Pediatric Critical Care Medicine:
Predisposition to Sepsis
Sepsis in pediatric burn patients
Sheridan, Robert L. MD
From the Department of Surgery, Division of Burns, Shriners Hospital for Children, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
This work was supported by the Mannion Family Fund—Center for the Critically Ill Child, Division of Critical Care Medicine at Children's Hospital Boston, the PALISI Network, and the ISF.
Objective: To review the specific infections common in pediatric burns, including their categorization, diagnosis, and treatment.
Design: Review of the literature and expert opinion.
Results: Children with serious burns are prone to a host of septic complications. This proclivity to infection is secondary to the immunosuppressive effect of burn injury, the loss of the skin and mucosal physical barriers, and the requirement for invasive support devices.
Conclusion: Sepsis is common in the pediatric burn patient and can markedly increase morbidity and mortality. Anticipation, prompt diagnosis of infection, and effective therapy can result in successful outcomes for many of these children.
Burn patients die for three main reasons: burn shock during the first few hours after injury, respiratory failure in the following days, and septic complications and organ failures during the subsequent weeks (1). Fluid resuscitation formulas, developed initially in the 1930s and 1940s (2, 3) and subsequently refined (4, 5), have markedly reduced the prevalence of death due to resuscitation failure (6). The development and refinement of techniques of positive-pressure ventilation have sharply reduced the prevalence of respiratory death (7, 8). Paradoxically, the reduced rates of early death from burn shock and respiratory failure have resulted in an increasing prevalence of infection as a cause of late mortality and morbidity in the burn unit (9, 10).
In times past, the dominant infection in burn units was found in the wounds themselves. However, since the wide adoption of early excision of deep wounds in the 1980s and 1990s, wound sepsis is much less frequent (11–13). As early burn excision and closure has reduced the incidence of burn-wound infection (14), the occurrence of other more complex infectious complications has increased. These infections not only cause direct morbidity and mortality, but even when successfully treated, they may trigger systemic inflammation and organ failures (10, 15). Infection is the single biggest killer in the burn unit (16).
Existing incidence data for pediatric burn infections, although scanty and compromised by variability in definitions and reporting, seems to suggest that specific infection rates in children hospitalized for burns at the present time are higher than in critically ill nonburn patients. Infection rates are similar to other immunocompromised groups and include: (1) central catheter infection rate of 4.9/1000 central venous catheter days, (2) burn-wound infection rate of 5.6/1000 patient days, (3) ventilator-related pneumonia rate of 11.4/1000 ventilator days, and (4) urinary catheter-related urinary tract infection rate of 13.2/1000 urinary catheter days (17). Burn unit-based infection surveillance programs can help to decrease the rate of infection in these children (18) and should be a part of all organized burn programs.
Pathogenesis of Infection
Serious burns render children markedly susceptible to a variety of infectious complications (19, 20). Both local and systemic factors contribute to this susceptibility. Local factors include the open wounds, an incompetent gut barrier, and exposure of the globe, bones, cartilage, and joints. As long as wounds are open, underlying tissues are at risk of contamination and infection (21). The invasive devices required to support these children also add new potential portals of entry for infection. Central venous and arterial catheters, endotracheal tubes, bladder catheters, and transnasal tubes all increase the exposure of injured children to potential infection. These critically important tools should be promptly discontinued when they are no longer needed. Prompt and effective wound excision and closure will decrease the child's dependence on invasive devices.
Systemic factors are also important contributors to the increased susceptibility to infection. There is a well-documented global decrease in cellular immune function associated with burns (22–24). Neutropenia is common, neutrophil function is depressed (25), and T-cell transcription is altered (22). Increased gut permeability has been documented (26, 27). Burn patients experience occult bacteremia with wound manipulations (28, 29). Data suggest that excessive transfusion of blood products may exacerbate global immunosuppression (30). In ways that are not yet understood, these factors combine to result in an increased susceptibility to infection (31).
Prevention of Infection
Quick and effective closure of deep burns is the cornerstone of infection prevention. Other methods include prophylactic antibiotics, topical antimicrobial agents, and infection control practices.
Prophylactic antimicrobials have been used in burn patients in four settings: 1) antistreptococcal drugs to prevent burn-wound cellulitis, 2) oral and enteral administration of antifungal agents to prevent candidiasis or antibiotics to prevent bacterial infection, 3) perioperative administration of antibiotics, and (4) broad-spectrum antibiotics pending return of culture information in febrile or hypotensive patients.
Before early excision and closure of deep wounds was common practice, group A streptococcal burn-wound cellulitis was common and was often fatal. This prompted routine administration of penicillin to burn patients. However, this practice was associated with its own set of problems and expense (32) without data to support its efficacy. In a recent study of 917 children admitted for burn care during a 6-yr interval, it was documented that group A streptococcal infection was infrequent and was not further reduced by prophylactic penicillin as long as those who had group A streptococcal at admission or on surveillance cultures were treated (33). This is no longer part of the general standard of care.
Oral and enteral administration of antifungal agents to prevent candidiasis (34) or of antibiotics to decontaminate the gut (35–37) has been periodically recommended, although neither practice is part of the standard of care. Available data suggest that enteral antifungals are not effective in reducing the prevalence of fungal infection (38). Selective decontamination of the gut has not been adopted, either, because data simply are not sufficient to support the practice, and generation of resistant organisms is feared (39).
Perioperative antibiotics are commonly administered to decrease the prevalence of graft or donor-site infection, although there are no data to support the efficacy of this practice (40). In acute burns, antibiotics are chosen to suppress the known or suspected wound flora. It has been well documented that burn-surgery wound manipulations are associated with a substantial rate of bacteremia (41, 42), and perioperative antibiotics may protect against intravascular catheter contamination.
Prophylactic antimicrobials are commonly administered to the febrile or hypotensive child in the burn unit. However, children with significant burns are commonly febrile in the absence of infection (43), and overuse of broad-spectrum antibiotics may be harmful. The newly febrile child in the burn unit should have a careful history and physical examination. Intravascular catheter sites should be evaluated. Often, this will bring to light a potential or actual focus on occult infection. Cultures of blood, urine, sputum, and wounds should be sent. If the child is toxic, with significant change in mental status, hypotension, thrombocytopenia, neutropenia, or new leukocytosis, it is not unreasonable to administer broad-spectrum antibiotics pending return of culture information. If no infectious focus is identified, these can be stopped in 48 or 72 hrs. Overuse of broad-spectrum antibiotics may generate resistant organisms, and this tendency should be resisted.
A wide variety of topical antimicrobials are commonly applied to burn wounds. The general objectives are: 1) to decrease water vapor loss, 2) to prevent desiccation of exposed viable tissues, 3) to contribute to pain control, and 4) to inhibit bacterial and fungal growth. Periodic gentle cleaning of wounds to remove accumulated topical agent and wound exudate seems important. This can generally be done using light sedation at the bedside. Immersion hydrotherapy has been traced as a source of cross-infection and is less commonly used (44). Silver sulfadiazine is the most common topical in general use. It is an opaque, white cream that is painless on application, has fair to poor eschar penetration, has no metabolic side effects, and has a broad antibacterial spectrum. Mafenide acetate is painful on application and a carbonic anhydrase inhibitor, but it penetrates eschar and has a broad antibacterial spectrum. Aqueous 0.5% silver nitrate is also painless on application, but it has poor eschar penetration and leeches electrolytes. However, it has a broad spectrum of activity (including fungi) and can be used on adjacent wounds, grafts, and donor sites. Superficial burns can be treated with a number of occlusive, viscous antibiotic ointments.
A number of temporary membranes are available for use on superficial wounds or donor sites to decrease infection and facilitate comfort (45). Among them are fresh or reconstituted porcine xenograft, synthetic bilaminates, hydrofibers, semipermeable membranes, hydrocolloid dressings, and human allograft. Some of these membranes are impregnated with silver to reduce bacterial and fungal growth. All are useful in the management of selected wounds. When using wound membranes, it is essential that the wounds be regularly evaluated, as an occlusive dressing over eschar can lead to enclosed infection and serious problems (46). An increasing variety of other topical antimicrobials and membranes exist. All have advantages and disadvantages, making them useful in specific clinical situations. Regardless of the specific topical agent used, regular assessment of all wounds for early signs of infection is essential.
Burns are tetanus-prone wounds. If immune status is questionable, children should undergo active immunization with tetanus toxoid. If children have not been immunized, or their tetanus immune status is unknown, both active with tetanus toxoid and passive immunization with tetanus hyperimmune globulin is appropriate. This is particularly true if burns are extensive, deep, or heavily contaminated.
Infection control programs play an important role in infection prevention (47). The primary objectives of these programs include: 1) protection of patients and staff from resistant bacterial species (48), 2) surveillance of patients and the environment, 3) education of staff and family members, 4) monitoring staff performance of universal precautions, and 5) identifying and eliminating potential sources of cross-infection (49). These programs have been shown to be highly effective in reducing the spread of resistant species (50, 51).
Diagnosis and Management of Bacterial Infections
Most infections in burned children are bacterial. Infections can be very subtle and diagnosis elusive in this setting. Localizing signs are commonly obscured by wounds, operative sites, dressings, wound-associated fever, and drug-induced analgesia. A high index of suspicion and very careful history and physical examination are essential. Virtually all burn patients are febrile. Injudicious use of antibiotics may facilitate emergence of resistant bacterial strains or fungi that can be very difficult to treat. Also, the pharmacokinetics of many antibiotics, particularly the aminoglycosides, are altered in burned children (52), so dose adjustment based on serum levels is often necessary.
Wound sepsis was a very common cause of death before the wide introduction of early wound excision (53). Although much less common today, it remains a serious threat and is regularly seen. The most common organisms are Staphylococcus aureus and Pseudomonas aeruginosa. Vaccination against the latter organism has been explored (54, 55) but has not been widely used because early identification, excision, and closure of wounds is more effective (56). A variety of classification schemes have been used for burn-wound infections. A recently developed set of clinically focused definitions, including 1) “burn impetigo” or superficial infection with loss of epithelium, 2) open burn-related surgical wound infection, 3) burn-wound cellulitis, and 4) invasive burn-wound infection, will be used here (Table 1) (57). Like impetigo in unburned skin, burn impetigo is usually associated with S. aureus or Streptococcus pyogenes. Often, only S. aureus is isolated. This is particularly common in burns of the scalp. Treatment requires wound cleansing, which often mandates shaving of nearby hair-bearing areas. Topical treatment with antistaphylococcal medications, such a mupirocin (58), is generally sufficient, although systemic treatment may be required in some cases. On occasion, skin grafting of denuded areas is required for healing to occur.
Open burn-related surgical wound infection describes purulent infection that develops in excised wounds and donor sites. These infections usually drain fluid containing white cells and are commonly associated with systemic toxicity, such as fever and hypotension, and loss of skin grafts. In many situations, these infections are associated with inadequately excised wounds, the unexcised necrotic skin and subcutaneous tissue being the nidus of infection. Treatment requires debridement of necrotic and infected material with delayed wound closure. Staphylococcal toxic shock syndrome has been reported in children with superficial burns and donor sites and is a risk, particularly when occlusive dressings are employed over deep burns in young children (46).
Burn-wound cellulitis (Fig. 1) refers to spreading dermal infection in uninjured skin around a burn wound or donor site. This can vary from an early subtle erythema a centimeter or so around the wound to a brawny erythema involving an entire limb or torso. It is often asymmetric in pattern, and it is usually difficult to recover an organism from wound swabs or dermal aspirates because infection typically spreads in dermal lymphatics of unburned skin around the wound. This is most commonly seen in the first few days after a burn or as a postoperative donor-site complication (59). In the past, prevention of such infections was a principal reason for the administration of prophylactic penicillin. When deep burns undergo prompt excision and closure, this should infrequently occur (60). Burn cellulitis is commonly caused by S. pyogenes, and the diagnosis is usually based on clinical examination.
Invasive burn-wound infection (Fig. 2) is a clear threat to life. Children with invasive burn-wound infection are systematically toxic with high fever and a hyperdynamic circulatory state. Subsequently, bacteremia, hypotension, and cardiovascular collapse occur (48). There has been a great deal of controversy over how a diagnosis of invasive burn-wound infection is appropriately established. Three methods have been advocated by various authors: 1) clinical examination (61), 2) quantitative cultures of a burn-wound biopsy (60), and 3) burn-wound histology (62). Clinical signs of invasive infection include a change in the appearance of the wound in the setting of a toxic patient. Typical changes include punctate hemorrhage, change in color, new drainage, and rapidly progressive liquefaction. Quantitative cultures require a 1-g specimen of eschar, which is homogenized and cultured. If >105 colony-forming units per gram of tissue are cultured, infection is diagnosed. Histologic diagnosis of infection can be done by frozen or permanent section, the latter being perhaps more accurate. A grading system has been reported (62), with a diagnosis of invasive infection supported by bacteria invading viable tissue. Both quantitative culture and histologic examination are subject to sampling error and can cause clinical delays in treatment. When compared with burn-wound biopsy, quantitative cultures have been demonstrated to overdiagnose infection (63). From a practical perspective, clinical diagnosis of these infections suffices for the vast majority of situations.
Prompt treatment of invasive burn-wound infection is essential because these are life-threatening events. Although subeschar infiltration of antibiotics has been advocated (64), most of these infections are best managed with parenteral antibiotics, resuscitation from septic shock, and wound excision and closure (65). Heavily contaminated wounds, particularly in septic patients, are often more appropriately allografted and later autografted. On occasion, unusual organisms related to the mechanism of injury will cause invasive infection. In these circumstances, knowledge of the likely organisms based on history and surveillance cultures can guide effective antibiotic therapy. An example is early wound infection with waterborne organisms, such as Aeromonas or Flavobacteria, when burns are extinguished with contaminated water (66, 67).
The supporting cartilage of the ear is almost avascular and is therefore highly susceptible to infection when the overlying delicate skin is deeply burned. Auricular chondritis presents with pain, fever, and rapidly progressive edema of the ear and is followed by liquefaction of the cartilage. This sequence of events can be effectively prevented with topical mafenide acetate. This agent has a broad antibacterial spectrum and readily penetrates eschar (68). When established, auricular chondritis requires operative debridement of infected, liquefying cartilage.
Sinusitis and otitis media are complications of transnasal gastric and endotracheal tubes. The tubes, or secondary mucosal edema, obstruct the eustachian tubes or sinus orifices. Diagnosis can be difficult in the critically ill child who will not complain of ear or sinus pain. A high index of suspicion and regular examination, supplemented by radiographs and sinus aspiration, will allow the diagnosis to be made. Treatment requires moving the offending tubes, if possible, out of the nares. Topical decongestants, antibiotics, and occasionally, surgical drainage of infected closed spaces are important ancillary treatments.
The avascular corneal stroma is protected from invading bacteria only by a fragile layer of corneal epithelium. If this thin protective layer is damaged by direct thermal injury, chemical burn, or ectropion and desiccation, the underlying cornea can quickly become infected with disastrous results. Corneal exposure and infection can cause permanent scarring only repairable with corneal transplantation. Infected corneal ulcers can perforate and result in herniation of the lens and loss of the eye (Fig. 3) (69). These complications are best avoided by early and ongoing examination of the eye. Direct corneal burns are treated with vigilant eye lubrication using topical ophthalmic antibiotic ointments applied every 2 to 4 hrs. Globe exposure secondary to progressive contracture of burned eyelids and facial skin is managed with acute eyelid release (Fig. 4).
Children who have serious burns are at high risk for pulmonary infections for several reasons (70), and this causes significant morbidity and mortality in burn units (71). Children with inhalation injury demonstrate loss of ciliary clearance from necrosis of respiratory epithelium and small airway obstruction from sloughed endobronchial debris. Children requiring endotracheal intubation have the upper airway protective mechanisms compromised. Hematogenous seeding of the lungs can occur from wound or other infectious foci.
There are two common types of pulmonary infection seen: pneumonia and tracheobronchitis. Pneumonia or tracheobronchitis occurs in up to 35% of those with inhalation injury. A diagnosis of pulmonary infection is made when the child develops a fever, a change in quantity and character of sputum, a Gram stain revealing abundant polymorphonuclear leukocytes and bacteria, and a sputum culture revealing a dominant organism. If the chest radiograph is consistent with a diffuse or lobar process, the diagnosis of pneumonia is made. If there are no such radiographic abnormalities, purulent tracheobronchitis is the likely diagnosis. Although bronchoscopy can be used to support a diagnosis of tracheobronchitis, bronchoalveolar lavage and protected brush specimens are of no established utility (72). Treatment consists of antibiotics directed by the sensitivities of recovered organisms and pulmonary toilet. Pulmonary toilet, regular suctioning of endobronchial secretions, is of particular value given the common loss of native clearance mechanisms secondary to necrosis of respiratory epithelium in those with inhalation injury with consequent loss of ciliary clearance. Toilet bronchoscopy can be useful in older children.
Chest tubes in children with chest wall burns can lead to empyema if the tube must be placed through a wound. Chest tubes should be removed as soon as practical. It goes without saying that subclavian catheter placement in such children carries added hazard because a complicating hemopneumothorax may require chest tube placement through eschar. In this setting, subclavian catheterization should be done by experienced people with great care. If empyema is established, treatment is surgical if antibiotics and drainage fail.
Endovascular infections are uncommon but cause significant morbidity and mortality when they arise. Before the wide use of central venous catheters in the critically ill, suppurative peripheral vein thrombophlebitis was a common cause of systemic sepsis. The use of percutaneous central venous catheters has reduced this complication. Endovascular infections generally present with fever and bacteremia in the absence of localizing signs of infection. Both diagnosis and therapy can be very difficult. Septic peripheral thrombophlebitis is diagnosed by careful examination of all sites of previous cannulation and treated by excision of the thrombosed purulent vein to normal vein. Septic central thrombophlebitis can be diagnosed by physical examination and imaging studies such as ultrasound. Treatment of central septic phlebitis requires prolonged antibiotic therapy and systemic anticoagulation, when safe in light of potential bleeding from burn wounds. Cardiac valvular endocarditis is diagnosed by cardiac ultrasound. Endocarditis may occur more frequently in children with pulmonary arterial catheters (73). Endocarditis is treated with protracted antibiotic courses and, in selected cases, valve replacement.
Central venous catheter sepsis is the most common endovascular infection in the burn unit, presenting with bacteremia and fever. It is diagnosed by examination of the catheter site, peripheral blood culture, and semiquantitative culture of the catheter tip. Treatment requires catheter removal and antibiotics. Scheduled rotation of central vein catheters may reduce the prevalence of this infection (74). Although prophylactic catheter rotation policies remain controversial (75), they are probably effective in high-risk populations (76). A policy including weekly central venous catheter rotation is associated with a rate of catheter sepsis of about 10% (74, 77). Arterial catheters rarely become infected (75), probably because of the high flow rates around the catheters.
On occasion, serious intraabdominal infections will arise in burn patients, often presenting an occult focus on sepsis. Acute cholecystitis can occur in older children and adolescents, particularly if protracted periods pass without enteral nutrition. This presents with fever, cholestatic chemistries, and often no localizing signs in obtunded patients. It can mimic sepsis-induced cholestatic liver dysfunction. Diagnosis is made by bedside ultrasound. Treatment can be by percutaneous transhepatic drainage (78) or surgery with adjunctive antibiotics. Acute pancreatitis can complicate severe burns and is managed with bowel rest. Secondary pancreatic abscess may require percutaneous drainage or surgery, with adjunctive antibiotics (79). Appendicitis is seen with some regularity in the burn unit, and this diagnosis can be difficult to make in the heavily sedated child. A high index of suspicion and liberal use of imaging are useful.
Splanchnic ischemia occurs in critically ill children and can be followed by peritonitis in severe cases (80). Diagnosis is by examination and radiography, and treatment is surgical. Thankfully this is a rare problem in the well-resuscitated child. Clostridium difficile colitis presents with fever and diarrhea. Diagnosis is by clinical picture and C. difficile stool titer. Treatment is enteral vancomycin or metronidazole, the latter being less expensive and equally effective. Gastrointestinal permeability increases with inadequate splanchnic perfusion, burn size, and infection (27) and is likely related to splanchnic ischemia caused by inadequate resuscitation. Translocation may contribute to the inflammatory state and may be the cause of overt infection.
Intracompartmental sepsis can follow missed or occult compartment syndromes with subsequent hematogenous seeding of necrotic muscle (81). It is not difficult to miss an evolving compartment syndrome early in the course of a large burn because most of the signs are obscured in the obtunded child. Diagnosis requires a high index of suspicion, serial physical examination, and liberal surgical exploration. Compartment pressure measurement can supplement diagnosis in selected children. Treatment is surgical, and many such limbs can be salvaged (Fig. 5).
Suppurative costal chondritis and osteomyelitis can occur when bone or costal cartilage is exposed and becomes desiccated and superinfected. Diagnosis is by examination and radiography; bone scans can be overly sensitive. Treatment is by debridement of necrotic tissue with adjunctive antibiotics. Intraarticular sepsis can occur over deeply burned major joints. Diagnosis is by examination. Treatment requires drainage and antibiotic administration.
Abscesses can develop beneath hypertrophic scars in the later phase of recovery in some patients, presenting with fever and minor local tenderness. Frequently, the thickness and stiffness of the tissue makes it a surprisingly difficult diagnosis. Treatment is by surgical exploration, drainage, and often, excision, release, and grafting.
Diagnosis and Management of Nonbacterial Infections
The large majority of infectious complications in burned children are bacterial. However, there are some important viral and fungal infections that are seen regularly. These infections are less frequently lethal but cause significant morbidity and occasional mortality.
Burn patients have reduced cellular immune function (24, 82), and viral infections are more common in burned children than is generally appreciated (83, 84). Herpes simplex virus, cytomegalovirus, and varicella are of particular importance. Herpes simplex virus tracheobronchitis, pneumonia (85, 86), and wound infection have been reported in burned children (87–89) (Fig. 6). Specific defects in the processing of herpes virus by the immune system have been described after thermal injury (90, 91). Reactivation of latent herpetic infection commonly causes rapidly progressive perioral and intraoral lesions (92). Morbidity from cytomegalovirus infection in burn units is extremely rare, despite the relative infrequency of cytomegalovirus immunity in young children and the common use of blood transfusions. Human allograft is a potential source of cytomegalovirus transmission, but infection is essentially nonexistent in clinical practice (93).
Varicella pneumonitis can be particularly virulent in immunocompromised burned children (51), although wound-related morbidity is rare. Prophylactic acyclovir or varicella zoster immune globulin may be appropriate in recently exposed children with serious injuries. Exposed children should be placed in strict isolation to prevent cross-infection in other susceptible children during the incubation period.
Candida and Aspergillus are the dominant pathogens in this setting. They do not seem to carry a higher mortality, in themselves, than the bacterial infections that so often occur simultaneously. Candidemia is seen particularly in the setting of prolonged exposure to broad-spectrum antibiotics in the face of heavily colonized open wounds (38). Wound closure and avoidance of injudicious broad-spectrum antibiotic use will minimize the occurrence of candida infection. Prophylactic enteral administration of antifungal agents has been used to reduce the prevalence of this complication (34), but this is not in general use, as data do not consistently support the effectiveness of the practice (38). Treatment requires administration of systemic antifungal agents and the eradication of the source, when possible. Infected wounds should be excised and closed (65, 94), and infected catheters should be removed.
When in the wound, Aspergillus causes discreet areas of indolent, burrowing wound invasion (95). Pulmonary aspergillus infections are usually seen only in very compromised patients (96). Wound infections are best managed with excision and with topical and systemic antifungal agents. Pulmonary infection is treated with pulmonary toilet and systemic antifungal agents.
Infection remains the largest single cause of morbidity and mortality in acutely burned children (21). Anticipation of the common burn-related infections facilitates early and more effective treatment. If infection can be controlled and wounds closed, most seriously burned children will have very satisfying outcomes (97, 98).
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burns; infection; sepsis; pneumonia; critical illness; multiple organ failure
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