AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sepsis is a problem that presents a management challenge to those who care for infants and children; however, early recognition and intervention clearly improves the outcome for infants and children with infections or intoxications that lead to sepsis. Generally, sepsis is considered to comprise a spectrum of disorders that result from infection by bacteria, viruses, fungi, or parasites or the toxic products of these microorganisms. Bacteremia, viremia, fungemia, and parasitemia refer to bloodstream invasions that may be associated with fever but have no other signs or symptoms of circulatory compromise or end-organ malperfusion or dysfunction.

For further details of topics not fully discussed here, please refer to the particular articles (eg, Bacteremia, Herpes Simplex Virus Infection, Candidiasis, Malaria). Additionally, neonatal sepsis is discussed in a separate article (see Neonatal Sepsis).

The spectrum of sepsis ranges from microbial invasion of the bloodstream or intoxication with early signs of circulatory compromise, including tachycardia, tachypnea, peripheral vasodilation, and fever (or hypothermia), to full-blown circulatory collapse with multiorgan system failure and death. All these manifestations are part of the more appropriately termed systemic inflammatory response syndrome (SIRS), which is used interchangeably with sepsis to signify any of these manifestations, whatever the etiology. SIRS results from an insult, whether infectious, traumatic, chemical, malignant, autoimmune, or idiopathic, and the host response that follows. The outcome depends on the intricate interplay of upregulating and downregulating cytokines and inflammatory cells and the direct effects of the insult itself.

In recent years, experts have come together to develop a consensus on the definitions of sepsis, SIRS, severe sepsis and septic shock.¹ Age-related variables have been applied to the definition of SIRS and sepsis. The definition of SIRS now requires either fever or WBC involvement to meet the criteria.

Pathophysiology

Fever is the most common presenting symptom of children with SIRS. Fever is one component of the triad of hyperthermia (or hypothermia), tachypnea, and tachycardia that typifies the earliest, mildest manifestation of SIRS. If SIRS is identified and reversed early, the subsequent inflammatory cascade can often be avoided or mitigated. However, in some situations, further damage occurs because the insult or the resultant host immune response is too great. This damage can result in increased cardiac output, peripheral vasodilation, increased tissue oxygen consumption, and a hypermetabolic state (ie, warm shock). If SIRS is not identified and reversed early, cardiac output may fall, peripheral vascular resistance may increase, and shunting of blood may ensue (ie, cold shock). This results in resultant tissue hypoxia, end-organ dysfunction, metabolic acidosis, end-organ injury and/or failure, and death.

Frequency

United States

Risk of sepsis decreases with age; neonates are at the highest risk, with bacterial sepsis occurring in 1-10 per 1000 live births. SIRS remains an infrequent but significant cause of death among infants and children in the United States.

International

Incidence of sepsis in the developing world is somewhat higher than in the United States. However, reports are fewer, and precise figures are unavailable.

Mortality/Morbidity

Almost half of neonatal deaths are caused by sepsis, although advances in diagnosis and treatment have caused this rate to considerably decrease, especially in preterm infants. Again, the mortality rate tends to decrease as age increases in the pediatric population.

Race

No particular racial predilection is noted for sepsis, except that invasive bacterial infections are more common in Eskimos, American Indians, and individuals with hemoglobin SS disease.

Sex

Except for urosepsis, which may be more common in females, no sex predilection for sepsis is known.

Age

The risk of sepsis is inversely related to age. Therefore, sepsis is most often found in neonates, and its likelihood decreases with age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Obtain a complete history as part of the evaluation of the infant or child with possible systemic inflammatory response syndrome (SIRS). A parental report of measured (not tactile) fever can generally be assumed to be reliable.

• Discuss the child's activity level.
• Perform an age-appropriate evaluation of mental status.
• Ask about urine output because it is the most sensitive historical marker of dehydration and potential renal hypoperfusion.
• Ask the caregiver whether any of the following have been noted: a racing heart, rapid or labored breathing, cool extremities, or color changes.
• Identify exposures to infectious illnesses and other sources of insult.
• Verify immunization and drug allergy statuses.

Physical

Perform a complete physical examination of the infant or child with suspected SIRS.

• Subtle changes in vital signs (eg, minimal tachycardia, widened pulse pressure, minimal tachypnea, minimally delayed capillary refill) may be the first signs of impending SIRS.
• Hypotension, mental status changes, and anuria are late signs of SIRS.
• Hypothermia is often a more ominous sign than fever.
• Elicit localizing signs of infection.
• A petechial or purpuric rash associated with fever is of particular concern.
• Frequent reassessment during interventions is required.

Causes

Myriad bacteria, viruses, fungi, and parasites can cause SIRS. Among the bacterial causes of sepsis, some age-related patterns are observed.

• Early-onset neonatal sepsis: Streptococcus agalactiae, Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes are the most frequent organisms encountered.
• Late-onset neonatal sepsis: Coagulase-negative Staphylococcus, Staphylococcus aureus, E coli, Klebsiella species, Pseudomonas aeruginosa, Enterobacter species, Candida species, S agalactiae, Serratia species, Acinetobacter species, and various anaerobes are some of the most commonly involved organisms.
• Sepsis in infancy
• • Streptococcus pneumoniae and Neisseria meningitidis predominate in the United States and the developed world because conjugate H influenzae type b (Hib) vaccination has essentially eliminated disease caused by that organism.
  • Hib, S pneumoniae, N meningitidis, and Salmonella species are the most frequent causes of bacterial sepsis among most infants worldwide.
  • In regions where malaria occurs, Plasmodium falciparum is a frequent cause of SIRS in infancy.
• Sepsis in childhood: The same pathogens cause SIRS in childhood, although the presence of encapsulated organisms generally becomes less frequent as a child's immune response to polysaccharide antigens improves with age.
• Special considerations: Underlying conditions predispose to infection with particular pathogens.
• • Acquired immunodeficiency syndrome (AIDS) predisposes to SIRS from various usual and unusual pathogens, particularly pneumococcus.
  • Children with hemoglobin SS disease have a 400-fold increased risk of sepsis due to pneumococcus and Salmonella, among other pathogens.
  • Congenital heart disease is a risk factor for endocarditis and SIRS.
  • Genitourinary anomalies often increase the risk of urosepsis.
  • Infants and children with significant burns are at risk for SIRS, caused by skin flora and nosocomial gram-negative pathogens in particular.
  • Splenic dysfunction or absence, as well as complement, immunoglobulin, and properdin deficiency, predispose to sepsis due to encapsulated organisms.
  • Infants and children with hematologic and solid-organ malignancies (before or during treatment) are at increased risk for SIRS from a considerable variety of organisms.
  • Neonates, infants, and children who are hospitalized (particularly in the intensive care unit [ICU]) are at increased risk of SIRS.
  • Those with indwelling devices or prosthetic material and other breaches in barrier protective function are also at increased risk of SIRS.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cardiogenic shock
Coagulase-negative Staphylococcus
Complement deficiency
Congenital heart disease
Fungal infections
Hemophagocytic syndromes
Inborn errors of metabolism
Infections after solid organ transplantation
Macrophage activation syndromes
Neoplasms
Poisoning
Pulmonary embolus
S agalactiae

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Whenever possible, obtain a blood culture prior to starting antibiotics.
• • The yield is clearly correlated to the volume of blood sampled.
  • Culture of bone marrow may have a higher yield for certain pathogens (eg, Histoplasma capsulatum).
• Obtain a urine culture unless, in an older child, a genitourinary source of infection can be reliably excluded. Urinalysis may have a role in clarifying the level of risk of urinary tract infection in infants and children.
• Obtain a cerebrospinal fluid (CSF) culture before initiating antibiotic therapy in a child whose condition is stable in whom clinical evaluation cannot exclude CNS infection.
• • Many pathogens can be recovered from CSF cultures several hours after a dose of antibiotics; thus, the child whose condition is unstable should receive antibiotics and be stabilized prior to lumbar puncture.
  • Once the infant or child's condition is stabilized, the identification of CSF pleocytosis is helpful, even if prolonged antibiotic therapy is likely to have rendered culture results negative.
• Culture of skin lesions, eye drainage, throat, vagina, rectum, cellulitic areas, nasal secretions, sputum, tracheal aspirates, and stool may be helpful in the appropriate clinical context.
• Viral cultures may have a role in certain contexts, although many viral infections are diagnosed serologically.
• Obtain a CBC count.
• • In the era of pneumococcal occult bacteremia, the likelihood of a positive blood culture result for pneumococcus increased as the WBC count increased. However, whether an elevated WBC count will continue to be predictive of bacteremia with widespread pneumococcal conjugate vaccination is not clear.
  • Elevated band and other immature counts, toxic granulation, toxic vacuolation, Dohle bodies, and, particularly, low white blood cell counts are findings of particular concern
  • Hemoconcentration may be present and helpful as a gauge of hydration status.
• Electrolyte level tests, renal and liver function tests, and other chemistry tests may have a role. Serum transaminase levels and other measures of liver dysfunction are often elevated in cases such as disseminated viral and anaerobic infections.
• Measures of clotting function and coagulation parameters may be helpful. Disseminated intravascular coagulopathy, hypercoagulability, and other clotting dysfunctions may be seen in infants and children with systemic inflammatory response syndrome (SIRS).
• Etiology-specific serologies may be helpful.
• The use of inflammatory markers and acute phase reactants (eg, erythrocyte sedimentation rate, C-reactive protein, interleukins 1-b, interleukin-6, interleukin-8, tumor necrosis factor–alpha, leukotriene B4, procalcitonin) in the diagnosis and management of SIRS is unclear.

Imaging Studies

• Obtain a chest radiograph; pneumonia, pleural effusions, adenopathy, and other conditions may be revealed.
• Pursue other imaging modalities as the clinical context dictates.

Other Tests

• Echocardiography may be indicated in certain clinical settings.

Procedures

• Lumbar puncture may be indicated for CSF evaluation.
• Sampling of other fluids or biopsy of various organs or tissues may be necessary.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements. Appropriate antimicrobial therapy should be started as soon as possible after evaluation occurs. Ongoing re-evaluation is essential.

• Most of these infants and children require monitoring and treatment in an intensive care setting.
• • Cardiac output may need to be assessed repeatedly.
  • Multiple peripheral intravenous, intraosseous, and/or central venous access devices are likely necessary.
  • Frequent sampling of arterial blood is often required.
• Ventilatory support with supplemental oxygen therapy, aggressive fluid resuscitation and support of cardiac output, maintenance of adequate hemoglobin concentration, correction of physiologic and metabolic derangements, and monitoring of urine output and other end-organ functioning are often vital.
• Adjunctive therapies such as inhaled nitric oxide, extracorporeal membrane oxygenation, corticosteroids, pentoxifylline, intravenous immunoglobulin, and various other mediators of the inflammatory response may be needed.
• In cases of refractory shock, newer adjunctive therapies (such as terlipressin) have shown potential benefit in initial trials.² Further clinical studies are required, but the risks of the drug may be outweighed by its benefits in certain circumstances.

Surgical Care

Surgical intervention (eg, draining an abscess, venous access, appendectomy) is occasionally required.

Consultations

• Critical care expertise is essential for moderate-to-severe cases.
• Consultation with an infectious disease specialist may be necessary.
• Other consultations should be made based on the clinical circumstances.

Diet

Generally, patients with systemic inflammatory response syndrome (SIRS) should not be fed until gut hypoxia and hypoperfusion have been ruled out. Once feeding can safely begin, immune-enhancing nutrition may reduce the mortality rate in sepsis. Arginine, omega-3 fatty acids, and messenger RNA (mRNA) have been identified in preliminary studies to be of potential benefit.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Rapid fluid resuscitation with crystalloid or colloid parenteral solutions should be initiated immediately. If circulatory derangements do not resolve with 3 intravenous (IV) boluses of 20 mL/kg of fluids, vasopressor support should follow. Antimicrobial agents should be given as soon as possible, according to most likely pathogens.

Empiric antimicrobial therapy for the infant or child with systemic inflammatory response syndrome (SIRS) of unclear etiology should be based upon the most frequently encountered pathogens in each age group. For example, newborns and infants in the first 6-8 weeks of life should generally receive ampicillin and gentamicin, ampicillin and cefotaxime, or ampicillin and ceftriaxone for empiric therapy of sepsis without a clear etiology. Older infants and children most often receive a third-generation cephalosporin (or ampicillin/sulbactam) alone in this situation. Patients who have indwelling catheters or those who are at high risk for methicillin-resistant S aureus infection may require vancomycin as well. Patients who have fever and neutropenia should receive broad-spectrum coverage with an emphasis on gram-negative rods.

The most frequently used antibacterial, antifungal, antiviral, and inotropic agents and albumin are described below. Other antimicrobial agents that are used less frequently include caspofungin, fluconazole, foscarnet, ganciclovir, liposomal amphotericin B, itraconazole, and voriconazole. Posaconazole (Noxafil) is also used and was recently approved by the US Food and Drug Administration (FDA) in children aged 13 years or older and in adults for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk due to severe immunosuppression.

Drotrecogin alfa (Xigris) is approved by the FDA for sepsis in adults but its phase III clinical trial for use in pediatric patients was discontinued. Drotrecogin alfa is a recombinant human-activated protein C indicated for reduction of mortality in adults with severe sepsis. Enrollment in the pediatric trial was halted in March 2005 after a review of interim results determined that drotrecogin alfa was unlikely to demonstrate improvement over placebo.^{3, 4} The study also showed increased CNS bleeding when compared with placebo.

Other examples of experimental agents to consider include dexamethasone, intravenous immunoglobulin, methylprednisolone, nitric oxide, and pentoxifylline.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Ampicillin and sulbactam (Unasyn)
Description	Drug combination of beta-lactamase inhibitor with ampicillin. Covers skin, enteric flora, and anaerobes. Not ideal for nosocomial pathogens.
Adult Dose	1.5 (1 g ampicillin + 0.5 g sulbactam) to 3 g (2 g ampicillin + 1 g sulbactam) IV/IM q6-8h; not to exceed 4 g/d sulbactam or 8 g/d ampicillin
Pediatric Dose	<3 months: Not established 3 months to 12 years: 100-200 mg ampicillin/kg/d (150-300 mg Unasyn) IV divided q6h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Drug Name	Cefotaxime (Claforan)
Description	For septicemia and treatment of infections caused by susceptible organisms. Arrests bacterial cell-wall synthesis, which, in turn, inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum but efficacious for many gram-positive organisms and most routine pediatric invasive pathogens. Generally preferred over ceftriaxone for neonates, since cefotaxime is less likely to cause or aggravate kernicterus.
Adult Dose	Moderate-to-severe infections: 1-2 g IV/IM q6-8h Life-threatening infections: 1-2 g IV/IM q4h
Pediatric Dose	Neonates: 100-200 mg/kg/d IV/IM divided q6-12h Infants and children: 50-200 mg/kg/d IV/IM divided q4-6h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; has been associated with severe colitis

Drug Name	Ceftriaxone (Rocephin)
Description	For septicemia and treatment of infections caused by susceptible organisms. Arrests bacterial cell-wall synthesis, which, in turn, inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum but efficacious for many gram-positives and most routine pediatric invasive pathogens.
Adult Dose	Severe infections: 1-2 g IV qd, or divided bid; not to exceed 4 g/d
Pediatric Dose	Neonates >7 days: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/d Infants and children: 50-100 mg/kg/d IV/IM divided q12h; not to exceed 4 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding women; may displace bilirubin from protein binding sites, increasing chance of kernicterus in the newborn with elevated bilirubin levels

Drug Name	Gentamicin (Garamycin)
Description	Aminoglycoside antibiotic for gram-negative coverage. Often used in combination with agent covering gram-positive organisms and/or one that covers anaerobes. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose on basis of CrCl and changes in volume of distribution. May be given IV/IM.
Adult Dose	Serious infections and normal renal function: 3 mg/kg/dose IV q8h Loading dose and maintenance dose: 1-2.5 mg/kg IV and 1-1.5 mg/kg IV, respectively, q8h Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h Follow each regimen by at least a trough level drawn on third or fourth dose (0.5 h before dosing); may draw peak level 0.5 h after 30-min infusion
Pediatric Dose	Premature neonate <1 kg: 3.5 mg/kg/dose IV q24h Postnatal age 0-7 days: 2.5 mg/kg/dose IV q12-24h >7 days: 2.5 mg/kg/dose IV q8-12h Infants and children <5 years: 2.5 mg/kg/dose IV/IM q8h Children >5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Narrow therapeutic index (not intended for long-term therapy); nephrotoxicity and ototoxicity may occur and are directly associated with cumulative dose and treatment duration; caution in neonates because of renal immaturity and those with renal failure (patients not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Imipenem and cilastatin (Primaxin)
Description	Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria for treatment of infection by multiple organisms in which other agents do not have wide spectrum coverage or are contraindicated because of potential for toxicity. More likely to cause seizures than other carbapenems.
Adult Dose	Base initial dose on severity of infection and administer in equally divided doses; dose may range from 250-500 mg q6h IV for a maximum of 3-4 g/d Alternatively, 500-750 mg q12h IM or intra-abdominally
Pediatric Dose	0-4 weeks and <1.2 kg: 20 mg/kg/dose IV q18-24h Postnatal age <7 days: 20-25 mg/kg/dose IV q12h Postnatal age 7-28 days: 20-25 mg/kg/dose IV q8-12h 4 weeks to 3 months: 25 mg/kg/dose IV q6h Infants >3 months and children <12 years: 15-25 mg/kg/dose IV q6h Infections with fully susceptible organisms: Not to exceed 2 g/d Infections with moderately susceptible organisms: Not to exceed 4 g/d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase CNS side effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dose in renal insufficiency; avoid use in children <12 y; seizures may occur in children with CNS infections; avoid use in children with meningitis

Drug Name	Meropenem (Merrem)
Description	Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negatives and slightly decreased activity against staphylococci and streptococci compared with imipenem.
Adult Dose	1 g IV q8h
Pediatric Dose	Neonates: 20 mg/kg/dose IV q8-12h >3 months: Mild-to-moderate infections: 20 mg/kg/dose IV q8h Meningitis: 40 mg/kg/dose IV q8h
Contraindications	Documented hypersensitivity
Interactions	Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication

Drug Name	Vancomycin (Vancocin)
Description	Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who cannot receive, or have failed to respond to, penicillins and cephalosporins or have infections with resistant staphylococci. For abdominal penetrating injuries, is combined with an agent active against enteric flora and/or anaerobes.
Adult Dose	500 mg to 2 g/d IV divided q6-8h
Pediatric Dose	0-4 weeks: 15 mg/kg/dose IV q8-24h Infants >1 month and children: 40 mg/kg/d IV divided q6-8h
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; caution with other nephrotoxic drugs (eg, loop diuretics, cisplatin); effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal failure, adjust dose according to CrCl; may cause neutropenia; red man syndrome is caused by too-rapid IV infusion (dose given over a few min) but rarely happens when dose given IV over 2 h or as PO or IP administration; red man syndrome is not an allergic reaction

Drug Category: Antifungal agents

These agents are indicated for treating serious fungal infections. Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug Name	Posaconazole (Noxafil)
Description	Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Adult Dose	200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric Dose	<13 years: Not established >13 years: Administer as in adults
Contraindications	Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)
Interactions	Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Drug Category: Antiviral agents

These agents are indicated for treating serious viral (particularly herpetic) infections. Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Drug Category: Vasopressor and inotropic agents

These drugs are administered to support blood pressure, cardiac output, and tissue and organ perfusion.

Drug Name	Dopamine (Intropin)
Description	Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors that in turn produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation produced by higher doses. After initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response obtained. More than 50% of patients are satisfactorily maintained on doses <20 mcg/kg/min.
Adult Dose	1-5 mcg/kg/min IV; not to exceed 50 mcg/kg/min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pheochromocytoma or ventricular fibrillation
Interactions	Alpha- and beta-adrenergic blockers may decrease dopamine effects; alpha- and beta-adrenergic agonists, general anesthesia, and MAOIs increase toxicity or prolong effects of dopamine; coadministration with phenytoin may result in seizures or severe hypotension
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Closely monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during infusion; before infusion, correct hypovolemia with whole blood or plasma, as indicated; monitoring central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia

Drug Name	Epinephrine (Adrenalin)
Description	Considered the single most useful drug in cardiac arrest. Increases coronary perfusion pressure.
Adult Dose	0.1-1 mcg/kg/min IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; during labor (may delay second stage of labor)
Interactions	Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in elderly patients, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias

Drug Name	Norepinephrine (Levophed)
Description	For protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases. After obtaining a response, the rate of flow should be adjusted and maintained at a low normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.
Adult Dose	4 mcg/min IV and titrate to desired response
Pediatric Dose	0.05-0.1 mcg/kg/min IV initially; titrate upward if needed, not to exceed 1-2 mcg/kg/min
Contraindications	Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended
Interactions	Effects increase when administered concurrently with tricyclic antidepressants, MAOIs, antihistamines, guanethidine, methyldopa, ergot alkaloids; atropine may block reflex tachycardia caused by norepinephrine and enhances pressor response
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Correct blood-volume depletion, if possible, before administering therapy; should be administered into a large vein because extravasation may cause severe tissue necrosis; caution in occlusive vascular disease

Drug Category: Colloid solutions

These agents are used for volume expansion.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients whose circulatory, metabolic, and respiratory derangements are not rapidly corrected should be cared for in an intensive care setting.

Transfer

• Transfer should be arranged if the appropriate specialists and intensive care settings are not locally available.

Deterrence/Prevention

• Vaccination is the key to preventing many of these infections.
• Travelers should be warned of the possibility of serious infections during travel.

Complications

• Because the manifestations of systemic inflammatory response syndrome (SIRS) are protean, possible complications are as well. Complications depend on the nature of the triggering insult and the resultant host response.

Prognosis

• Mortality from pediatric SIRS ranges from 9-35%.
• Different insults are associated with different outcomes.
• Host immune status is important in determining outcome.
• Aggressive fluid resuscitation early in the course of SIRS results in decreased mortality rates.

Patient Education

• Parents of newborns should understand that any fever in the first few months of life necessitates immediate evaluation.
• The importance of fever as a marker of possible serious infection, rather than a concerning symptom itself, should be emphasized.
• Front-line providers must recognize the importance of aggressive resuscitation for the patient with early signs of SIRS.
• For excellent patient education resources, visit eMedicine's Infections Center. Also, see eMedicine's patient education article Sepsis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider meningitis in the appropriate setting
• Failure to recognize early systemic inflammatory response syndrome (SIRS) and to treat it appropriately

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Dec 7, 2007