Re-evaluation of Sudden Death in Wiskott-Aldrich Syndrome: Forensically Problems in Distinguishing Natural Hemorrhage Versus Trauma, Surge of Intracranial Pressure After Vomiting and Putting Forward a Hypothesis of Hemorrhage Threshold to Perfect Elucidation of Murders in Pediatric Hemology.

We report the case of a 10-month-old male infant diagnosed with Wiskott-Aldrich syndrome, who was brought to our medico-legal postmortem center after being declared dead. The external examination and autopsy findings, considering both pathological and medico-legal aspects, are discussed in light of the limited literature on this subject. This case highlights the importance of differentiating natural lesions from traumatic and accidental causes.

After completing this article, readers should be able to: Staphylococci are hardy aerobic bacteria that are present in the environment and as normal flora of humans and animals. They are resistant to heat and drying and may be recovered from the environment months after contamination. These organisms are gram-positive cocci that grow in characteristic grapelike clusters. Staphylococci are distinguished from streptococci by a positive catalase (H2O2) test. Species are classified as Staphylococcus aureus if they are coagulase-positive or as one of many species of coagulase-negative staphylococci (eg, S epidermidis, S saprophyticus). S aureus is the most common cause of pyogenic infection of the skin; it also may cause osteomyelitis, septic arthritis, wound infection, abscess, pneumonia, empyema, endocarditis, pericarditis, meningitis, and toxin-mediated diseases, including food poisoning, staphylococcal scarlet fever, scalded skin syndrome, and toxic shock syndrome (TSS). Coagulase-negative staphylococci tend to be less pathogenic unless a foreign body (eg, intravascular catheter) is present.Many neonates are colonized with S aureus within the first postnatal week. Thereafter, up to 50% of healthy individuals carry at least one strain of S aureus in the anterior nares at any given time. The organisms may be transmitted from the nose to the skin, where colonization seems to be more transient. Persistent umbilical perianal and vaginal carriage has been described. S aureus generally is transmitted by direct contact, primarily on the hands. Autoinfection is common. Handwashing by caretakers between contacts with patients decreases the spread of staphylococci from patient to patient. Many different strains of S aureus are capable of causing a wide variety of diseases (Fig. 1); these strains, and the diseases they commonly cause, may change in a community over time.Strains of S aureus are identified best by the virulence factors they produce (Fig. 1). These factors have four different roles: protecting the organism from host defenses, localizing infection, causing local tissue damage, and acting as toxins affecting noninfected tissue sites.Many staphylococci produce a loose polysaccharide capsule, or slime layer, that may interfere with phagocytosis. Coagulase causes plasma to clot by interacting with fibrinogen, which may play an important role in localization of infection (ie, abscess formation) –a hallmark of S aureus infection. Clumping factor interacts with fibrinogen to cause the formation of large clumps of organism that interfere with effective phagocytosis. Production of coagulase and clumping factor differentiates S aureus from S epidermidis and other coagulase-negative staphylococci. Another important enzyme elaborated by staphylococci is penicillinase (or beta-lactamase), which inactivates penicillin.Many strains of S aureus produce substances that destroy local tissue. A number of immunologically distinct hemolysins have been identified. Alpha-toxin acts on cell membranes and causes tissue necrosis. Panton-Valentine leukocidin, which is produced by some virulent strains of S aureus, combines with the phospholipid of the phagocytic cell membrane, producing increased permeability, leakage of protein, and eventual death of the neutrophil and macrophage.Many strains of S aureus release exotoxins. Exfoliatin A and B are two serologically distinct proteins that produce skin separation by splitting the desmosome and altering the intracellular matrix in the stratum granulosum, resulting in localized (eg, bullous impetigo) or generalized (eg, scalded skin syndrome, staphylococcal scarlet fever) rashes (Fig. 2). One or more staphylococcal enterotoxins (types A, B, C1, C2, D, E) are elaborated by most strains of S aureus. Ingestion of preformed enterotoxin is associated with vomiting and diarrhea and is a principal cause of food poisoning. Toxic shock syndrome toxin-1 (TSST-1) is associated with TSS related to menstruation and focal staphylococcal infection. TSST-1 induces production of interleukin-1 and tumor necrosis factor, resulting in hypotension, fever, and multisystem involvement. Enterotoxin A and enterotoxin B also may be associated with nonmenstrual TSS. Epidemiologic and in vitro studies suggest that these toxins are produced selectively in the clinical environment commonly found in abscesses and in the vagina with tampon use during menstruation. The risk factors for symptomatic disease require a nonimmune host colonized with a toxin-producing organism that is exposed to focal growth conditions (eg, menstruation plus tampon use or abscess), which induce toxin production.The development of staphylococcal disease is related to resistance of the host to infection and to the virulence of the organism. The intact skin and mucous membranes serve as barriers to invasion by staphylococci. Defects in the mucocutaneous barriers produced by trauma, surgery, foreign surfaces (eg, sutures, shunts, intravascular catheters), and burns increase the risk of infection.Infants may acquire type-specific humoral immunity to staphylococci transplacentally. Antibody to the various S aureus toxins appears to protect against those specific toxin-mediated diseases but not necessarily focal or disseminated S aureus infection with the same organisms.Individuals who have congenital defects in chemotaxis (Job, Chédiak-Higashi, and Wiskott-Aldrich syndromes), defective phagocytosis, and defective humoral immunity (antibodies required for opsonization) are at increased risk of infection with staphylococci. Patients who have chronic granulomatous disease, in which phagocytosis proceeds normally but killing of ingested catalase-positive bacteria is severely impaired, are particularly susceptible to staphylococcal disease. Local host defense compromise (eg, surgical wound, cystic fibrosis) often is complicated by S aureus infection.S aureus is identified by its growth on blood agar and a positive catalase and coagulase test. Antibiotic susceptibility testing has become increasingly important. In the past, most strains were resistant to penicillin but susceptible to methicillin and the cephalosporins and termed methicillin-susceptible S aureus (MSSA). An increasing number have acquired the mecA gene that alters beta-lactam antibiotic binding to the staphylococcal cell wall, causing them to become methicillin (and cephalosporin)- resistant S aureus (MRSA). For many years, MRSA strains were seen primarily in hospitals and often were resistant to other antibiotics. Rare resistance to vancomycin also has been reported. In the past few years, community-associated methicillin-resistant S aureus (CA-MRSA) strains have become more common. In some locales, these strains remained susceptible to clindamycin and trimethoprim-sulfamethoxazole, but erythromycin-induced clindamycin resistance has become increasingly common. Most strains continue to be susceptible to trimethoprim-sulfamethoxazole.The signs and symptoms of S aureus infection vary with the specific strain and the location of the infection, which although located most commonly on the skin, may involve any tissue (Fig. 1). The classic manifestation of staphylococcal infection is a localized abscess. Disease states of various degrees of severity generally result from local tissue injury, systemic dissemination with metastatic infection, or systemic effects of toxin production. Although the nasopharynx may be colonized with S aureus, disease due to this organism is relatively uncommon. Lesions, especially those of the skin, are considerably more prevalent among persons living in low socioeconomic circumstances and particularly among those in tropical climates.Pyogenic skin infections may be primary or due to wound infection with S aureus. S aureus infection is the most common cause of both crusted impetigo and bullous impetigo. S aureus, group A streptococci, or both may cause crusted impetigo. Bullous impetigo commonly occurs in the diaper area and is due to exfoliatin-producing S aureus strains that cause bullae in locally infected lesions (see scalded skin syndrome). Folliculitis, hydradenitis, furuncles (boils), carbuncles, and wound infections are all different manifestations of localized infections caused by S aureus. Recently, necrotizing fasciitis has been described associated with CA-MRSA.Infections of the upper respiratory tract due to S aureus are uncommon, considering the frequency with which this area is colonized. Otitis media and sinusitis due to S aureus occasionally may occur. Staphylococcal tonsillopharyngitis is rare in otherwise healthy children. Unilateral cervical lymphadenitis is caused commonly by S aureus, especially in young children. A membranous tracheitis that complicates viral croup may be infected with S aureus but also by other organisms. Treatment requires antibiotics and careful airway management.Staphylococci may cause a necrotizing pneumonitis with empyema. Pneumatoceles, pyopneumothorax, and bronchopleural fistulas develop frequently. Hematogenous pneumonia may be due to septic emboli, right-sided endocarditis, or the presence of infected intravascular devices.A localized staphylococcal abscess in muscle associated with elevation of muscle enzyme concentrations but without septicemia has been called tropical pyomyositis. Although this disorder has been reported most frequently from tropical areas, it also has occurred in the United States in otherwise healthy children. Multiple abscesses occur in 30% to 40% of cases. Surgical drainage and appropriate antibiotic therapy are essential.Meningitis due to S aureus is not common; it is associated with cranial trauma and neurosurgical procedures (eg, craniotomy, cerebrospinal fluid shunt placement) and, less frequently, with endocarditis, parameningeal foci (eg, epidural or brain abscess), diabetes mellitus, or malignancy. Coagulase-negative Staphylococcus (CONS) is not ordinarily as virulent as S aureus, but it has a high affinity for attaching to foreign materials and is the most common cause of shunt-related infections.Acute bacterial endocarditis may follow staphylococcal bacteremia. S aureus is a common cause of acute endocarditis on native valves. Perforation of heart valves, myocardial abscesses, heart failure, conduction disturbances, acute hemopericardium, purulent pericarditis, and sudden death may ensue. CONS is a frequent cause of endocarditis affecting prosthetic heart valves.S aureus is a common cause of renal and perinephric abscess, usually of hematogenous origin. Urinary tract infection due to S aureus is unusual but more commonly may be caused in males by S saprophyticus.Staphylococcal bacteremia may be associated with any localized infection (Fig. 1). The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Organisms may localize subsequently at any site but are found especially in the lungs, heart, joints, bones, kidneys, and brain. S aureus is the most common cause of osteomyelitis and suppurative arthritis in children.In some instances, especially in young adolescent males, disseminated staphylococcal disease occurs, characterized by fever, persistent bacteremia despite antibiotics, and focal involvement of two or more separate tissue sites (eg, skin, bone, joint, kidney, lung, liver, heart). Endocarditis and septic thrombophlebitis must be ruled out.TSS is an acute multisystem disease characterized by high fever, hypotension, vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, strawberry tongue, and an erythematous rash with subsequent desquamation on the hands and feet (TableT1). Many cases occur in menstruating women 15 to 25 years of age who use tampons or other vaginal devices (eg, diaphragm, contraceptive sponge) in the presence of vaginal colonization or infection with TSST-1-producing strains of S aureus. TSS, however, also occurs in children, nonmenstruating women, and men. Nonmenstrual TSS has been associated with wound infection, nasal packing, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia.Complications include acute respiratory distress syndrome, myocardial failure, and renal failure and are commensurate with the degree of shock. Recovery occurs within 7 to 10 days and is associated with desquamation, particularly of palms and soles. Hair and nail loss also have been observed after 1 to 2 months. Many cases of apparent scarlet fever without shock may be caused by TSST-1-producing S aureus strains.Group A Streptococcus can cause a similar TSS-like illness, termed streptococcal TSS, which often is associated with streptococcal bacteremia or a focal streptococcal infection such as necrotizing fasciitis or pneumonia.Staphylococcal scalded skin syndrome represents a spectrum of clinical entities mediated by exfoliatin-producing S aureus strains (Fig. 2). Patients who do not have antibody to the toxin develop generalized disease due to hematogenous dissemination of the toxin. The rash is characterized by a painful erythroderma with a positive Nikolsky sign, but signs are more severe in newborns (Ritter disease) and milder in older children (staphylococcal scarlet fever).Food poisoning may be caused by ingestion of enterotoxins that are preformed by staphylococci contaminating foods. Sudden, severe vomiting begins approximately 2 to 7 hours after ingestion of the toxin. Watery diarrhea may develop, but fever is absent or low. Symptoms rarely persist longer than 12 to 24 hours. Rarely, shock and death may occur.The diagnosis of staphylococcal infection depends on isolation of the organisms from normally noncolonized sites, such as skin lesions, abscess cavities, blood, or other sites of infection. Isolation from the nose or skin does not necessarily imply causation because these are normally colonized sites. The organisms can be grown readily on solid media. After isolation, identification is made on the basis of Gram stain and catalase, coagulase, or clumping factor reactivity. Patterns of susceptibility to antibiotics should be assessed in serious cases because resistance to penicillin is common and resistance to the penicillinase-resistant beta-lactam antibiotics is increasing (MRSA).The increasing resistance of S aureus to multiple antimicrobials both in the hospital and the community and another common cause of soft-tissue or toxin-mediated infection (group A Streptococcus) being resistant to trimethoprim-sulfamethoxazole make it imperative to initiate antimicrobial therapy likely to be effective for both organisms in serious infections (eg, sepsis, endocarditis, TSS, necrotizing fasciitis). The combination of vancomycin with the addition of clindamycin for toxin-mediated disease is a reasonable choice for such infections because clindamycin has been shown to reduce TSST-1 production by 90% in culture. Rare vancomycin-resistant strains of both S aureus and enterococci have been reported mostly in patients being treated with vancomycin. Vancomycin should be continued only in children who have proven MRSA infections. Linezolid and quinupristin-dalfopristin may be useful for serious S aureus infections highly resistant to other antibiotics. The combination of nafcillin (or vancomycin), gentamicin, and rifampin has been recommended for the initial treatment of S aureus endocarditis.The antibiotic used, as well as the dose, route, and duration of treatment, depend on the site of infection, the response of the patient to treatment, and the susceptibility of the organisms recovered from blood or local sites of infection. Appropriate cultures always should be obtained so the causative organism can be identified and susceptibility testing performed to optimize therapeutic decisions. Antibiotic therapy alone rarely is effective for individuals who have undrained abscesses or infected foreign bodies. Loculated collections of purulent material should be drained. Foreign bodies should be removed, if possible.Therapy for serious infection determined to be caused by MSSA usually is successful with a penicillinase-resistant antibiotic (eg, nafcillin, oxacillin, or a first- or second-generation cephalosporin).Intravenous treatment is recommended for most patients who have serious staphylococcal infection until the patient has been afebrile for 72 hours and other signs of infection have disappeared. Oral treatment may be provided in milder infections or to complete the course of treatment when parenteral therapy has been discontinued. Dicloxacillin is penicillinase-resistant, absorbed well orally, and clinically effective, although many children do not like its taste. The first-generation cephalosporins, amoxicillin combined with the beta-lactamase inhibitor clavulanic acid, clindamycin, or trimethoprim-sulfamethoxazole administered orally may be effective, depending on antimicrobial susceptibilities. Skin and soft-tissue infections and minor upper respiratory tract infections often may be managed by oral therapy alone, but in areas that have an increasing incidence of CA-MRSA, culture and susceptibility are necessary to optimize antimicrobial selection.For TSS, initial parenteral administration of a beta-lactamase-resistant antistaphylococcal antibiotic (eg, nafcillin or a first-generation cephalosporin) or vancomycin in locales where MRSA is increasingly prevalent is recommended after appropriate cultures have been obtained. The addition of clindamycin in severe or unresponsive cases may terminate toxin production. Drainage of the vagina, by removal of any retained tampons in menstrual TSS, and of focally infected sites in nonmenstrual TSS is important for successful treatment. Fluid replacement should be aggressive to prevent or treat hypotension, renal failure, and cardiovascular collapse. Inotropic agents may be needed to treat shock; corticosteroids and intravenous immune globulin may be helpful for severe cases.Untreated staphylococcal septicemia is associated with a high fatality rate. Fatality rates have been reduced dramatically by appropriate antibiotic treatment. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases of abscess formation, surgical drainage is required.Staphylococcal infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another. Use of a soap containing an iodophor, chlorhexidine, or hexachlorophene is recommended. In hospitals or other institutional settings, all persons who have acute staphylococcal infections should be isolated until they have been treated adequately. Surveillance for nosocomial staphylococcal infections should be constant within hospitals. When MRSA is recovered, isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. It also may be necessary to identify colonized hospital personnel and eradicate carriage in affected individuals. Strains of S aureus resistant to vancomycin that have limited treatment options have been reported, emphasizing the need for restricting the prescription of unnecessary antibiotics and the importance of isolating the causative organism and susceptibility testing in serious infections.The low risk of acquiring TSS (1 to 2 cases per 100,000 menstruating women per year) may be reduced by not using tampons or by using them intermittently during each menstrual period. If a fever, rash, or dizziness develops during menstruation, any tampon should be removed immediately and medical attention sought.

After completing this article, readers should be able to: Staphylococci are hardy aerobic bacteria that are present in the environment and as normal flora of humans and animals. They are resistant to heat and drying and may be recovered from the environment months after contamination. These organisms are gram-positive cocci that grow in characteristic grapelike clusters. Staphylococci are distinguished from streptococci by a positive catalase (H2O2) test. Species are classified as Staphylococcus aureus if they are coagulase-positive or as one of many species of coagulase-negative staphylococci (eg, S epidermidis, S saprophyticus). S aureus is the most common cause of pyogenic infection of the skin; it also may cause osteomyelitis, septic arthritis, wound infection, abscess, pneumonia, empyema, endocarditis, pericarditis, meningitis, and toxin-mediated diseases, including food poisoning, staphylococcal scarlet fever, scalded skin syndrome, and toxic shock syndrome (TSS). Coagulase-negative staphylococci tend to be less pathogenic unless a foreign body (eg, intravascular catheter) is present.Many neonates are colonized with S aureus within the first postnatal week. Thereafter, up to 50% of healthy individuals carry at least one strain of S aureus in the anterior nares at any given time. The organisms may be transmitted from the nose to the skin, where colonization seems to be more transient. Persistent umbilical perianal and vaginal carriage has been described. S aureus generally is transmitted by direct contact, primarily on the hands. Autoinfection is common. Handwashing by caretakers between contacts with patients decreases the spread of staphylococci from patient to patient. Many different strains of S aureus are capable of causing a wide variety of diseases (Fig. 1); these strains, and the diseases they commonly cause, may change in a community over time.Strains of S aureus are identified best by the virulence factors they produce (Fig. 1). These factors have four different roles: protecting the organism from host defenses, localizing infection, causing local tissue damage, and acting as toxins affecting noninfected tissue sites.Many staphylococci produce a loose polysaccharide capsule, or slime layer, that may interfere with phagocytosis. Coagulase causes plasma to clot by interacting with fibrinogen, which may play an important role in localization of infection (ie, abscess formation) –a hallmark of S aureus infection. Clumping factor interacts with fibrinogen to cause the formation of large clumps of organism that interfere with effective phagocytosis. Production of coagulase and clumping factor differentiates S aureus from S epidermidis and other coagulase-negative staphylococci. Another important enzyme elaborated by staphylococci is penicillinase (or beta-lactamase), which inactivates penicillin.Many strains of S aureus produce substances that destroy local tissue. A number of immunologically distinct hemolysins have been identified. Alpha-toxin acts on cell membranes and causes tissue necrosis. Panton-Valentine leukocidin, which is produced by some virulent strains of S aureus, combines with the phospholipid of the phagocytic cell membrane, producing increased permeability, leakage of protein, and eventual death of the neutrophil and macrophage.Many strains of S aureus release exotoxins. Exfoliatin A and B are two serologically distinct proteins that produce skin separation by splitting the desmosome and altering the intracellular matrix in the stratum granulosum, resulting in localized (eg, bullous impetigo) or generalized (eg, scalded skin syndrome, staphylococcal scarlet fever) rashes (Fig. 2). One or more staphylococcal enterotoxins (types A, B, C1, C2, D, E) are elaborated by most strains of S aureus. Ingestion of preformed enterotoxin is associated with vomiting and diarrhea and is a principal cause of food poisoning. Toxic shock syndrome toxin-1 (TSST-1) is associated with TSS related to menstruation and focal staphylococcal infection. TSST-1 induces production of interleukin-1 and tumor necrosis factor, resulting in hypotension, fever, and multisystem involvement. Enterotoxin A and enterotoxin B also may be associated with nonmenstrual TSS. Epidemiologic and in vitro studies suggest that these toxins are produced selectively in the clinical environment commonly found in abscesses and in the vagina with tampon use during menstruation. The risk factors for symptomatic disease require a nonimmune host colonized with a toxin-producing organism that is exposed to focal growth conditions (eg, menstruation plus tampon use or abscess), which induce toxin production.The development of staphylococcal disease is related to resistance of the host to infection and to the virulence of the organism. The intact skin and mucous membranes serve as barriers to invasion by staphylococci. Defects in the mucocutaneous barriers produced by trauma, surgery, foreign surfaces (eg, sutures, shunts, intravascular catheters), and burns increase the risk of infection.Infants may acquire type-specific humoral immunity to staphylococci transplacentally. Antibody to the various S aureus toxins appears to protect against those specific toxin-mediated diseases but not necessarily focal or disseminated S aureus infection with the same organisms.Individuals who have congenital defects in chemotaxis (Job, Chédiak-Higashi, and Wiskott-Aldrich syndromes), defective phagocytosis, and defective humoral immunity (antibodies required for opsonization) are at increased risk of infection with staphylococci. Patients who have chronic granulomatous disease, in which phagocytosis proceeds normally but killing of ingested catalase-positive bacteria is severely impaired, are particularly susceptible to staphylococcal disease. Local host defense compromise (eg, surgical wound, cystic fibrosis) often is complicated by S aureus infection.S aureus is identified by its growth on blood agar and a positive catalase and coagulase test. Antibiotic susceptibility testing has become increasingly important. In the past, most strains were resistant to penicillin but susceptible to methicillin and the cephalosporins and termed methicillin-susceptible S aureus (MSSA). An increasing number have acquired the mecA gene that alters beta-lactam antibiotic binding to the staphylococcal cell wall, causing them to become methicillin (and cephalosporin)- resistant S aureus (MRSA). For many years, MRSA strains were seen primarily in hospitals and often were resistant to other antibiotics. Rare resistance to vancomycin also has been reported. In the past few years, community-associated methicillin-resistant S aureus (CA-MRSA) strains have become more common. In some locales, these strains remained susceptible to clindamycin and trimethoprim-sulfamethoxazole, but erythromycin-induced clindamycin resistance has become increasingly common. Most strains continue to be susceptible to trimethoprim-sulfamethoxazole.The signs and symptoms of S aureus infection vary with the specific strain and the location of the infection, which although located most commonly on the skin, may involve any tissue (Fig. 1). The classic manifestation of staphylococcal infection is a localized abscess. Disease states of various degrees of severity generally result from local tissue injury, systemic dissemination with metastatic infection, or systemic effects of toxin production. Although the nasopharynx may be colonized with S aureus, disease due to this organism is relatively uncommon. Lesions, especially those of the skin, are considerably more prevalent among persons living in low socioeconomic circumstances and particularly among those in tropical climates.Pyogenic skin infections may be primary or due to wound infection with S aureus. S aureus infection is the most common cause of both crusted impetigo and bullous impetigo. S aureus, group A streptococci, or both may cause crusted impetigo. Bullous impetigo commonly occurs in the diaper area and is due to exfoliatin-producing S aureus strains that cause bullae in locally infected lesions (see scalded skin syndrome). Folliculitis, hydradenitis, furuncles (boils), carbuncles, and wound infections are all different manifestations of localized infections caused by S aureus. Recently, necrotizing fasciitis has been described associated with CA-MRSA.Infections of the upper respiratory tract due to S aureus are uncommon, considering the frequency with which this area is colonized. Otitis media and sinusitis due to S aureus occasionally may occur. Staphylococcal tonsillopharyngitis is rare in otherwise healthy children. Unilateral cervical lymphadenitis is caused commonly by S aureus, especially in young children. A membranous tracheitis that complicates viral croup may be infected with S aureus but also by other organisms. Treatment requires antibiotics and careful airway management.Staphylococci may cause a necrotizing pneumonitis with empyema. Pneumatoceles, pyopneumothorax, and bronchopleural fistulas develop frequently. Hematogenous pneumonia may be due to septic emboli, right-sided endocarditis, or the presence of infected intravascular devices.A localized staphylococcal abscess in muscle associated with elevation of muscle enzyme concentrations but without septicemia has been called tropical pyomyositis. Although this disorder has been reported most frequently from tropical areas, it also has occurred in the United States in otherwise healthy children. Multiple abscesses occur in 30% to 40% of cases. Surgical drainage and appropriate antibiotic therapy are essential.Meningitis due to S aureus is not common; it is associated with cranial trauma and neurosurgical procedures (eg, craniotomy, cerebrospinal fluid shunt placement) and, less frequently, with endocarditis, parameningeal foci (eg, epidural or brain abscess), diabetes mellitus, or malignancy. Coagulase-negative Staphylococcus (CONS) is not ordinarily as virulent as S aureus, but it has a high affinity for attaching to foreign materials and is the most common cause of shunt-related infections.Acute bacterial endocarditis may follow staphylococcal bacteremia. S aureus is a common cause of acute endocarditis on native valves. Perforation of heart valves, myocardial abscesses, heart failure, conduction disturbances, acute hemopericardium, purulent pericarditis, and sudden death may ensue. CONS is a frequent cause of endocarditis affecting prosthetic heart valves.S aureus is a common cause of renal and perinephric abscess, usually of hematogenous origin. Urinary tract infection due to S aureus is unusual but more commonly may be caused in males by S saprophyticus.Staphylococcal bacteremia may be associated with any localized infection (Fig. 1). The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Organisms may localize subsequently at any site but are found especially in the lungs, heart, joints, bones, kidneys, and brain. S aureus is the most common cause of osteomyelitis and suppurative arthritis in children.In some instances, especially in young adolescent males, disseminated staphylococcal disease occurs, characterized by fever, persistent bacteremia despite antibiotics, and focal involvement of two or more separate tissue sites (eg, skin, bone, joint, kidney, lung, liver, heart). Endocarditis and septic thrombophlebitis must be ruled out.TSS is an acute multisystem disease characterized by high fever, hypotension, vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, strawberry tongue, and an erythematous rash with subsequent desquamation on the hands and feet (TableT1). Many cases occur in menstruating women 15 to 25 years of age who use tampons or other vaginal devices (eg, diaphragm, contraceptive sponge) in the presence of vaginal colonization or infection with TSST-1-producing strains of S aureus. TSS, however, also occurs in children, nonmenstruating women, and men. Nonmenstrual TSS has been associated with wound infection, nasal packing, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia.Complications include acute respiratory distress syndrome, myocardial failure, and renal failure and are commensurate with the degree of shock. Recovery occurs within 7 to 10 days and is associated with desquamation, particularly of palms and soles. Hair and nail loss also have been observed after 1 to 2 months. Many cases of apparent scarlet fever without shock may be caused by TSST-1-producing S aureus strains.Group A Streptococcus can cause a similar TSS-like illness, termed streptococcal TSS, which often is associated with streptococcal bacteremia or a focal streptococcal infection such as necrotizing fasciitis or pneumonia.Staphylococcal scalded skin syndrome represents a spectrum of clinical entities mediated by exfoliatin-producing S aureus strains (Fig. 2). Patients who do not have antibody to the toxin develop generalized disease due to hematogenous dissemination of the toxin. The rash is characterized by a painful erythroderma with a positive Nikolsky sign, but signs are more severe in newborns (Ritter disease) and milder in older children (staphylococcal scarlet fever).Food poisoning may be caused by ingestion of enterotoxins that are preformed by staphylococci contaminating foods. Sudden, severe vomiting begins approximately 2 to 7 hours after ingestion of the toxin. Watery diarrhea may develop, but fever is absent or low. Symptoms rarely persist longer than 12 to 24 hours. Rarely, shock and death may occur.The diagnosis of staphylococcal infection depends on isolation of the organisms from normally noncolonized sites, such as skin lesions, abscess cavities, blood, or other sites of infection. Isolation from the nose or skin does not necessarily imply causation because these are normally colonized sites. The organisms can be grown readily on solid media. After isolation, identification is made on the basis of Gram stain and catalase, coagulase, or clumping factor reactivity. Patterns of susceptibility to antibiotics should be assessed in serious cases because resistance to penicillin is common and resistance to the penicillinase-resistant beta-lactam antibiotics is increasing (MRSA).The increasing resistance of S aureus to multiple antimicrobials both in the hospital and the community and another common cause of soft-tissue or toxin-mediated infection (group A Streptococcus) being resistant to trimethoprim-sulfamethoxazole make it imperative to initiate antimicrobial therapy likely to be effective for both organisms in serious infections (eg, sepsis, endocarditis, TSS, necrotizing fasciitis). The combination of vancomycin with the addition of clindamycin for toxin-mediated disease is a reasonable choice for such infections because clindamycin has been shown to reduce TSST-1 production by 90% in culture. Rare vancomycin-resistant strains of both S aureus and enterococci have been reported mostly in patients being treated with vancomycin. Vancomycin should be continued only in children who have proven MRSA infections. Linezolid and quinupristin-dalfopristin may be useful for serious S aureus infections highly resistant to other antibiotics. The combination of nafcillin (or vancomycin), gentamicin, and rifampin has been recommended for the initial treatment of S aureus endocarditis.The antibiotic used, as well as the dose, route, and duration of treatment, depend on the site of infection, the response of the patient to treatment, and the susceptibility of the organisms recovered from blood or local sites of infection. Appropriate cultures always should be obtained so the causative organism can be identified and susceptibility testing performed to optimize therapeutic decisions. Antibiotic therapy alone rarely is effective for individuals who have undrained abscesses or infected foreign bodies. Loculated collections of purulent material should be drained. Foreign bodies should be removed, if possible.Therapy for serious infection determined to be caused by MSSA usually is successful with a penicillinase-resistant antibiotic (eg, nafcillin, oxacillin, or a first- or second-generation cephalosporin).Intravenous treatment is recommended for most patients who have serious staphylococcal infection until the patient has been afebrile for 72 hours and other signs of infection have disappeared. Oral treatment may be provided in milder infections or to complete the course of treatment when parenteral therapy has been discontinued. Dicloxacillin is penicillinase-resistant, absorbed well orally, and clinically effective, although many children do not like its taste. The first-generation cephalosporins, amoxicillin combined with the beta-lactamase inhibitor clavulanic acid, clindamycin, or trimethoprim-sulfamethoxazole administered orally may be effective, depending on antimicrobial susceptibilities. Skin and soft-tissue infections and minor upper respiratory tract infections often may be managed by oral therapy alone, but in areas that have an increasing incidence of CA-MRSA, culture and susceptibility are necessary to optimize antimicrobial selection.For TSS, initial parenteral administration of a beta-lactamase-resistant antistaphylococcal antibiotic (eg, nafcillin or a first-generation cephalosporin) or vancomycin in locales where MRSA is increasingly prevalent is recommended after appropriate cultures have been obtained. The addition of clindamycin in severe or unresponsive cases may terminate toxin production. Drainage of the vagina, by removal of any retained tampons in menstrual TSS, and of focally infected sites in nonmenstrual TSS is important for successful treatment. Fluid replacement should be aggressive to prevent or treat hypotension, renal failure, and cardiovascular collapse. Inotropic agents may be needed to treat shock; corticosteroids and intravenous immune globulin may be helpful for severe cases.Untreated staphylococcal septicemia is associated with a high fatality rate. Fatality rates have been reduced dramatically by appropriate antibiotic treatment. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases of abscess formation, surgical drainage is required.Staphylococcal infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another. Use of a soap containing an iodophor, chlorhexidine, or hexachlorophene is recommended. In hospitals or other institutional settings, all persons who have acute staphylococcal infections should be isolated until they have been treated adequately. Surveillance for nosocomial staphylococcal infections should be constant within hospitals. When MRSA is recovered, isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. It also may be necessary to identify colonized hospital personnel and eradicate carriage in affected individuals. Strains of S aureus resistant to vancomycin that have limited treatment options have been reported, emphasizing the need for restricting the prescription of unnecessary antibiotics and the importance of isolating the causative organism and susceptibility testing in serious infections.The low risk of acquiring TSS (1 to 2 cases per 100,000 menstruating women per year) may be reduced by not using tampons or by using them intermittently during each menstrual period. If a fever, rash, or dizziness develops during menstruation, any tampon should be removed immediately and medical attention sought.

To the Editor: We read with interest the paper by Kario et al,1 indicating that an excessive morning surge in blood pressure is a predictor of subsequent stroke in a sample population of elderly Japanese hypertensives. On one hand, the evident diurnal variation in the onset of many acute cardiovascular events, eg, myocardial infarction, angina, cardiac arrest, sudden death, and pulmonary embolism, is closely related to the circadian pattern of blood pressure.2 On the other, there is no doubt that hypertension plays a key role as a risk factor for cerebrovascular accidents. However, recent studies from our group found that patients with and without hypertension had the same 24-hour pattern of onset of both ischemic3 and hemorrhagic4 stroke, characterized by a morning peak. Moreover, other cardiovascular events, eg, acute aortic dissection, show an evident …

Sleep is generally considered to be a protected period, when the cardiovascular system benefits from the restorative influences of the sleeping brain. However, the dynamics of cardiovascular control during sleep can tax the capacity of the diseased coronary circulation and myocardium with surges in sleep-state–related autonomic activity and disruptions in airway function and central nervous system regulation. In this regard, sleep may constitute an autonomic stress test for the heart. The scope of sleep-related risk for atrial and ventricular arrhythmias is substantial. The major subgroups susceptible to adverse influences of surges in autonomic activity during sleep are those with ischemic heart disease, heart failure, and channelopathies (Table).1 It is significant that 20% of myocardial infarctions and 15% of sudden deaths occur at night in the United States.2 Most atrial arrhythmias in patients younger than 61 years of age have nocturnal onset.3 The young are not immune to risk, as sudden infant death syndrome (SIDS) claims 2500 lives in the United States annually.4 Cardiovascular risk is compounded by comorbid factors, most notably apnea, which affects an estimated 4% to 9% of the general population5 and is considerably more prevalent among obese individuals.6 The more common form is obstructive sleep apnea (OSA), with partial or complete collapse of the pharynx. Half of heart failure patients experience either OSA or central sleep apnea (CSA) with central nervous system–mediated periodic breathing, commonly referred to as Cheyne-Stokes respiration. Such cardiorespiratory disturbances profoundly alter autonomic nervous system activity and increase risk of arrhythmia, hypertension, and myocardial infarction. View this table: Table. Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events It is surprising, as recently underscored by Malhotra and Loscalzo,7 that the significance of cardiovascular risk during sleep may not be duly recognized within the cardiology community. The reasons are …

Because osmotic fluid shifts may occur over the blood-brain barrier, patients with acute brain injury are theoretically at risk of surges in intracranial pressure (ICP) during hemodialysis. However, this remains poorly investigated. We studied changes in ICP during hemodialysis in such patients. We performed a retrospective study of patients with acute brain injury admitted to Rigshospitalet (Copenhagen, Denmark) from 2012 to 2016 who received intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT) while undergoing ICP monitoring. Data from each patient's first dialysis session were collected. Area under the curve divided by time (AUC/t) for ICP was calculated separately before and during dialysis. Thirteen patients were included. During dialysis, ICP increased from a baseline of 11.9mm Hg (median; interquartile range 6.3-14.7) to a maximum of 21mm Hg (18-27) (P=0.0024), and AUC/t for ICP was greater during dialysis (15.2 (13.4-18.8) vs 11.7mm Hg (6.4-15.1), P=0.042). The maximum ICP increase was independent of dialysis modality, but peak values were reached earlier in patients treated with IHD (N=4) compared to CRRT (N=9) (75 [30-90] vs 375min [180-420] after start of treatment, P=0.0095). The maximum ICP increase correlated positively to the baseline plasma urea concentration (Spearman's r=0.69, P=0.017). Hemodialysis is associated with increased ICP in neurocritically ill patients, and the magnitude of the increase may be related to initial plasma urea levels.

Autoregulation is dysfunctional in the injured brain. Increases in intracranial and arterial pressure may therefore result in extension of the primary injury. Rapid sequence intubation (RSI) is a well-known cause of surges in both arterial pressure and intracranial pressure. Neuroprotective agents, namely lidocaine and fentanyl, have the potential to minimize the pressure surges implicated in secondary brain injury. The purpose of this study was to determine the frequency with which neuroprotective agents were used for neuroprotective RSI in the emergency department. We conducted a retrospective chart review of all 139 patients intubated in the emergency department of Vancouver General Hospital between March and October 2003. Patients were eligible if there was an indication for neuroprotective agents defined as presumed intracranial pathology and a mean arterial pressure (MAP) > 85 mm Hg. Contraindications to fentanyl included MAP < 85 mm Hg or allergy to fentanyl. Seventy-seven patients were intubated for primary neurological indications. Indication for intubation included non-traumatic causes (n = 37) (including cerebrovascular accident or intracranial hemorrhage) and closed head injury (n = 40). The mean age (+/- standard deviation) was 52.3+/-20.4 years, and 31.4% were female. Fifty-seven (74.0%) patients had indications for neuroprotective agents, without contraindications. When neuroprotective agents were indicated, lidocaine was used in 84.2% (95% confidence interval [CI] 72.6%-91.5%) of patients while fentanyl was used in 33.3% (95%CI 22.4%-46.3%) of patients. Eleven percent of the intubations were performed with a fentanyl dose of delta 2 mcg/kg, which is the lower limit considered effective. Despite the potential benefit of using lidocaine and fentanyl in appropriate patients undergoing neuroprotective RSI in the emergency department, our study identified a significant underutilization of optimal premedication. The identification of barriers to use and the implementation of strategies to optimize use are necessary.

Cerebral vessels are extensively innervated by sympathetic nerves arising from superior cervical ganglia, and these nerves might play a protective role during the large arterial pressure surges of active sleep (AS). We studied lambs (n=10) undergoing spontaneous sleep-wake cycles before and after bilateral removal of the superior cervical ganglia (SCGx, n=5) or sham ganglionectomy (n=5). Lambs were instrumented to record cerebral blood flow (CBF, flow probe on the superior sagittal sinus), carotid arterial pressure (P(ca)), intra-cranial pressure (P(ic)), cerebral perfusion pressure (Pcp=Pca-Pic) and cerebral vascular resistance (CVR). Prior to SCGx, CBF (mL min-1) was significantly higher in AS than in Quiet Sleep (QS) and Quiet Wakefulness (QW) (17+/-2, 13+/-3, and 14+/-3 respectively, mean+/-SD, P<0.05). Following SCGx, baseline CBF increased by 34, 31, and 29% respectively (P<0.05). CVR also decreased in all states by approximately 25% (P<0.05). During phasic AS, surges of Pca were associated with transient increases in Pcp, Pic and CBF. Following SCGx, peak CBF and Pic during surges became higher and more prolonged (P<0.05). Our study is the first to reveal that tonic sympathetic nerve activity (SNA) constricts the cerebral circulation and restrains baseline CBF in sleep. SNA is further incremented during arterial pressure surges of AS, limiting rises in CBF and Pic, possibly by opposing vascular distension as well as by constricting resistance vessels. Thus, SNA may protect cerebral microvessels from excessive distension during AS, when large arterial blood pressure surges are common.

Recent reports indicate that lidocaine hydrochloride may attenuate surges in intracranial pressure (ICP) produced experimentally by air embolism and clinically resulting from surgical stimulation during craniotomy or endotracheal suctioning and intubation. This study was undertaken to examine the role of lidocaine hydrochloride in reducing raised intracranial pressure produced by an intracranial space-occupying lesion. Our results indicate that intracranial pressure (ICP) is reduced consistently by an average of 26% with a concomitant increase in cerebral perfusion pressure of 13%.

Obstructive sleep apnea (OSA) places an enormous pressure load on the cardiovascular system by inducing a temporary blood pressure (BP) surge (sleep BP surge (SLBPS)), often resulting in target organ damage and cardiovascular events, such as left ventricular hypertrophy, sudden death, myocardial infarction and stroke. Accurate measurement of SLBPS would be valuable for the risk stratification of OSA patients. We developed a new oxygen-triggered BP monitoring system based on a variable SpO(2) threshold (VT algorithm) to selectively detect severe SLBPS, which are associated with morbidity, and evaluated its performance in comparison with a previous technique based on a fixed SpO(2) threshold (FT algorithm). In 23 OSA patients, the correlation between individual minimum SpO(2) values and SLBPS was not significant when the FT algorithm was used alone (r=0.400, P=0.058) but became significant (r=0.725, P<0.0001) when the VT algorithm was additionally used. In another 13 OSA patients, when the FT algorithm was eliminated from the FT+VT algorithm, the number of BP readings was drastically reduced (36±22.7 vs. 61±55.0 times, P=0.004) with a similar correlation between minimum SpO(2) and SLBPS. The correlation between the apnea hypopnea index and SLBPS was significant when measured with the present method, but not when assessed with ambulatory BP monitors (ABPM) simulation (r=0.519, P=0.001 vs. r=0.149, P=0.385). In conclusion, oxygen-triggered BP monitoring with a variable threshold is able to detect severe OSA-related BP surges more specifically and reduce the number of BP readings required during sleep compared with detection using a fixed threshold or the conventional ABPM method.

Rebound Surges of Intracranial Pressure as a Consequence of Forced Ultrafiltration Used to Control Intracranial Pressure in Patients With Severe Hepatorenal Failure

The second of this four-part review encompasses the inpatient management of hepatic encephalopathy (HE) in patients with decompensated cirrhosis, acute-on-chronic liver failure (ACLF) and acute liver failure (ALF). The management of overt HE in cirrhosis consists of excluding alternative causes of altered mental state, identifying and correcting precipitants, instigating nutritional support and initiating pharmacological therapy. The presence of HE in combination with other organ failures defines ACLF, and these patients are frequently managed in the intensive care setting. Aside from the treatment of precipitants and organ support in ACLF, there is an emerging role for emergency liver transplantation in highly selected patients. ALF is characterised by the development of severe hepatocellular injury accompanied by coagulopathy and HE, in patients usually without pre-existing chronic liver disease. The often rapid development of hyperammonaemia in ALF may culminate in cerebral oedema and intracranial hypertension, which is specific to this syndrome and, as such, management of HE in ALF differs from that in cirrhosis. A package of neuroprotective care is delivered, including specific monitoring for cerebral oedema, and osmotic therapy is employed for surges in intracranial pressure. Specific ammonia-lowering therapies recommended include continuous renal replacement therapy and therapeutic plasma exchange, with emergency liver transplantation the definitive treatment in the absence of liver regeneration and spontaneous recovery. Independent of underlying aetiology, patients with grade 3–4 HE should be managed in the intensive care unit due to risk of airway compromise and aspiration.

IRM cérébrale en neurotraumatologie

Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality. Acutely, ICH is associated with a sudden surge in intracranial pressure (ICP), as the volume of hematoma increases the pressure in the closed head, leading to non-specific symptoms of ICP: headache, nausea, vomiting, and alterations in consciousness. In the early phase, damage to the brain tissues surrounding the hematoma causes progression of neurologic symptoms. Expansion of supratentorial ICHs may result in transtentorial herniation, causing mental status deterioration and loss of pupillary light reflex. Compared to ischemic stroke, seizure is more common in ICH.

Acute neurological injury may occur in patients with end-stage kidney disease on dialysis. Less frequently, acute kidney injury requiring renal dialytic support develops following acute neurological injury. Surrounding any site of neurological injury there is a penumbra of damage which is potentially reversible. To maximize full potential neurological recovery in patients requiring renal dialytic support, it is important that treatments do not themselves cause further cerebral ischemia. Standard intermittent hemodialysis is associated with cerebral swelling even in healthy outpatients and often with episodes of intradialytic hypotension. Continuous modes of renal replacement therapy have been shown to cause fewer surges in intracranial pressure and greater stability of cerebral perfusion pressure than standard intermittent techniques. In patients with acute neurological injury, renal replacement therapy should be carefully adapted to minimize cardiovascular instability and reduce the rate of change of serum osmolality.