A 13 month old infant presents to the emergency department with a 2 day history of low-grade fevers, runny nose and increasing fussiness. She also developed a rash and vomiting. Her mother notes that the red-purple lesions on her legs have increased in number since this morning.
Exam: VS T 39.6, P 170, R 50, BP 80/50. She is weak, poorly responsive and sick (toxic) appearing with occasional grunting. Her oral mucosa is sticky. Lungs are clear. Heart is tachycardic. Abdomen is scaphoid, without hepatosplenomegaly. Her extremities are slightly mottled with asymmetrical maculopapular and few petechial lesions over upper and lower extremities. Her capillary refill time is delayed (about 3 seconds).
You are worried about meningococcal disease and explain to her parents that you must start parenteral antibiotic treatment and fluid replacement immediately. While trying to obtain IV access, the infant becomes more lethargic and her blood pressure drops further. You place an intraosseous needle and administer fluids, pressor medications and ceftriaxone (a third generation cephalosporin). Despite these measures, she continues to deteriorate, developing large purpuric lesions on her lower extremities. Her laboratory findings reveal thrombocytopenia, prolonged PT/PTT and increased fibrin degradation products (indicative of disseminated intravascular coagulation - DIC). You intubate the patient and transfer her to the ICU. You notice that it has been less than 40 minutes since you first saw this patient (i.e., the deterioration has been quite rapid).
Her blood culture later grows Neisseria meningitidis. Her antibiotic coverage is changed to high dose, intravenous penicillin. A lumbar puncture is normal indicating that she does not have meningitis. She is successfully extubated on the third day of her hospitalization. Most of the purpuric lesions have regressed but she develops necrosis of the 4th and 5th toes of her right foot, which requires amputation.
Meningococcemia is a classical example for severe sepsis. It is classically said that, patients are well at 12 o'clock and dead by 3 o'clock. Early diagnosis and immediate empiric treatment are life saving as in this case. Patients with severe sepsis can develop complications and die even with appropriate antimicrobial and supportive treatments. Each year, sepsis develops in more than 500,000 people in the United States with a mortality rate of 35-45% in adults (1). Sepsis is estimated to be the 13th leading cause of death overall in patients older than 1 year of age. The highest mortality rates in children are among infants. Approximately two thirds of the cases occur in patients hospitalized for other illnesses (e.g., cancer). There are several definitions used to describe the conditions associated with sepsis (1-3):
Bacteremia (or fungemia) is the presence of viable bacteria (or fungi) in the blood. Septicemia is a systemic illness caused by the spread of microbes or their toxins via the blood stream. This means that septicemia is worse than bacteremia. The two terms are not synonymous.
Systemic inflammatory response syndrome (SIRS) is characterized by at least two of the following :
. . . . . - Oral temperature of >38C (>100.4F) or <36C (<96.8F).
. . . . . - Tachypnea (Respiratory rate of >60 breaths/min for infants, >50 breaths/min for children) or PaCO2 of <32 torr.
. . . . . - Tachycardia (Heart rate of >160 beats/minute for infants, >150 beats/minute for children).
. . . . . - Leukocyte count of >12,000/L or <4,000/L or >10% bands.
SIRS may have an infectious or noninfectious etiology. SIRS that has a proven or suspected etiology is called sepsis. Sepsis syndrome is sepsis with one or more signs of organ dysfunction, hypoperfusion, or hypotension, such as metabolic acidosis, acute alteration in mental status, oliguria, or ARDS (adult respiratory distress syndrome). Septic shock is sepsis with hypotension that is unresponsive or poorly responsive to fluid resuscitation plus organ dysfunction or perfusion abnormalities.
Noninfectious etiologies of SIRS that need to be considered include trauma, adrenal insufficiency, anaphylaxis, burns, bleeding, cardiac tamponade, dissecting or ruptured aortic aneurysm, drug overdose, neoplasms, myocardial infarction, pancreatitis, post-cardiopulmonary bypass syndrome and pulmonary embolism.
The causative organism varies considerably by age. Streptococcus pneumoniae, Neisseriae meningitidis, Staphylococcus aureus, and group A streptococci are major causes of sepsis in children beyond the newborn period. Blood cultures yield bacteria or fungi in 20-40% of cases of severe sepsis and in 40-70% of cases of septic shock.
Although the infection is an essential part of the development of sepsis, the septic response occurs when immune defenses fail to contain the invading microbe(s). Sepsis due to gram negative microorganisms and endotoxic shock are major triggers for the septic syndrome. The lipopolysaccharide (LPS or endotoxin) of gram negative bacteria is transferred to CD14 on the surfaces of phagocytic and polymorphonuclear cells by a LPS binding protein. This interaction triggers the release of mediators, such as TNF-alpha, that further amplify this signal and transmit it to other cells and tissues. Gram positive microorganisms, especially Staphylococcus aureus can elaborate exotoxins, which appear to act through a similar signal pathway to that of endotoxins, triggering the release of inflammatory mediators. How these signals initiate inflammation and how the host responds to them are active areas of research. It has been shown that the inflammation signals are specific to the plasma membranes and a family of proteins named "toll-like receptors" (TLR) are shown to be cellular components of host defense against bacterial challenge. Toll receptors were initially described in Drosophila and shown to activate host defenses against fungal infection in the adult fruitfly. Subsequently, mammalian homologs of these proteins were shown and named as toll-like receptors (TLR). Different members of TLR family may have different roles in inflammation and sepsis. TLR4 appears to confer responsiveness to bacterial lipopolysaccharide (gram negative infections) and TLR2 appears to mediate stimulation by gram positive, gram negative microorganisms and mycobacteria. These proteins basically help the host in transduction of inflammatory signals and they share these pathways (due to their high homology) with the IL-1 receptor in humans. IL-1 is also a critical component of the general inflammatory response.
The septic response then involves complex interactions among microbial signal molecules, leukocytes, humoral mediators and vascular endothelium. Inflammatory cytokines amplify and diversify the overall response. Microbial toxins stimulate the production of cytokines like TNF-alpha and IL-1-beta, which in turn promote endothelial cell-leukocyte adhesion, release of proteases and arachidonic acid metabolites and activation of clotting. IL-8, a neutrophil chemotaxin, may have an especially important role in perpetuating tissue inflammation. IL-6 and IL-10, which are counter-regulatory, inhibit the generation of TNF-alpha, augment the action of acute phase reactants and immunoglobulins, and inhibit T-lymphocyte and macrophage function. IL-6 along with other mediators can also promote intravascular coagulation.
Many tissues may be damaged by the septic response. The probable underlying mechanism is widespread vascular endothelial injury, with fluid extravasation and microthrombosis that decrease oxygen substrate utilization by the affected tissues. Additionally, stimuli such as TNF- alpha induce vascular endothelial cells to produce and release cytokines, procoagulant molecules, platelet activating factor (PAF), endothelium derived relaxing factor (nitric oxide) and other mediators. Moreover, vascular integrity may be damaged by neutrophil enzymes (such as elastase) and toxic oxygen metabolites so that local hemorrhage ensues (4). Nitric oxide is implicated as a mediator septic shock in animals.
The manifestations of sepsis are usually superimposed on the symptoms and signs of the patient's underlying illness and primary infection. Symptoms can be variable. Nonspecific mental status changes and hyperventilation are often the early findings in older children and adults. Irritability, lethargy or confusion can be seen even if meningitis is absent. Young children can exhibit signs of diminished perfusion while maintaining a normal blood pressure, such as delayed capillary refill, weak peripheral pulses, and cool extremities. Nausea, vomiting, diarrhea and ileus can be present. Cholestatic jaundice with elevated levels of serum bilirubin (mostly conjugated) and alkaline phosphatase may precede the other signs. Blood glucose concentration often initially increases as a stress response.
While most patients have fever, some have a normal temperature or are hypothermic. Tachypnea and tachycardia are common signs. Hypotension and DIC, which can complicate sepsis, predispose to cyanosis and ischemic necrosis of peripheral tissues. Other skin lesions such as ecthyma gangrenosum (Pseudomonas aeruginosa), petechial rash (meningococcemia, rarely H. influenzae type B), and purpura fulminans can be suggestive of specific pathogens. The skin and mucosa should be examined carefully and repeatedly for lesions.
Cardiac output is initially normal or increased (the "hyperdynamic phase") in sepsis and helps in distinguishing septic shock from other types of shock. A definitive diagnosis requires the isolation of the microorganism from blood or a local site of infection. At least two and probably three sets of cultures should be obtained. Buffy-coat smear of peripheral blood is a quick and inexpensive method and can assist in more effective therapy; however it is not very sensitive. In early sepsis, abnormalities may include leukocytosis or leukopenia, left shift (with or without toxic granulations), thrombocytopenia, increased lactic acid levels and proteinuria. Active hemolysis suggests clostridial bacteremia, malaria, a drug reaction, or DIC.
With the critically ill child, as in the case scenario, time must not be wasted on performing an extensive diagnostic evaluation. Obtaining a blood culture before initiating antibiotic therapy may be prudent in these children. Other diagnostic labs and a lumbar puncture may be delayed so that antimicrobial treatment can be started immediately in critically ill patients. Severe coagulopathy, as frequently seen in meningococcemia, may also delay lumbar puncture because of the risk of spinal epidural hematoma and bleeding.
Risk factors and prognostic factors include host related factors such as malnutrition, splenectomy, HIV infection, burns, hematologic malignancies and neoplasms; or treatment related factors such as surgical invasive procedures, high dose of corticosteroids or other immunosuppressive drugs, mechanical ventilation, neutropenia and presence of indwelling mechanical devices.
Numerous sepsis scoring systems have been developed in adults and children, particularly for meningococcemia. The best indicator of sepsis and poor outcome is the presence of shock (5). Multiorgan failure is the leading cause of mortality in sepsis patients. The outcome is influenced by the patient's underlying disease and by the microorganism. The outcome is worse in bacteremia caused by Candida and enterococcus species when compared with the coagulase negative staphylococci. Recently, several polymorphisms in genes coding for key inflammatory molecules have been identified and suggested as a risk factor in sepsis and adverse outcomes.
Cardiopulmonary complications include ventilation-perfusion mismatching which produces a fall in arterial pO2 early in the course of sepsis. Increasing alveolar capillary permeability results in an increased pulmonary water content, which decreases pulmonary compliance. Progressive diffuse lung infiltrates and hypoxemia indicate the development of acute respiratory distress syndrome (ARDS). ARDS develops in up to half of adult patients with severe sepsis. Depression of cardiac function (diminished contractility) develops within 24 hours in most patients with advanced sepsis. Although myocardial dysfunction may contribute to hypotension, refractory hypotension is usually due to a low systemic vascular resistance. Death results from refractory shock or the failure of multiple organs.
Renal complications include renal failure following acute tubular necrosis. In some patients glomerulonephritis, renal cortical necrosis or interstitial sepsis can also cause renal failure.
Thrombocytopenia occurs in up to one-third of the patients. Disseminated intravascular coagulation (DIC) may be seen. Prolonged or severe hypotension may induce acute hepatic injury or ischemic bowel necrosis.
If sepsis lasts weeks to months, critical-illness polyneuropathy may develop as a neurologic complication.
Sepsis is a medical emergency and urgent measures for the treatment of infection as well as hemodynamic and respiratory support need to be taken. Priorities in resuscitation of the child who has septic shock mirror those with any other type of shock (6). All children should receive supplemental oxygen. The child in respiratory distress should be intubated. Drugs that cause vasodilation or myocardial depression should be avoided. At least two separate IV lines are required to administer fluids and medications. Intraosseous infusion may be used when peripheral vascular access cannot be obtained rapidly. Cardiovascular support using inotropic medications such as dopamine, dobutamine, and possibly epinephrine, is necessary in almost all patients with severe sepsis.
Empiric antimicrobial therapy should be initiated as soon as blood and other relevant sites are cultured. However, difficulty obtaining cultures should not delay antibiotic administration which must be started as soon as possible. Maximal recommended doses of drugs should be given parenterally. The immune status of the patient, the underlying condition (including illicit injecting drug abuse, splenectomy) are important in deciding the appropriate treatment. Removal of indwelling intravenous catheters and removal or drainage of a focal source of infection are essential. The duration of treatment is influenced by factors such as the site of tissue infection, the adequacy of surgical drainage, the patient's underlying disease and the antimicrobial susceptibility of the pathogen. A typical empiric treatment regimen in children usually includes a third generation cephalosporin and further coverage for gram negative bacteria may be needed such as aminoglycosides, anti-pseudomonal penicillins, extended-generation penicillin with beta-lactamase inhibitor or carbapenems. In areas with increased pneumococcal or staphylococcal resistance or for patients who have received frequent antibiotic therapy (sickle cell anemia) vancomycin can also be started for suspected gram positive infections
Despite aggressive management, many patients with severe sepsis or septic shock will die. Two types of agents that may help in preventing these deaths are being investigated:
1. Drugs that neutralize bacterial endotoxin, thereby potentially benefiting the patients who have gram negative infection.
2. Drugs that interfere with one or more mediators of the inflammatory response and may benefit all patients with sepsis. Recently, activated protein C is approved by FDA for treatment of selected patients with sepsis.
1. Which one of the following is not a parameter in the definition of SIRS?
. . . . . a. Hypotension
. . . . . b. Tachycardia
. . . . . c. Tachypnea
. . . . . d. Leukocytosis
. . . . . e. Hypothermia
2. Which is an early finding in septic shock?
. . . . . a. Decreased urine output
. . . . . b. Increased cardiac output
. . . . . c. Decreased blood pressure
. . . . . d. Diffuse lung infiltrates
3. A number of different principles apply to the immediate management of a child in septic shock. In general, management should be prioritized in order of urgency. Which of the following is not an immediate priority in the resuscitation phase of a child in septic shock (2)?
. . . . . a. Ensure adequate airway support
. . . . . b. Correct anemia
. . . . . c. Administer volume resuscitation
. . . . . d. Cardiovascular support
. . . . . e. Empiric antibiotic treatment
4. Which microorganism is a common etiology in endotoxic shock?
. . . . . a. Staphylococcus aureus
. . . . . b. Streptococcus pyogenes
. . . . . c. Streptococcus pneumoniae
. . . . . d. Escherichia coli
5. Which of the following skin examination findings is generally not associated with sepsis?
. . . . . a. Pyogenic granuloma
. . . . . b. Ecthyma gangrenosum
. . . . . c. Purpura fulminans
. . . . . d. Petechiae
1. Sepsis. In: Gorbach SL, Falagas M (eds). The 5 minute infectious diseases consult. 2001, Philadelphia: Lippincott Williams and Wilkins, pp. 50-51.
2. Schexnayder SM. Pediatric septic shock. Pediatr Rev 1999;20:303-308.
3. Jafari RS, McCracken GH. Sepsis and septic shock: a review for clinicians. Pediatr Infect Dis J 1992;1:739-749.
4. Marshall JC. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 2001;29:S99-S106.
5. Martinot A, Leclerc F, Cremer R, Leteurtre S, Fourier C, Hue V. Sepsis in neonates and children: definitions, epidemiology and outcome. Pediatr Emerg Med 1997;13:277-281.
6. Anderson MR, Blumer JL. Advances in the therapy for sepsis in children. Pediatr Clin North Am 1997;44:179-205.
Answers to questions
1.a, 2.b, 3.b, 4.d, 5.a