece of clean clothing. Place a cold pack over the dressing. Do not peek to see if the bleeding has stopped.

8. If bleeding continues and seeps through the material being held on the wound, do not remove it. Simply place another cloth over the first one. Be sure to seek medical attention.

9. If the bleeding is severe, get medical help and take steps to prevent shock. Keep the injured body part completely still. Lay the person flat, raise the feet about 12 inches, and cover the person with a coat or blanket. DO NOT move the person if there has been a head, neck, back, or leg injury, as doing so may make the injury worse. Get medical help as soon as possible.

Bleeding from most injuries can be stopped by applying direct pressure to the injury. This keeps from cutting off the blood supply to the affected limb.

Bleeding from most injuries can be stopped by applying direct pressure to the injury. This keeps from cutting off the blood supply to the affected limb. When there is severe bleeding, where a major artery has been severed, pressure may be insufficient and a tourniquet may be necessary.

When there is severe bleeding where a major artery has been severed, pressure may be insufficient and a tourniquet may be necessary. Tourniquets are an effective way of stopping bleeding from an extremity. They do, however, stop circulation to the affected extremity and should ONLY be used when other methods, such as pressure dressings, have failed (or are likely to fail). Pressure from tourniquets must be relieved periodically to prevent damage to the tissue from lack of oxygen.

DO NOT

• DO NOT apply a tourniquet to control bleeding, except as a last resort. Doing so may cause more harm than good. A tourniquet should be used only in a life-threatening situation and should be applied by an experienced person
• If continuous pressure hasn't stopped the bleeding and bleeding is extremely severe, a tourniquet may be used until medical help arrives or bleeding is controllable.
• It should be applied to the limb between the bleeding site and the heart and tightened so bleeding can be controlled by applying direct pressure over the wound.
• To make a tourniquet, use bandages 2 to 4 inches wide and wrap them around the limb several times. Tie a half or square knot, leaving loose ends long enough to tie another knot. A stick or a stiff rod should be placed between the two knots. Twist the stick until the bandage is tight enough to stop the bleeding and then secure it in place.
• Check the tourniquet every 10 to 15 minutes. If the bleeding becomes controllable, (manageable by applying direct pressure), release the tourniquet.
• DO NOT peek at a wound to see if the bleeding is stopping. The less a wound is disturbed, the more likely it is that you'll be able to control the bleeding
• DO NOT probe a wound or pull out any embedded object from a wound. This will usually cause more bleeding and harm
• DO NOT remove a dressing if it becomes soaked with blood. Instead, add a new one on top
• DO NOT try to clean a large wound. This can cause heavier bleeding
• DO NOT try to clean a wound after you get the bleeding under control. Get medical help

When to Contact a Medical Professional

Seek medical help if:

• Bleeding can't be controlled, required the use of a tourniquet, or was caused by a serious injury
• The wound might need stitches
• Gravel or dirt cannot be removed easily with gentle cleaning
• You think there may be internal bleeding or shock
• Signs of infection develop, including increased pain, redness, swelling, yellow or brown fluid, swollen lymph nodes, fever, or red streaks spreading from the site toward the heart
• The injury was due to an animal or human bite
• The patient has not had a tetanus shot in the last 5-10 years

Prevention

Use good judgment and keep knives and sharp objects away from small children.

Stay up-to-date on vaccinations, especially the tetanus immunization.

The body’s response to blood loss

Introduction

Maintenance of circulating blood volume is one of the most important homeostatic mechanisms that the body must support. Poor blood supply to the tissues ultimately affects every cell in the body and organ dysfunction will quickly develop if tissue perfusion fails. Haemorrhagic shock is defined as a failure of adequate tissue perfusion resulting from a loss of circulating blood volume. Homeostatic and subcellular mechanisms Significant blood loss from any cause initiates a sequence of stress responses that are intended to preserve flow to vital organs and to signal cells to expend internal energy stores. Haemorrhagic shock reduces wall tension in the large intrathoracic arteries, which activates baroreceptors. Adrenergic reflexes that have neural and circulating hormonal components are also activated. Neural effects are immediate; hormonal changes may be rapid, but some time is needed for them to take full effect. The two major neural components are sympathetic fibres from the stellate ganglion, which stimulate the heart, and sympathetic fibres from regional ganglia, which cause peripheral arterial vasoconstriction. The circulating ‘stress hormones’ derive mainly from the hypothalamic −pituitary adrenomedullary axis. They lead to secretion of epinephrine and norepinephrine from the adrenal medulla and corticosteroids from the adrenal cortex, renin from the kidney, and glucagon from the pancreas. These hormones signal the liver to break down glycogen in order to release glucose into the plasma, promote release of fatty acids from adipose tissue via lipolysis, and stimulate the breakdown of tissue glycogen stores. At a cellular level, blood loss first affects the mitochondria. Mitochondria function at the lowest oxygen tension in the body, but consume almost all the body’s supply of oxygen. More than 95% of aerobic chemical energy comes from mitochondrial combustion of fuel substrates (fats, carbohydrates, ketones) using oxygen to produce carbon dioxide (CO² ) and water. Most cellular energy transfer derives from acetyl coenzyme A (aCoA) formed by one of two pathways: α - oxidation or decarboxylation of pyruvate. Either fatty acids or ketones are produced by α -oxidation. Pyruvate derives from either glycolysis or lactate dehydrogenation. ACoA is consumed by the tricarboxylic acid (TCA) cycle and forms reduced pyridine and flavin nucleotides. These pass electrons along a series of proteins in the inner mitochondrial membrane, culminating in the reduction of molecular oxygen to form water. The mitochondrion thus harnesses energy from this process to form adenosine triphosphate from adenosine diphosphate plus inorganic phosphate. This forms the basis of all cellular energy production. In the early stage of shock, the skeletal muscle and splanchnic organs are affected more by oxygen deprivation than by a lack of delivery of fuel substrate. As a result, shock rapidly stalls transfer of electrons in the mitochondria and ‘jams’ the pathways of acetyl coenzyme A input into the TCA cycle. Lactic acid results and is transported actively across the cell membrane by way of a specific protein transporter. In the resuscitated haemorrhagic shock patient, lactate production may also occur from skeletal muscle, not entirely because of low mitochondrial oxygenation, but because the delivery of pyruvate from glycolysis overwhelms the ability of dehydrogenase enzymes in the TCA cycle to dispose of pyruvate. Pyruvate is then converted into lactate, a condition known as aerobic glycolysis. Thus, it can be seen that elevated concentrations of lactate in the blood are a sentinel marker

of widespread inadequate tissue perfusion. When adequate resuscitation has been achieved, lactate levels return to normal. Global physiological effects The physiological responses that the body mounts to increasing blood loss are well defined by the American College of Surgeons in their Advanced Trauma Life Support Education Programme . These changes are observed as the percentage of blood lost reaches certain levels and are graded as different classes of haemorrhage. Important physiological parameters to aid recognition and treatment of major haemorrhage are mental status, respiratory rate, peripheral perfusion, pulse rate, blood pressure and urine output. These parameters form the basis of the four classes of haemorrhage recognized in a 70-kg adult. Cardiovascular response to haemorrhage can vary with underlying cardiopulmonary status, age, presence of hypo- or hyperthermia and presence of ingested drugs. This should be remembered when applying this classification. This classification does not apply to small children or infants, who are more dependent on heart rate rather than blood-pressure maintenance to compensate for blood loss. A fall in blood pressure in a child is a preterminal event.

Class I haemorrhage (0–15% total blood volume) This represents up to 750 ml blood loss. Minimal physiological changes occur at this level. A patient may exhibit mild anxiety, but heart rate, blood pressure and peripheral circulation largely remain unchanged. Urine output is only slightly decreased. The body can compensate well for this degree of haemorrhage. This situation is mimicked by a blood donation.

Class II haemorrhage (15–30% total blood volume) Beyond 750 ml blood lost, sympathetic nerve stimulation occurs as described above. A modest elevation in heart rate and a decrease in the pulse pressure, as the diastolic pressure rises, are to be expected. A degree of peripheral ‘shut down’, i.e. cool extremities and digital cyanosis, accompanied by pallor, occur. Inexperienced staff may fail to recognize the diastolic pressure rise associated with increasing blood loss. A blood pressure of 120/70 changing to a pressure of 120/95 may be a sign of the impending cardiovascular collapse associated with a blood loss in excess of 1500 ml. This physiological change is a direct result of the vasoconstriction induced by sympathetic nerve stimulation of the vascular tree. Hyperventilation to a respiratory rate of over 20 breaths/min can also be expected at this stage as the tissues are starting to suffer a lack of oxygenation and increasing production of lactic acid stimulates the respiratory centre.

Class III haemorrhage (30–40% total blood volume) Now haemorrhagic shock is well established and a critical phase is reached, with a drop in systolic and diastolic blood pressure. Mental confusion and anxiety are normal, respiratory rate is high, peripheral perfusion is very poor, and the patient appears pale and diaphoretic. The pulse rate is invariably well over 100 beats/min and the production of urine is negligible. Under these circumstances, widespread failure of tissue oxygenation is occurring, with diversion of what blood flow there is to essential organs such as brain, kidney and heart.

Class IV haemorrhage (over 40% of blood volume) This situation is immediately life-threatening and within 15 min a mortality of 50% is to be expected. Blood pressure has dropped to be, in some cases, unrecordable, and the pulse is barely palpable. Vital organ perfusion is failing. Other guides to recognition of haemorrhagic shock Not all haemorrhagic shock is as obvious as the ATLS classification would suggest. A change in arterial acid base status will often precede any significant decrease in cardiac output with haemorrhage. The arterial and venous blood bicarbonate level and base deficit will decrease early in haemorrhage even if pH and blood pressure remain in the normal range. Distinguishing simple haemorrhage from haemorrhagic shock is possible by noting that when the base deficit becomes pathologically low, widespread tissue hypoperfusion may be suspected. Patients with tachycardia, a low base deficit, and low urine output should be suspected of having haemorrhagic shock. The base deficit is defined as the amount of strong base that would have to be added to a litre of blood to normalize the pH. In the clinical setting the base deficit is indirectly calculated from the pH and arterial CO² partial pressure (PaCO² ) and is normally higher than − 2 mM . The brainstem chemoreceptor responds to acidaemia by increasing respiratory rate, leading to reduced PaCO². After approximately one third of the total blood volume is acutely lost, cardiovascular reflexes can no longer cause adequate filling of the arterial tree, and hypotension supervenes. Arterial hypotension is generally defined as an arterial blood pressure below 90 mmHg, but this threshold should be increased to 100 mmHg in patients with known systemic hypertension and in patients over age 60 years. With the development of hypotension, the patient can no longer hyperventilate sufficiently to maintain a normal arterial pH, and acidaemia occurs. Blood gases can therefore provide very useful information regarding the early detection of acute blood loss. Treatment of haemorrhagic shock Conventional wisdom regarding shock has been directed at rapid correction of the source of haemorrhage and rapid restoration of normal circulating blood volume and perfusion. The ATLS curriculum advocates the immediate establishment of largebore intravenous access and infusion of resuscitative fluids, characteristically up to 2 l of Hartmann’s solution, followed by blood. The goal is to return the blood pressure to normal. If blood pressure subsequently falls again, this is taken as a sign of serious injury, which must be addressed by immediate surgery. Maintenance of blood pressure during the period of active haemorrhage is presumed to reduce the risk of organ-system failure and irreversible shock. This approach may not be as sensible as it seems. The analogy of pouring water into a bucket with a hole at the bottom can be made. The greater the volume of water added to the bucket, the more rapidly it runs from the hole. In the traumatized patient, this means greater blood loss, a longer duration of bleeding, and disruption of the normal plasma composition including dilution of clotting factors. Aggressive fluid administration and higher blood pressure potentially increase the extent of haemorrhage. Surgical control must be rapidly achieved. What is not understood at the present is the priority that must be given to these two conflicting goals: maintenance of perfusion and limitation of haemorrhage. Deliberate hypotension is employed in elective head and neck surgery, prostate resections, and major orthopaedic procedures as a means of reducing the blood loss and need for transfusion. Trauma patients, however, may have already lost a substantial amount of blood before hospital arrival and be in some degree of shock. Identifying the optimal balance between fluid resuscitation and haemorrhage control is one of the most difficult and controversial areas in trauma care today. Delayed or limited resuscitation until surgical control is available may improve outcome. The effects of persisting inadequate circulating volume Untreated or inadequately treated haemorrhagic shock will ultimately have serious consequences for the patient. Life hreatening problems can occur a considerable time after the traumatic event. With limited or inadequate restoration of circulating volume, initiation of inflammatory changes can be expected. Shock causes neutrophil activation and liberation of adhesion molecules, which promote binding of neutrophils to lung and vascular endothelium. Within the lung, this initiates capillary leak that can produce the adult respiratory distress syndrome. Within the circulation, inflammatory cytokines are liberated during resuscitation, and membrane injury occurs in many cells. In the liver, damage from inflammation and reactive oxygen species from neutrophils is compounded by persistent microischaemia. During resuscitation from haemorrhagic shock, the normal balance of vasodilatation by nitric oxide versus vasoconstriction by endothelins becomes distorted, producing patchy centrilobular ischaemic damage in the liver, which may produce an immediate rise in blood transaminase levels. A growing body of evidence suggests that re-transfusion from haemorrhage exerts greater injury to the heart than the actual hypotensive insult. Depending on the degree of hypotensive insult, the kidney may manifest acute spasm of the preglomerular arterioles, causing acute tubular necrosis. Systemic metabolic changes can impair fuel delivery to the heart and brain, secondary to depressed hepatic glucose output, impaired hepatic ketone production, and inhibited peripheral lipolysis. Activated, sticky neutrophils can also directly damage organs by liberating toxic reactive oxygen species, N-chloramines, and proteolytic enzymes. Neutrophils can also plug capillaries and cause microischaemia. Although much of the knowledge about the inflammatory responses in shock has evolved from the study of septic shock, the consensus is that any low-perfusion state that produces widespread cellular hypoxia can trigger systemic inflammation. Haemorrhagic shock is one such low-flow state. Multiple tissues (e.g. macrophages, endothelial and epithelial cells, muscle cells) are signalled to enhance transcription of messenger ribonucleic acid (mRNA) coding for cytokines, including tumour necrosis factors (TNF-α , TNF-α) and interleukins (IL-1, IL-6). The effects of intravascular cytokine release on the body are manifest as systemic inflammatory response syndrome (SIRS). SIRS can progress to sepsis syndrome and ultimately septic shock. One additional mechanism by which this is suggested to occur is a breakdown in the integrity of the gut mucosa caused by inadequate perfusion of the gut wall. This leads to bacterial translocation of Gram-negative gut bacteria into the bloodstream, thus inducing cytokine release and septic shock. The prevention of inadequate circulation by the timely surgical intervention and restoration of circulating volume will ameliorate the above pathological processes.

Conclusions

The consequences of inadequate circulating blood volume are life-threatening. Recognition of haemorrhage by the classical physiological signs is important for clinicians to diagnose shock and prevent both short- and long-term complications of this condition. These interventions centre on surgical control of bleeding and rapid restoration of blood volume.

Lower gastrointestinal tract bleeding: a problem based approach

Clinical presentation

McGuire and Haynes reviewed the literature from 1956 to 1971 and found 473 cases of massive lower GI bleeding. More than three-fourths of patients were successfully treated nonoperatively with a 22% rebleeding rate but only a 3% mortality. One hundred and three of four hundred and seventy-three (22%) underwent operations, 28 of the 62 (45%) hemicolectomies rebled and nine of the 62 (15%) died. Only three of 34 (9%) patients undergoing subtotal colectomy died and none rebled. McGuire recently reviewed the natural history of 79 patients with 108 episodes of acute lower GI bleeding. Bleeding stopped spontaneously in 76% but 24% required emergency surgery. In the 66 patients with lower gastrointestinal bleeding who required no more than three units blood transfusion over a 24 hour period, 98.5% stopped spontaneously. When greater than three units were transfused in a 24 hour time period, 25 of 42 (60%) patients needed emergency surgery. Patients with acute LGIB can demonstrate a decrease in hemoglobin as well as changes in hemodynamics (50%), orthostatic changes (30%), syncope (10%), or cardiovascular collapse (9%).

History and physical examination

Information such as a prior history of peptic ulcer disease, diverticulosis, aortic vascular surgery, radiation therapy, use of medications such as non-steroidal anti-inflammatory and anti-coagulants, or recent endoscopy with biopsy may indicate the origin of bleeding. Diagnostic and resuscitative manuevers must occur simultaneously if hemodynamic instability is present. Initial laboratories should include complete blood count, type and crossmatch, platelet count and coagulation parameters. Digital rectal examination with stool guaiac is a routine part of the physical examination in the initial evaluation of all patients with gastrointestinal bleeding as 80% will have blood per rectum.

Diagnosis and therapeutics

Exclusion of an upper gastrointestinal source of bleeding per rectum including nasogastric tube aspiration and/or upper endoscopy is mandatory prior to evaluation of potential lower gastrointestinal tract sources. Aspiration of the nasogastric tube excludes all but a small percentage of upper GI sources. Sigmoidoscopy/anoscopy has been routinely performed early in the course of evaluation of LGIB to rule out anorectal sources of hemorrhage. Colonoscopy permits examination of the entire colon and potential therapeutic interventions in LGIB. The diagnostic yield for colonoscopy is related to the rate of bleeding and the ability to obtain an adequate bowel preparation. Overall diagnostic yield for a total of 1561 patients undergoing urgent colonoscopy in acute LGIB was 68%, with an incomplete procedure rate of 2%, and a reported complication rate of 1.3%. Endoscopic techniques to control hemorrhage have typically been attempted far less frequently in LGIB than in UGIB with reported rates of utilization of 27% and 51% respectively. When colonoscopy is non diagnostic, unavailable or incomplete the workup of acute lower GI bleeding after exclusion of upper GI bleeding, may include some form of nuclear medicine scan. If results of these scans demonstrate acute hemorrhage then selective angiography is indicated. The diagnostic inaccuracy of 20% in pooled data from tagged red blood cell scanning in localization of acute LGIB has led to the recommendation that surgical resection cannot be solely based on the results of nuclear scans. Even in cases where a positive TRBC scan was noted, a wide range (7–61%) of angiograms were noted to be abnormal. Segmental colectomy may subsequently be planned in those patients in whom site of bleeding is demonstrated by angiogram and when there is clinical evidence of ongoing hemorrhage.

The need for this myriad of diagnostic studies evolved from the premise that subtotal colectomy was to be avoided and that the benefits of segmental colectomy outweighed the risks of angiography and associated delay in surgical intervention. Subtotal colectomy was thought to be associated with a higher mortality rate and an increased incidence of disabling diarrhea than hemicolectomy. The view that subtotal colectomy with ileorectal anastamosis leads to a higher morbidity and mortality rates is certainly debatable. Early studies, predating current sophisticated critical care management, demonstrated a low mortality after subtotal colectomy for lower GI bleeding. Fazio et al. reviewed 163 patients undergoing elective ileorectal anastamosis and found only a 1.2% leak rate and 1.9% operative mortality. A higher leak rate (28–33%) for ileorectal anastamosis, however, has been noted in the emergency setting. The surgeon must strongly consider fecal diversion, avoiding construction of a tenous anastamosis in hypoperfused patients undergoing any emergency colectomy, to minimize the risk for anastamotic dehiscence. It now appears that severe disabling diarrhea rarely occurs after subtotal colectomy with ileorectal anastamosis. Most patients’ bowel habits are relatively normal following subtotal colectomy, averaging 2 to 4 bowel movements per day after emergency or elective surgery for cancer, ulcerative colitis or acute lower GI bleeding. Preserving a length of remaining ileum, (greater than 15 cm), is critical to maintain normal bowel habits. The loss of the ileocecal valve appears to have little impact on stool volume or electrolyte composition or upon the number of bowel movement. Thus, subtotal colectomy, in the absence of extensive resection of the ileum, rarely causes difficulties with frequent defecation.

Angiography has been used to identify sites of intestinal bleeding for more than three decades supposedly to minimize the extent of colonic resection. In addition, the use of therapeutic angiography (vasopressin and embolization) has been thought to possibly minimize the need for operative intervention. While angiography does occasionally localize the origin of hemorrhage, studies are negative in more than one-half of patients requiring emergency operation. Furthermore, the angiogram can be misleading, showing only some of multiple bleeding site, leading to an inadequate segmental resection.

Surprisingly, selective angiography has been shown to be clinically beneficial in only 8%–28% of patients. Nath and colleagues reported that in only 10 of 49 patients evaluated, angiography led to a segmental resection. Similarly, Britt et al. found that just 11 of 40 patients undergoing angiography for lower GI bleeding received a segmental resection. Browder and co-workers reported that 8 of 50 patients had emergent operations but four of the eight underwent subtotal colectomy for multiple bleeding sites. Unfortunately, complication rates of angiography are not insignificant with reported overall rate of 9.3%. Major complications include femoral artery thrombosis, hematoma, contrast reactions, renal failure, and transient ischemic attacks. Furthermore, it is unclear how the delay in performing a definitive operative intervention may impact on the development of organ failure and death in these populations alternatively therapeutic angiography has been utilized with variable success to stop bleeding with vasoconstrictive agents and embolization. Angiography has also been used to induce an identify occult bleeding sites by employing anticoagulants, fibrinolytic agents, and vasodilators. In a review of 83 patients with intra-arterial infusion of vasopressin for colonic bleeding, it was found that 41% rebled. The long term consequences of angiographic control of hemorrhage are unknown, but the colon appears to be at increased risk of ischemia and colonic stricture after transcatheter embolization.

In summary, mortality rates for lower gastrointestinal bleedings are less than five percent and hemorrhage related deaths are actually infrequent. After resuscitation, placement of a nasogastric tube to exclude an upper gastrointestinal source, and screening anoscopy/sigmoidoscopy to rule out the presence of anorectal pathology is required. (Fig.) It is our preference to proceed to subtotal colectomy when transfusion requirements exceed three units. However, an acceptable alternative includes TRBC followed by angiography and possible segmental colectomy. A positive TRBC requires verification by angiography typically and subsequent attempt to halt hemorrhage with vasopressin infusion. If angiography is negative in the setting of a positive TRBC, provocative tests utilizing anti-coagulants or vasodilators may be attempted. If after these attempts no site is localized on angiography, subtotal colectomy is recommended. If no active bleeding is evident clinically (< 4 unit transfusion over 24 hours), whole gut lavage should be performed, and colonoscopy should be carried out. If no lesion is identified on colonoscopy and the patient continues to actively bleed total abdominal colectomy is recommended. Patients who have > 3 unit blood transfusion requirement during a 24 hour period should be considered to be immediate surgical candidates.

Diagnostic algorithm.

Management of massive blood loss: a template guideline

The management of acute massive blood loss is considered and a template guideline is formulated, supported by a review of the key literature and current evidence. It is emphasized that, if avoidable deaths are to be prevented, surgeons, anaesthetists, haematologists and blood-bank staff need to communicate closely in order to achieve the goals of secure haemostasis, restoration of circulating volume, and effective management of blood component replacement.

Complications of major blood loss and massive transfusion may jeopardize the survival of patients from many specialties, and challenge haematological and blood transfusion resources.

Avoidable deaths of patients with major haemorrhage are well recognized,1 2 and locally agreed and/or speciality-specific guidelines3 are needed to ensure effective management. Current UK published guidelines4 5 6 are based on historical transfusion practice and are not easily referred to in an emergency situation. A symposium on massive transfusion was organized by the National Blood Service Northern Zone in December 1998 and was attended by anaesthetists, traumatologists, haematologists, nurses and blood-bank personnel. At the conclusion of the meeting, a number of key principles were agreed and, in consultation with delegates, a guideline document was produced and is now available in hospitals served by the Leeds, Liverpool, Manchester, Newcastle and Trent Blood Centres as a basis for local protocols.

The guideline is presented in this article (Table) as a simple template which may be modified to take into account local circumstances and displayed in clinical areas. The left-hand column of the template outlines the key steps or goals, the centre column adds procedural detail and the right-hand column provides additional advice and information.

Acute massive blood loss: template guideline

Table

Acute massive blood loss: template guideline

Goal	Procedure	Comments
Restore circulating volume	Insert wide bore peripheral cannulae	14 G or larger
	Give adequate volumes of warmed crystalloid, ?colloid,	Monitor central venous pressure
	blood	Blood loss is often underestimated
	Aim to maintain normal blood pressure and urine output	Refer to Advanced Trauma Life Support guidelines
	>30 ml h^–1	Keep patient warm
Contact key personnel	Clinician in charge	Nominated coordinator should take responsibility for
	Duty anaesthetist	communication and documentation
	Blood bank
	Duty haematologist
Arrest bleeding	Early surgical or obstetric intervention
	Interventional radiology
Request laboratory investigations	FBC, PT, APTT, fibrinogen; blood bank sample, biochemical profile, blood gases or pulse oximetry	Take samples at earliest opportunity as results may be affected by colloid infusion
	Ensure correct sample identity	Misidentification is commonest transfusion risk
	Repeat FBC, PT, APTT, fibrinogen every 4 h or after 1/3 blood volume replacement	May need to give components before results available
	Repeat after blood component infusion
Request suitable red cells	Un crossmatched group O Rh negative	Rh positive is acceptable if patient is male or
	In extreme emergency	postmenopausal female
	No more than 2 units
	Un crossmatched ABO group specific	Laboratory will complete cross match after issue
	When blood group known
	Fully cross matched	Further cross match not required after replacement of 1 blood volume (8–10 units)
	If irregular antibodies   present
	When time permits
	Use blood warmer and/or rapid infusion device.	Blood warmer indicated if flow rate >50 ml kg^–1  h^–1 in adult
	Employ blood salvage if available and appropriate	Salvage contraindicated if wound heavily contaminated
Request platelets	Allow for delivery time from blood centre	Target platelet count:
	Anticipate platelet count <50×10^9litre^–1 after 2 × blood volume replacement	>100×10^9 litre^–1 for multiple/CNS trauma or if platelet function abnormal
		>50×10^9 litre^–1 for other situations
Request FFP	Aim for PT and APTT <1.5× control mean	PT and APTT >1.5× control mean correlates with
(12–15 ml kg^–1 body weight=1 litre or 4 units for an adult)	Allow for 30 min thawing time	increased surgical bleeding
Request cryoprecipitate	Replace fibrinogen and factor VIII	Fibrinogen <0.5 strongly associated with microvascular
(1–1.5 packs/10 kg body weight)		bleeding
	Aim for fibrinogen >1.0 g litre^–1 Allow for delivery time plus 30 min thawing time	Fibrinogen deficiency develops early when plasma poor red blood cells used for replacement
Suspect DIC	Treat underlying cause if possible	Shock, hypothermia, acidosis leading to risk of DIC
		Mortality from DIC is high

The accompanying commentary is not intended to be an exhaustive review, but provides key references on which the recommendations are based.

The Hospital Transfusion Committee has a central role in ensuring the optimum and safe use of blood components. The development of protocols for the management of massive transfusion is an important part of the remit of such committees and it is hoped that this article will facilitate this process.

Previous SectionNext SectionCommentary

Background

Massive blood loss is usually defined as the loss of one blood volume within a 24 h period,7 normal blood volume being approximately 7% of ideal body weight in adults and 8–9% in children. Alternative definitions include 50% blood volume loss within 3 h or a rate of loss of 150 ml min–1.8 Such definitions emphasize the importance of the early recognition of major blood loss and the need for effective action to prevent shock and its consequences.

Priorities for treatment are:

• restoration of blood volume to maintain tissue perfusion and oxygenation;

• achieving haemostasis by:

  • treating any surgical source of bleeding;

  • correcting coagulopathy by the judicious use of blood component therapy.

A successful outcome requires prompt action and good communication between clinical specialties, diagnostic laboratories, blood-bank staff and the local blood centre. Blood component support takes time to organize and the blood centre may be up to 2 h away from the hospital.

Early consultation with surgical, anaesthetic and haematology colleagues is advisable, and the importance of good communication and cooperation in this situation cannot be overemphasized. A member of the clinical team should be nominated to act as the coordinator responsible for overall organization, liaison, communication and documentation. This is a critical role for a designated member of the permanent clinical staff. The Hospital Transfusion Committee should provide a forum in which a rapid communication cascade can be agreed and massive transfusion episodes reviewed.

Resuscitation

Prolonged oligaemic shock carries a high mortality rate because of organ failure and disseminated intravascular coagulation. Restoration of circulating volume is initially achieved by rapid infusion of crystalloid or colloid through large-bore (14 gauge or larger) peripheral cannulae.9 The use of albumin and non-albumin colloids versus crystalloids for volume replacement has recently been the subject of debate after two controversial meta-analyses,10 11 and the use of colloid is not recommended in the latest American College of Surgeons Advanced Trauma Life Support Guidelines.12 Further trials are required before firm recommendations can be made.

Red cell transfusion is likely to be required when 30–40% of blood volume is lost; the loss of over 40% of blood volume is immediately life-threatening.12 Hypothermia increases the risk of disseminated intravascular coagulation and other complications12 13 and may be prevented by prewarming the resuscitation fluids, patient-warming devices such as warm air blankets, and the use of temperature-controlled blood warmers.

Blood loss is usually underestimated, and it must be remembered that haemoglobin and haematocrit values do not fall for several hours after acute haemorrhage.9

For acutely anaemic patients, the American Society of Anesthesiologists Task Force on Blood Component Therapy has concluded, on the basis of the available evidence, that transfusion is rarely indicated when the haemoglobin concentration is >10 g dl–1 but is almost always indicated when it is <6 g dl–1.14 Determination of whether intermediate haemoglobin concentrations justify red cell transfusion should be based on the patient’s risk factors for complications of inadequate oxygenation, such as the rate of blood loss, cardiorespiratory reserve, oxygen consumption and atherosclerotic disease. Measured cardiological variables, such as heart rate, arterial pressure, pulmonary capillary wedge pressure and cardiac output, may assist the decision-making process, but it should be emphasized that silent ischaemia may occur in the presence of stable vital signs.

Intraoperative blood salvage may be of great value in reducing the requirement for allogeneic blood, but bacterial contamination of the wound is a relative contraindication.15

Investigations

Blood samples should be sent to the laboratory at the earliest possible opportunity for blood grouping, antibody screening and compatibility testing, as well as for baseline haematology, coagulation screening, including fibrinogen estimation and biochemistry investigations.

When dealing with an evolving process, it is important to check the parameters frequently (at least four-hourly and after each therapeutic intervention) to monitor the need for and the efficacy of component therapy.

Expert advice should be sought from a haematologist regarding appropriate investigations, their interpretation and the optimum corrective therapy.

Previous SectionNext SectionBlood component therapy

Red cells

In an extreme situation it may be necessary to use group O un-crossmatched red cells if the blood group is unknown. In an emergency, premenopausal females whose blood group is unknown should be given ORh(D) negative red cells in order to avoid sensitization and the risk of haemolytic disease of the newborn in subsequent pregnancy. It is acceptable to give ORh(D) positive cells to males and postmenopausal females of unknown blood group.16 Group-specific red cells should be given at the earliest possible opportunity as group O blood is a scarce resource.

It is important to bear in mind that most transfusion-related morbidity is due to incorrect blood being transfused.17 It is therefore essential that protocols are in place for the administration of blood and blood components18 and that these are adhered to even in an emergency situation.

All blood components supplied by the UK transfusion services are now leucodepleted and the blood bank will provide red cells in optimal additive solution, containing virtually no plasma, platelets or leucocytes. The benefits of leucodepletion include reduced non-haemolytic febrile transfusion reactions, reduced transmission of leucocyte-associated viruses, such as cytomegalovirus, and reduced immunosuppressive effects of transfusion. An additional microaggregate filter is not necessary.

Platelets

Expert consensus argues that platelets should not be allowed to fall below the critical level of 50×109 litre–1 in acutely bleeding patients.20 A higher target level of 100×109 litre–1 has been recommended for those with multiple high-energy trauma or central nervous system injury.21 22 Empirical platelet transfusion may be required when platelet function is abnormal, as is found after cardiopulmonary bypass.

A platelet count of 50×109 litre–1 is to be anticipated when approximately two blood volumes have been replaced by plasma-poor red cells,23 but there is marked individual variation. In assessing the requirement for platelets, frequent measurements are needed, and it may be necessary to request platelets from the blood centre at levels above the desired target in order to ensure their availability when needed.

Fresh frozen plasma (FFP) and cryoprecipitate

Most clinical studies and guidelines have been based on the use of whole blood or plasma-reduced red cells, which contain some residual coagulation factor activity. Nowadays, red cell replacement is likely to be in the form of plasma-poor red cells suspended in optimal additive solution, in which coagulation factor activity is negligible. Under these circumstances, coagulation factor deficiency is the primary cause of coagulopathy. The level of fibrinogen falls first; the critical level of 1.0 g litre–1 is likely to be reached after 150% blood loss, followed by decreases in other labile coagulation factors to 25% activity after 200% blood loss.23 Prolongation of activated partial thromboplastin time (APTT) and prothrombin time (PT) to 1.5 times the mean normal value is correlated with an increased risk of clinical coagulopathy24 and requires correction.

Laboratory tests of coagulation should be monitored frequently and interpreted with advice from a clinical haematologist; laboratories should have in place standard operating procedures to ensure that clinical staff are contacted appropriately. Experienced laboratory staff should be empowered to issue blood components in the first instance using a locally agreed algorithm. It may be necessary to request components before results are available, depending on the rate of bleeding and the laboratory turnaround time. Although ‘formula replacement’ with fresh plasma is not recommended, it has been suggested that infusion of FFP should be considered after one blood volume has been lost.25 The dose should be large enough to maintain coagulation factors well above the critical level, bearing in mind that the efficacy may be reduced because of rapid consumption.21 25

FFP alone, if given in sufficient quantity, will correct fibrinogen and most coagulation factor deficiencies, but large volumes may be required. If fibrinogen levels remain critically low (<1.0 g litre–1), cryoprecipitate therapy should be considered.21 25

The Guidelines on Oral Anticoagulation of the British Committee for Standards in Haematology recommend prothrombin complex concentrate as an alternative to FFP when major bleeding complicates anticoagulant overdose.26 It should be remembered, however, that these preparations are potentially thrombogenic and the role of specific coagulation factor concentrate outwith hereditary bleeding disorders is unproven.

Disseminated intravascular coagulation (DIC)

DIC is a feared complication in the acutely bleeding patient. It carries a considerable mortality rate, and once established it is difficult to reverse. At particular risk are: patients with prolonged hypoxia or hypovolaemia; patients with cerebral or extensive muscle damage; and patients who become hypothermic after infusion of cold resuscitation fluids. Laboratory evidence of DIC should be sought before microvascular bleeding becomes evident so that appropriate and aggressive action can be taken to address the underlying cause. Frequent estimation of platelet count, fibrinogen, PT and APTT is strongly recommended; measurement of fibrinogen degradation products or d-dimers may be useful. Prolongation of PT and APTT beyond that expected by dilution, together with significant thrombocytopenia and fibrinogen of <1.0 g litre–1, are highly suggestive of DIC.

Treatment consists of platelets, FFP and cryoprecipitate, given sooner rather than later, in sufficient dosage but avoiding circulatory overload.

Previous SectionNext SectionDiscussion

A guideline has been defined as ‘a systematically developed statement that assists in decision-making about appropriate health care for specific clinical situations’.27 Successful implementation will depend on local ownership by adaptation to local circumstances and accessibility at the point of clinical activity.

In developing this template guideline, we have examined such sound scientific evidence as is available, reviewed the relevant literature and professional consensus statements, and taken into account discussion and comment from contributors and delegates at the National Blood Service Northern Zone Symposium on Massive Transfusion.

The recommendations contained in these guidelines must be regarded as Grade C, based as they are on uncontrolled observational studies and a consensus of expert opinion (Level 3 evidence). Well-designed case–control studies and randomized clinical trials are lacking in this important area of transfusion medicine.

A recent cohort study shows a significantly improved survival rate in massively transfused patients over a 10-yr period and associates this with more effective and efficient rewarming techniques, aggressive resuscitation and component therapy, and improved blood-banking.

There is a need for further studies to clarify these issues and provide firm evidence on which future recommendations can be based.