Management of Sepsis

Definition and prognosis

Sepsis, sepsis syndrome, septic shock, and multiorgan dysfunction are all part of a continuum of infection-related systemic illness. Table Definitions for Sepsis, Sepsis Syndrome, Septic Shock and Multiorgan Dysfunction Syndrome gives definitions for each of these entities. The pathogenesis of sepsis is very complex, involving a large number of mediators. A cascade is started when endotoxin or other products of microorganisms enter the circulation, resulting in the release of a variety of mediators from mononuclear phagocytes, endothelial cells and other cells. Initially the proinflammatory cytokines (tumor necrosis factor, IL-1β, IL-6, and IL-8) are elevated, although there are large individual variations. The anti-inflammatory cytokines (IL-10) and soluble cytokine receptors (STNF-RI, IL-lra) are also elevated and seem to have a regulatory function on the host response.

An indication of the extent of the problem that “sepsis” poses can be gained from recent studies. In a 2-month prospective inception cohort study involving 170 ICUs for adults in France, clinically suspected sepsis and confirmed severe sepsis occurred in 9% and 6.3% of the admissions, respectively. The 28-day mortality was 56% for patients with severe sepsis and 60% for those with culture-negative sepsis. Not only is the short-term mortality high in this group of patients but survivors have increased intermediate terms (≥3 month) and mortality rates, as well as considerable physical dysfunction. Perl and coworkers (1995) followed 100 patients with sepsis for 7667 months[AU: how many months?]. Sixty (60%) died a median of 30.5 days after sepsis. Thirty-two of these 60 died within the first month of the septic episode, 7 died within 3 months, and 4 more died within 6 months. Patients with resolved sepsis reported more physical dysfunction, including problems with work and activities of daily living and more poorly perceived general health than norms of the general population. However, their emotional health scores were higher than those in the general population. In a large study, Leibovici and colleagues (1995) studied 1991 patients with bacteremia or fungemia and compared them with matched control group for a matched age, sex, date of admission, and underlying disease. The median age was 72 years. The mortality rate for the study group at 1 month was 26%, at 6 months it was 43%, at 1 year 48%, and at 4 years it was 63%. Corresponding figures for the control group were 7% at 1 month, 27% at 1 year, and 42% at 4 years (P < 0.001).

Table Definitions for Sepsis, Sepsis Syndrome, Septic Shock and Multiorgan Dysfunction Syndrome

Sepsis	Clinical evidence of infection plus signs of a systemic response to the infection which includes 2 or more of: temperature >38 °C or <36 °C; respiratory rate >20 breaths per minute; heart rate >90 beats per minute; WBC >12 × 10⁹/L or >10% bands
Sepsis syndrome	Sepsis plus evidence of altered organ perfusion (one or more of: oliguria [<0.5 ml/kg urine output for at least 1 hour]; hypoxemia [PaO₂/FIO₂ <250]; elevated lactate)
Early septic shock	Sepsis syndrome plus hypotension — systolic blood pressure <90 mmHg or a 40 mmHg decrease below baseline that lasts for <1 hour and responds to a fluid challenge
Refractory septic shock	Sepsis syndrome plus hypotension that lasts >1 hour and does not respond to fluid administration or vasopressors
Systemic inflammatory response syndrome	Meets the definition of sepsis as given above, but this response can be due to infecion but it can also be noninfectious in etiology, e.g., pancreatitis
Multiorgan dysfunction syndrome	Progressive physiologic dysfunction in two or more organ systems after an acute threat to systemic homeostasis
SOURCE: ACCP/SCCM 1992.

Pathophysiology

Bone (1996) contends that the pathogenesis of sepsis has three stages, each of which has a proinflammatory and an anti-inflammatory component. Stage 1 occurs at the site of local injury or infection. Proinflammatory mediators combat infection, remove damaged tissue, and promote wound repair. Anti-inflammatory mediators then dampen the proinflammatory response. If homeostasis is not restored, mediators escape into the systemic circulation — stage 2. Again, if the anti-inflammatory mediators cannot restore homeostatis, shock and organ dysfunction result — stage 3. It is probably best then to characterize sepsis syndrome as cytokine dysregulation.

The pathophysiology of sepsis is complex. There are four overlapping processes< endothelial inflammation, altered regulation of coagulation, abnormalities of vascular tone, and myocardial suppression. Endothelial permeability is increased following exposure to tumor necrosis factor-α, IL-1, platelet-activating factor, leukotrienes, and thromboxane A2. Activation of the complement cascade and neutrophil activation may damage the endothelium. Exposure to endotoxin, tumor necrosis factor-α, IL-1, or to macrophage-derived procoagulants can activate the coagulation system. Exposure of collagen as a result of endothelial damage further activates the contact and coagulation systems and results in polymorphonuclear cell and platelet adhesion. Activity of the fibrinolytic system is initially increased, but it is later inhibited as a result of increased production of plasminogen activation inhibitors or decreased production of tissue plasminogen activation.

Vasodilation due to prostaglandin I₂, thromboxane A₂, histamine, bradykinin, endothelium-derived relaxing factor (nitric oxide) and endothelin-1 occurs. This results in the “warm” phase of septic shock with all the clinical findings of a hyperdynamic circulation. Reversible myocardial depression, ventricular dilation, and decreased left ventricular ejection fraction due to a myocardial depressant substance (not yet identified) occurs in septic shock. A variety of other mediators contribute to myocardial depression as well. PMNs from septic patients show marked shedding of L-selectin (a leukcocyte adhesion molecule that aids in polymorphonuclear cell adhesion to endothelial cells). Shedding of L-selectin reduces the rolling capacity of circulating PMNs and, hence, subsequent contact with cell walls of capillaries and thus decreased delivery to the site of infection.

The successful management of sepsis includes a high index of suspicion so that patients can be identified at the early stage, before they have progressed to septic shock. Appropriate cultures to identify the infecting microorganism and empiric antimicrobial therapy directed at the most likely pathogens are the next steps. Monitor vital signs and transfer to ICU if shock occurs. The ICU management of septic shock is beyond the scope of this chapter.

Some progress is being made in the management of this complex condition. For example, it is now recognized that hemodynamic therapy aimed at achieving supranormal values for cardiac index or normal values for mixed venous oxygen saturation does not reduce morbidity or mortality among critically ill patients. It is noteworthy that in one institution, fatality rates for septic patients with acute respiratory distress syndrome declined from 67% in 1990 to 40% in 1993.

There have been many unsuccessful attempts to modify the sepsis cascade, usually by inhibiting one mediator such as by administering monoclonal antibodies to block the effects of endotoxin or to use antibodies to tumor necrosis factor. Other trials have employed interleukin-1 receptor antagonist or platelet-activating factor antagonist. Early attempts at treatment of sepsis included corticosteroids to downregulate the inflammatory response. None of these therapies has been shown to be beneficial. At this point, use of broad-spectrum empiric antibiotics to cover the most likely pathogens, and careful supportive care in an ICU environment, remain the mainstay of management of these patients.

Prevention of Perioperative Infections

Shortly after the sulfonamides and penicillin were proved effective to treat infection, they were widely used by physicians to prevent infection in situations in which the risk of infection was high. Chemoprophylaxis has had variable success. Antimicrobial administration does not prevent bacterial pulmonary infections in unconscious or artificially ventilated patients, nor in patients with viral upper respiratory tract infections. Antibiotics do not prevent urinary tract infections in patients with indwelling Foley catheters. In fact, using antimicrobials in these settings selects for more resistant flora. Most surveys indicate that using antibiotics for prophylaxis accounts for 25 to 50% of all use of antimicrobials in hospitals. Despite the widespread administration of antibiotics to prevent infection, their use in this way is frequently controversial. Often their use is totally without merit, and potentially dangerous.

Guidelines for chemoprophylaxis

The term chemoprophylaxis implies administration of an antibiotic agent before contamination or infection with bacteria occurs. Early therapy denotes immediate or prompt institution of therapy as soon as contamination or infection is recognized. The latter situation is exemplified by beginning antibiotics after bacterial contamination and/or infection has occurred (e.g., gastrointestinal spillage from a ruptured viscus). Appropriate candidates for chemoprophylaxis to prevent infection include: patients who have clinically significant exposure to an infected individual with particular diseases (e.g., invasive meningococcal disease or influenza); patients exposed to environments with a high potential for acquisition of pathogenic microorganisms (e.g., travelers in the developing world who are at risk for bacterial gastroenteritis or malaria); and patients undergoing procedures or surgery that are likely to result in infection (e.g., a dental procedure in a patient with a prosthetic heart valve, or colorectal surgery in an otherwise healthy patient).

General principles of antimicrobial prophylaxis that should guide selection of an antimicrobial agent have been established.

Principles of antimicrobial prophylaxis include the following:

Benefit must exceed the risks of chemoprophylaxis.
The antimicrobial regimen must be effective against the major anticipated pathogens.
Therapeutic concentrations of an effective chemoprophylactic antimicrobial should be achieved in local tissues at the time of exposure.
Prolonged chemoprophylaxis is unwarranted.

Chemoprophylaxis with penicillin has been successful in the prevention of group A streptococcal pharyngitis. Likewise, prophylaxis with chloroquine, mefloquine, or chloroquine plus proguanil have helped in the prevention of malaria; treatment with amantadine or rimantadine has helped in the prevention of secondary cases of influenza; and rifampin has helped to prevent secondary cases of invasive meningococcal and H. influenzae diseases. Similarly, use of isoniazid has helped prevent systemic tuberculosis, and use of trimethoprim-sulfamethoxazole has helped prevent recurrent urinary tract infections due to E. coli. Unfortunately, in the vast number of other situations in which antimicrobials are given prophylactically, there is little documentation that efficacy outweighs the risk of drug administration, with the likely encouragement of the development of resistant strains.

Table Initial Antimicrobial Maagement of Sepsis and Sepsis Syndrome

A. Community-acquired infection
Most likely source of sepsis	Likely microorganisms	Antimicrobials
1. Urinary tract	Escherichia coli, Enterococcus spp.	Ampicillin and gentamicin, or vancomycin (if penicillin allergic) and gentamicin
2. Lower respiratory tract	Streptococcus pneumoniae Staphylococcus aureus Legionella pneumophila Haemophilus influenzae Aerobic gram-negative rods (e.g., Klebsiella pneumoniae, E. coli) Pseudomonas aeruginosa in those with bronchiectasis or chronic obstructive pulmonary disease	Erythromycin and ceftazidime, or ceftriaxone or a respiratory fluoroquinolone (levofloxacin, trovafloxacin, grepafloxacin)
3. Skin and soft tissues	Streptococcus pyogenes, Staphylococcus aureus	If toxic “strep” syndrome is diagnosed, use clindamycin and gamma globulin. Nafcillin or cloxacillin for all other cases.
4. Unknown source	Aerobic gram-negative bacteria (e.g., E. coli)	Cloxacillin (or nafcillin) and gentamicin
5. Intra-abdominal	Anaerobes; aerobic gram-negative bacteria	Piperacillin and gentamicin; or ampicillin, metronidazole and gentamicin; or piperacillin and ciprofloxacin
B. Nosocomial
— Classify the most likely source of infection as above. — Know the susceptibility patterns of common bacteria isolated in your institution. In particular, you must know if methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus is present in your hospital. — It is not uncommon that multidrug-resistant aerobic gram-negative bacteria such as Stenotrophomonas maltophilia can be present in an intensive care unit. — Enterobacter aerogenes and E. cloacae have depressed genes coding for extended spectrum beta-lactamases. When these bacteria are treated with cephalosporins (to which they are susceptible in vitro), the derepression is removed and the organism produces the β-lactamases and is now resistant to the cephalosporins. Quinolones such as ciprofloxacin or aminoglycosides are usually better choices for therapy of enterobacterial infections than are cephalosporins.
* Ampicillin sodium, ceftazidime, ceftriaxone sodium, ciprofloxacin HCl, clindamycin HCl, cloxacillin sodium, erythromycin, gamma-globulin, gentamicin sulfate, grepafloxacin, levofloxacin, metronidazole, nafcillin sodium, penicillin, piperacillin sodium, trovafloxacin, vancomycin HCl. ABBREVIATION: chronic obstructive pulmonary disease, chronic obstructive pulmonary disease.

Surgical prophylaxis

Antimicrobial prophylaxis for the prevention of postoperative infections has become accepted as standard care over the years. Controversies remain over the optimal choice, timing, and duration of prophylactic antimicrobials. Surgical wounds have been classified by the National Research Council as clean, clean-contaminated, contaminated, and dirty (see Table Surgical Infection Rate by Type of Surgical Procedure). Surgical site infections represent 24% of nosocomial infections. The CDC National Nosocomial Infection Surveillance Program has reported wound infection rates by class of wounds as follows: clean, 2.1%; clean-contaminated, 3.3%; contaminated 6.4%; and dirty, 7.1%. Haley and coworkers (1981) have suggested that surgical site infections increase length of stay by 1 week and can add up to 20% of the cost of hospitalization. Prophylaxis is routinely recommended for clean-contaminated and contaminated wounds, whereas antimicrobial treatment is recommended for dirty wounds.

Table Surgical Infection Rate by Type of Surgical Procedure^a

Type of surgery	Definition	A pproximate percentage of acute lymphoblastic leukemia operations	Reported infection rate (%)	Antibiotic prophlaxis recommended?
Clean	No entry into the respiratory, gastrointestinal or genitourinary tracts	75	1–5	No
Clean with insertion of prosthetic material or device	No entry into the respiratory, gastrointestinal or genitourinary tracts	1–4	1–5 but high morbidity and mortality	Yes
Clean-contaminated	Unavoidable entry into the respiratory, gastrointestinal or genitourinary tracts (e.g., appendectomy, hysterectomy)	14–5	8–15	Yes
Contaminated	Fresh trauma, major break in sterile technique, gross spillage of gastrointestinal content, entry into infected urinary or biliary tracts	4–5	15–20	Yes
Dirty	Old trauma wounds with devitalized tissue, foreign bodies, fecal contamination	4–5	30–40	Antibiotics are given to treat established infection
^aInfection rates listed are the expected infection rates in the absence of antibiotic prophylaxis. SOURCE: Reproduced with permission from Gilbert 1984.

Clean wounds have no break in aseptic technique, and the gastrointestinal, respiratory, or genitourinary tracts are not entered. These wounds undergo primary closure, and inflammation is not encountered. The prophylaxis of clean wounds remains highly debated. Insertion of prosthetic joints and vascular surgery requiring use of prosthetic material are now included in guidelines for surgical wound infection prophylaxis, whereas prophylaxis for hernia repairs and mastectomy require further data before recommendations can be made.

The development of an infection in a surgical wound depends on the microorganism (dose and virulence), the host’s resistance (underlying physiological status), and the condition of the surgical site at the end of surgery. Host factors associated with increased risk of wound infections include the following: extremes of age, malnutrition, active infection elsewhere, obesity, the presence of diabetes mellitus, and the use of corticosteroid therapy. Low albumin, weight loss, and malignancy have also been suggested as host risk factors. Surgical factors that increase the risk of wound infections include contaminated or dirty wounds; prolonged preoperative hospitalization (1 week or more); emergency operation; prolonged (more than 2 hours) surgery; shaving the operation site before the procedure; use of an electrosurgical knife; and insertion of drains through the wound at closure. Numerous studies have evaluated the role of chemoprophylaxis in the prevention of surgical wound infections. The consensus is that prophylactic antimicrobials are of benefit when an operation is associated with a high risk of infection or when a surgical site infection would have serious consequences for the patient.

In general, the efficacy of chemoprophylaxis depends on high antibiotic activity being present in blood and tissues at the time the incision is made and administration of an agent that is active against the most likely contaminating microorganism(s). Therefore, prophylactic antibiotics should be given within 2 hours of the surgery to achieve maximal concentration of drug at the site of the procedure. A second dose of antibiotic may have to be given intraoperatively if surgery is prolonged beyond the antimicrobial agent’s half-life.

Since staphylococci and coliform bacteria (E. coli, Proteus spp., Klebsiella spp., Enterobacter spp.) are usually the most common causes of wound infections; first-generation cephalosporins such as cefazolin are usually the most appropriate agents for surgical wound infection prophylaxis. Second-generation cephalosporins with anaerobe activity (e.g., cefotetan) or cefazolin plus metronidazole should be used when there is concern that anaerobic bacteria, in addition to staphylococci and coliforms, may contaminate the wound. Such procedures include surgery on the lower gastrointestinal tract. Vancomycin can be used as prophylaxis for orthopedic or neurosurgical procedures when the risk of methicillin-resistant staphylococcal (S. aureus or coagulase-negative staphylococci) infection is high. The risk of emergence of vancomycin-resistant enterococci and S. aureus is such that routine use of vancomycin as a prophylactic agent for these procedures is discouraged (CDC 1994c). There is no role for third-generation cephalosporins in surgical wound infection prophylaxis, as they have limited activity against staphylococci and anaerobic bacilli. Prophylactic antibiotics are indicated before transrectal prostate biopsy. Ciprofloxacin or norfloxacin are currently used. There is controversy as to whether oral metronidazole should be given as well.

There are no data to suggest that the rate of postoperative wound infection is lower if antimicrobial therapy is continued after the surgical procedure is completed. Indeed continuation of antimicrobial prophylaxis beyond 24 hours leads to the emergence of resistant bacteria and wound infections caused by antibiotic-resistant microorganisms.

Prevention of Endocarditis

Prevention of endocarditis by use of antibiotics before procedures that may cause transient bacteremia has been recommended for patients with selected valvular and congenital cardiac malformations. However, no controlled trials document the efficacy of such recommendations in preventing viridans streptococcal endocarditis after dental or upper respiratory tract procedures, or enterococcal endocarditis after gastrointestinal or genitourinary procedures. Prophylaxis for endocarditis is recommended for patients with the following underlying conditions: prosthetic valves, congenital cardiac malformations, surgically constructed systemic-pulmonary shunts, rheumatic and other acquired valvular dysfunction, idiopathic hypertrophic subaortic stenosis, previous history of bacterial endocarditis, and mitral valve prolapse with insufficiency. Prophylaxis for endocarditis is not recommended for patients who have undergone previous coronary artery bypass graft surgery or selected atrial secundum septal defects, cardiac pacemakers and implanted defibrillators, or physiologic, functional, or innocent heart murmurs.

Table Efficacy of Preoperative Prophylxis in Reducing Postoperative Surgical Infections and Incisional

INFECTIONS

Efficacy established for:

Colorectal operation

High-risk gastroduodenal surgery (gastric ulcer, relief of obstruction, stopping hemorrhage, or patients with achlorhydria)

Appendectomy (inflamed appendix)

High-risk biliary surgery (patients older than 70 years, with cholecystitis, undergoing common bile duct

explorations or removal of stones, or with jaundice)

Hysterectomy (vaginal)

Cesarean section in high-risk patients

Pulmonary resection

Vascular grafts of abdomen and lower extremity

Hip nailing, total hip arthroplasty, open fracture reduction Possible efficacy for:

Gastric bypass

Coronary bypass grafting

Prostatic surgery

Cardiac pacemaker implantation

Unproven efficacy for:

Low-risk gastroduodenal surgery

Low-risk cholecystectomy

Clean neurosurgery procedures without insertion of any prosthesis

Clean plastic surgery procedures without insertion of any prosthesis

External ventriculostomy

Herniorrhaphy, thyroidetomy, mastectomy, tonsillectomy

Repair of traumatic lacerations

SOURCE: Reproduced with permission from Conte et al. 1986.

Chemoprophylaxis is indicated before procedures that may lead to transient bacteremia, such as dental procedures that induce gingival bleeding, tonsillectomy, manipulation or biopsy of the respiratory, gastrointestinal, or genitourinary tracts, and incision and drainage of infected tissue. Clinicians should refer to schedules for endocarditis chemoprophylaxis when selecting the optimal regimen. In general, oral amoxicillin or intravenous ampicillin is given to prevent endocarditis. For higher-risk patients (those with prosthetic cardiac valves) undergoing procedures involving the gastrointestinal or urinary tracts, gentamicin is given along with ampicillin. Clindamycin, cephalexin, azithromycin, or vancomycin can be used in penicillin allergic patients. Therapy should be given just before the procedure begins so that peak concentrations of drug will be reached during the procedure. Drug therapy should not be prolonged (one dose before the procedure) so that more resistant organisms will not colonize the affected mucosal surfaces and infect the patient.

Principles

Antimicrobial prophylaxis can prevent and decrease the postoperative incidence of infection in only a select number of clinical conditions. When an antimicrobial is appropriately administered, the choices in timing, agents employed, and duration of chemoprophylaxis are crucial so as to maximize benefit and minimize toxicity. In general, one dose of an agent that kills the most likely pathogen, at the time of greatest risk of contamination or exposure, is considered optimal therapy.

Immunoprophylaxis

Acquired host resistance following infection is part of the natural history of many diseases. Long-lasting immunity is not common to all infections but usually follows most acute viral infections. Resistance to recurrent infection with bacteria and other higher organisms is more variable. Resistance is frequently attended by measurable increases in specific immunoglobulins and reactions mediated by the cellular immune system. The object of immunotherapy is to safely duplicate or exceed the functional resistance in the host that normally follows a natural infection. In contrast to antimicrobial prophylaxis, optimal immunotherapy converts the susceptible individual into a resistant host, offering protection against the risk of infection without recourse to the repeated use of drugs.

Immunotherapy is the most effective therapy available for many viral infections, since antiviral chemotherapy has not been as well developed as antibacterial chemotherapy. Immunotherapy may be administered passively through the parenteral administration of preformed specific immunoglobulin from human or animal sources. Active immunity can be induced through the use of killed or attenuated agent vaccines, through the administration of subunit chemically defined vaccines, or by giving modified but antigenically active products of an agent in the form of toxoids.

Principles

An ounce of prevention is worth a pound of cure: A milliliter of effective vaccine is often of greater value than any subsequent chemotherapeutic intervention.

Each newborn receives the benefits of natural passive immunization through the transplacental transfer of immunoglobulins from the maternal circulation. These immunoglobulins provide the newborn with sufficient protection to avoid infection with a wide variety of agents in the neonatal period. This protection wanes with the half-life of the maternal immunoglobulin G and has largely disappeared at 2 to 4 months of age.

Short-term protection against a wide group of diseases can be conveyed through the parenteral administration of immunoglobulins containing specific antibodies. Although past indications for this type of treatment have included prophylaxis or therapy of poliomyelitis, rubella, hepatitis, diphtheria, mumps, pertussis, and rubeola infections, these illnesses are now better managed by active immunization programs. Of these products, only botulinum immune serum, tetanus immune globulin, rabies hyperimmune globulin, hepatitis B immune globulin, and human immune globulin for the prophylaxis of hepatitis A are commonly used. Varicella-zoster immune globulin is in short supply and therefore only available under strict control for high-risk situations. Cytomegalovirus immunoglobulin has been available since 1990 for use in transplantation patients. Varicella-zoster immunoglobulin can be administered to nonpregnant females or immunocompromised individuals within 96 hours of the infectious contact and to newborns of nonimmune mothers who develop varicella within a period of 5 days before or up to 2 days after delivery.

Table Passive Immunotherapy Available in the United States

Preparation^a^,b	Use
Botulism antitoxin (equine)	Botulism (treatment)
Cytomegalovirus immunoglobulin (intravenous)	Cytomegalovirus (prophylaxis) in transplant recipients
Diphtheria antitoxin (equine)	Diphtheria (treatment)
Immune globulin (pooled)	Hepatitis A and measles (prophylaxis)
Immune globulin (pooled) (intravenous)	Replacement of antibody deficiency^c
Hepatitis B immune globulin	Hepatitis B (prophylaxis)
Rabies immune globulin	Rabies (prophylaxis and treatment)
Tetanus immune globulin	Tetanus (prophylaxis and treatment)
Vaccinia immune globulin	Smallpox (prophylaxis)
Varicella-zoster immune globulin	Varicella (prophylaxis)
^aSpecific antibodies unless otherwise specified ^bAdministered intramuscularly unless otherwise specified ^cAlso used in treatment of idiopathic thrombocytopenic purpura, Kawasaki disease, and chronic lymphocytic leukemia.

In the absence of previous immunizations, antisera for the prophylaxis or treatment of diphtheria, pertussis, measles, and polio are of some value, but these antisera are not presently widely available. The CDC is a reliable resource for information about immunoprophylaxis in general and maintains a clearinghouse for those products not commercially available. The CDC also maintains a variety of other hyperimmune sera for use in diseases not commonly seen in the United States, including a number of the more exotic arboviruses and other viral illnesses causing hemorrhagic fever.

Passive immunization is limited in its effectiveness by the half-life of immunoglobulin G (22 to 30 days). Thus, a relatively short period of protection is afforded by this approach. All hyperimmune sera and disease-specific immunoglobulins are in limited supply and are expensive. To be effective, they usually require comparatively large volumes for parenteral administration, and they cause unpleasant local reactions. Allergic reactions may be apparent immediately after injection and may be life-threatening. More commonly, the reactions are of the delayed-hypersensitivity or serum-sickness type. Careful questioning of the patient for a history of allergy to the animal that served as the source for the antiserum and possibly skin testing with the antiserum to be used should be considered before the administration of these agents. If the skin tests are positive, but the need is critical, a carefully administered “desensitization” program may be undertaken using increasing concentrations of the material. Appropriate procedures to accomplish desensitization have been described. As most immune globulins are available from human sources, antisera from animal sources are becoming less frequently required. Administration of immune globulins from human sources causes less adverse events but remains undesirable as the threat of transmission of infectious agents from infusion of immune globulin still exists.

Use of immunotherapy has been attempted for the treatment of septic shock. Polyclonal and monoclonal antibodies of the IgM and immunoglobulin G classes that bind to the core lipopolysaccharide moiety of gram-negative bacterial lipopolysaccharide protect against shock in animal models. A multicenter trial, using the polyclonal antibody J5, reported a reduction in mortality in gram-negative sepsis from 39% to 22% in human subjects. Further studies with monoclonal antibodies against the lipid A moiety of gram-negative lipopolysaccharides (HA-1A), IL-1 receptor antagonist (IL-1RA), and tumor necrosis factor have all failed to show benefit convincingly except in very well defined subsets of patients. Further monoclonal antibodies are in developmental and clinical trial phases. As more is known about the sepsis biochemical cascade, it appears quite certain that immunotherapy will play only a small role.

Intravenous immunoglobulin therapy has been reported to be effective in conditions such as Kawasaki syndrome and idiopathic thrombocytopenic purpura (idiopathic thrombocytopenia purpura). There are case reports of successful treatment of patients with streptococcal toxic shock syndrome or necrotizing fascitis with Intravenous immunoglobulin administration in combination with antimicrobial therapy. Evidence suggests an antitoxin role of Intravenous immunoglobulin in these patients is responsible for the decrease in morbidity and possible avoidance of mortality.

Active immunization

Active immunization depends on the host’s immune system response to vaccines to provide the protection usually acquired by natural infection. Vaccines may be either living (i.e., contain live microbes) or nonliving (i.e., contain dead microbes). Live vaccines contain organisms that are attenuated and therefore are capable of only limited replication in a normal host. Vaccinia, developed by Jenner in 1796, was the first clinically successful live vaccine. It is a product containing bovine poxvirus that has limited ability to invade the human host but is nevertheless able to produce sufficient local and regional infectivity to ensure that a host response results in resistance of the recipient to subsequent smallpox infection. The resistance was not lifelong, and vaccination had to be repeated approximately every 3 years. The worldwide elimination of smallpox in the 1980s by an effective immunization program is the most dramatic example of how vaccines can be used for the well-being of humankind. Since the risk of adverse reaction to smallpox vaccine now outweighs the chance of acquiring the disease, vaccination is recommended only for those working in smallpox research laboratories. Other routinely used vaccines are listed in Table Routine Vaccines for Humans.

Live vaccines may be administered either by natural routes (orally) as in oral polio vaccine or by an artificial route (parenterally) as in the presently available live measles vaccine. There is a theoretical advantage in the use of the natural route, since there is good evidence that the resultant formation of local (mucosal) antibodies is important in protection from subsequent wild-type infections. Nonliving vaccines may be divided into four groups: 1) suspensions of whole killed agents (e.g., influenza vaccine and typhoid vaccine); 2) suspensions of nonreplicating subparticles of infectious agents (e.g., meningococcal or pneumococcal polysaccharide vaccines); 3) modified products of infecting organisms (e.g., tetanus and diphtheria toxoid vaccine) and; 4) new subunit vaccines that contain chemically defined reagents (e.g., hepatitis B virus vaccine). The routine schedule for the active immunization of normal infants and children in the United States is presented in Table Schedule for Active Immunization of Normal Infants and Children. Certain combinations of live vaccines may be given simultaneously, but the close sequential administration of individual live vaccines and immunoglobulins is not recommended because of evidence of interference with immunogenicity leading to vaccine failure (CDC 1994). A delay of 2 weeks after vaccination should be allowed before giving immunoglobulins.