Infection 3: Sepsis in Adults Portal
PEDS: For newborn sepsis, see Vol III—NRP6, Meningitis/Sepsis in Newborn Portal and PED8, Sepsis
Sepsis is but one stage of the body’s inflammatory and procoagulatory response to infection. The progressive continuum of clinical stages of sepsis is currently defined as follows1:
Management of Septic Shock and Severe Sepsis—Definitions
Systemic Inflammatory Response Syndrome: Two of the following signs of inflammation:
- Temp > 100.9ºF (38.3ºC) or < 96.8ºF (36ºC)
- Heart rate > 90 bpm
- Respiratory rate > 20 or PaCO2 32 mm Hg
- WBC > 12 000 < 4000 or > 10% bands
Sepsis—SIRS resulting from infection (bacterial, viral, fungal or parasitic)
Severe Sepsis—Sepsis associated with signs of at least one organ dysfunction, hypoperfusion, or hypotension
Septic Shock—Sepsis-induced hypotension persisting despite adequate fluid resuscitation
Multi-organ dysfunction syndrome—Presence of altered function of two or more organs in an acutely ill patient such that hemostasis cannot be maintained without intervention.
Initial
Evaluation
History and physical exam
Laboratory studies
- Blood cultures (at least 2 with one drawn percutaneously and one drawn through each vascular access devise if in place > 48 hours)
- Cultures of urine, CSF, sputum, wound or other body fluids
- CBC, coagulation, BUN, Cr, HCO2, liver enzymes, amylase, UA
- Lactate (if > 4 mmole/L = severe sepsis)
Initial
Resuscitation
Fluids—This
is the first priority. Give 500 to 1000 cc of crystalloid over 30
minutes, then re-evaluate. Septic shock patients may require 6 to 10
liters of fluid in the first 24 hours.
Antibiotics—Give broad-spectrum antibiotics within the first hour after diagnosis of sepsis (after cultures obtained).
If after initial fluid bolus, the patient continues to be hypotensive (Septic shock) or shows signs or at least one organ dysfunction or elevated lactate (> 4 mmole/L) (Severe sepsis), initiate early goal directed therapy (below)
Early Goal-Directed Therapy
-
Place central line for monitoring CVP and central venous O2 saturation.
-
Fluid resuscitation. Administer normal saline 500 cc boluses until CVP is 8 to 12 (12 to 15 in mechanically ventilated patients). If unable to monitor CVP, continue fluid resuscitation until there is subtle evidence of intravascular volume overload (ie, Basilar rales on lung auscultation or a decrease in pulse oximetry.)
-
Vasopressor therapy. If the patient remains hypotensive despite adequate fluid resuscitation, place arterial line. If mean arterial pressure (MAP) is < 65, begin vasopressor therapy with norepinephrine or dopamine. Note: Give vasopressors through a central line, and place an arterial line in all patients receiving vasopressors. Maintain MAP of 65 to 90. If unable to provide arterial line or CVP monitoring, consider early transfer to tertiary level ICU.
-
Measure central venous O2 saturation (either by continuous monitor or individual sample). If ScvO2 < 70, check Hgb. If < 10 transfuse 1 unit of PRBC. If > 10, start inotropic therapy with dobutamine (preferred, especially if the patient is already receiving norepinephrine as a vasopressor) or dopamine. Also consider intubation and mechanical ventilation.
-
Steroids (stress dose). Glucocorticoid therapy may be beneficial to patients in severe septic shock (defined as a systolic BP < 90 mm Hg for more than 1 hour despite adequate fluid resuscitation plus vasopressor administration), especially if begun within 8 hours of the onset of shock. Start in any patient on vasopressor therapy because of relative adrenal insufficiency. Administer hydrocortisone 50 mg IV every 6 hours for 7 days. Consider the need to taper the dose following the 7-day course of treatment. May also give dexamethasone 3 mg IV every 6 hours.
-
Recombinant activated protein C (Xigris®). Consider giving this to patients who are at high risk of death (Apache score > 25, sepsis-induced multiorgan dysfunction, or sepsis-induced acute respiratory failure with no contraindication to absolute bleeding risk)
-
Glycemic control. Maintain blood glucose < 150. This may require a continuous insulin infusion.
-
DVT prophylaxis. Severe sepsis patients should receive deep vein thrombosis prophylaxis with either low-dose unfractionated heparin (5000 units SQ every 12 hours) or low molecular weight heparin (Lovenox 30 mg SQ every 12 hours).
-
Stress ulcer prophylaxis. Administer a proton pump inhibitor or H2 blocker to prevent stress ulcers.
-
Mechanical ventilation in acute lung injury/adult respiratory distress syndrome (ARDS). In patients who are mechanically ventilated, use low tidal volumes (6 mL/kg of predicted body weight) with the goal of maintaining end-expiratory plateau pressures of < 30 cm H2O.
End-organ dysfunctions include the ARDS, acute renal failure, disseminated intravascular coagulation (DIC), CNS changes, and cardiovascular dysfunction. If more than one organ is involved, it is referred to as multiorgan dysfunction syndrome. End-organ dysfunction and mortality have been shown to increase with progression through the above clinical stages.2
Non-infectious mimics of sepsis (sometimes called pseudosepsis) include: acute myocardial infarction, pulmonary embolism, GI hemorrhage, pancreatitis, diabetic ketoacidosis (DKA), systemic vasculitis, burns, trauma, and others. The boundary of this distinction becomes a bit blurry when infection interacts with non-infectious stimuli.
In order of frequency, the site of infection that gives rise to severe sepsis is lung> abdomino-pelvic area> urinary> soft tissue> and other.3 Note that in 20% to 30% of patients, a site is not determined. (See Vol III—IN4, Abdominal Sepsis for a more directed discussion on abdominal sepsis.)
Urosepsis is common in pregnancy (due to obstruction of the urinary tract) and in older patients. Lists of likely pathogens vary from site to site. Blood cultures are also only positive about 30% of the time,4 raising the question of true negatives (non-infectious SIRS, pseudosepsis, sepsis mimics) versus false negatives. Mortality rates are higher for patients who don’t receive antibiotics promptly.5 Until a rapid, reliable test becomes available that can rule out infection, empiric antibiotic therapy is the recommended treatment where sepsis is suspected. (No one medication can cover all possible bacterial scenarios [much less pathogenic viruses, fungi, or rickettsia].)
General management of sepsis patients begins with suspecting infection as a cause of the patient’s systemic response and aggressively searching for the source and the site with diagnostic tests to confirm infection. Culturing the sites of potential source(s) is critical, especially the blood. If an indwelling central line can be removed (clinical judgment indicated), culturing the tip may prove diagnostic. After cultures are taken, start empiric antibiotics pending results.
Simultaneously, the team must aggressively search for alternative (non-infectious) explanations for the patient’s condition. Suspected sepsis is a condition where extensive testing adds value to diagnosis and management.
Whether infection is ultimately proven or not, the third critical task is monitoring for target organ dysfunction/failure and intervening with the appropriate support:
-
Pulmonary: Sepsis severely stresses the lungs. Many patients with sepsis progress to ARDS, which is often mistaken for pneumonia or CHF. Early controlled ventilation is a critical intervention.
-
Cardiovascular: Identify perfusion abnormalities (preload, pump, postload), follow by fluid management and, if necessary, pharmacologic cardiac support. Cardiac troponin may be elevated indicating myocardial dysfunction.
-
CNS: The brain is acutely sensitive to the hypoperfusion and hypoxic effects of sepsis. Although meningitis is usually a recipient of infection from somewhere else (rather than the source of sepsis), patients with CNS-related signs and symptoms and suspected sepsis without a source need to be worked up for CNS infection.
-
Renal: BUN and creatinine elevation may indicate renal dysfunction. Correcting volume deficits and hypotension are current mainstays of renal dysfunction management.
-
Gastrointestinal: Hepatic failure is uncommon. Septic shock can cause ileus. Sepsis increases nutrition demands, which is not necessarily an emergency concern.
-
Hematologic: Coagulation dysfunction is assuming a greater importance in this disease (although full blown disseminated intravascular coagulation [DIC] is rare) as evidenced by the new recombinant activated protein C [rAPC] treatment. Thrombocytopenia may be an early sign of coagulation dysfunction in severe sepsis.
Consult with surgery if you suspect an intra-abdominal or pelvic source of sepsis. It is helpful to consult with an infectious disease specialist in those cases in which you suspect sepsis. Consultation should not delay therapy.
Specific non-antibiotic drug therapy
Recently recombinant activated protein C (rAPC also known as drotrecogin alfa) has been shown to be helpful for carefully selected patients with severe sepsis and septic shock, reducing the relative risk of death by 20%.6 By stimulating fibrinolysis, rAPC works against the procoagulant processes of sepsis. (It seems to counter some of the inflammatory processes also.) Inclusion criteria include:
- infection criteria: known or highly suspected infection
- modified systemic inflammatory response syndrome (SIRS) criteria.
- specific evidence/criteria of end organ dysfunction
Exclusion criteria include: patients with a high risk of bleeding, children, pregnancy or breastfeeding, immunosuppressed patients, thrombocytopenic/neutropenic patients, and certain medications.
Both inclusion and exclusion criteria are lengthy. If your patient fits these general criteria, contact pharmacy and/or read the package insert information for specific details before beginning therapy. Dose: 24 μg/kg/hours for 96 hours.
Drotrecogin alfa should be considered in severe sepsis patients with Apache II scores > 25.
Antibiotic drug therapy
Antibiotic therapy assumes several things: a bacterial cause, adult dosages, normal renal function, knowledge of whatever drugs are chosen, and knowledge of local bacterial resistance patterns. Note that many varied antibiotic recommendations exist besides those noted.
Non-neutropenic adult with life-threatening disease and an unclear source (usual causative agents: gram-positive cocci and gram-negative bacilli)7:
Primary treatment:
- imipenem 0.5 g IV every 6 hours or meropenem 1 g IV every 8 hours.
- Add vancomycin 1 g IV every 12 hours if methicillin-resistant Staphylococcus aureus is suspected.
- Add quinupristin/dalfopristin 7.5 mg/kg IV every 8 hours or linezolid 600 mg IV every 12 hours if vancomycin-resistant enterococci are suspected.
Alternative treatment:
- an aminoglycoside
(amikacin, tobramycin, or gentamycin; see below for
dosing alternatives) and one of the below:
- cefotaxime: 2 g IV every 8 hours (or every 4 hours if life threatening)
- ceftizoxime: 2 g IV every 4 hours
- ceftriaxone: 2 g IV every 12 hours
- ceftazidime: 2 g IV every 8 hours (anti-pseudomonal activity)
- cefepime: 2 g IV every 12 hours (anti-pseudomonal activity)
- ticarcillin/clavulanate: 3.1 g IV every 4 hours
- piperacillin/tazobactam : 3.375 g IV every 4 hours
- Add vancomycin 1 g IV every 12 hours if methicillin-resistant Staphylococcus aureus is suspected.
- Add quinupristin/dalfopristin 7.5 mg/kg every 8 hours or linezolid 600 mg IV every 12 hours if vancomycin resistant enterococci are suspected.
Aminoglycosides. Aminogycosides have serious side effects with no known way to eliminate these risks. Proper dosing may decrease the risks. These agents can be dosed once daily or by multiple daily dosing. After the loading dose, all subsequent doses are calculated according to renal function and peak/trough serum levels. This information is available in many reference texts and your pharmacy.
- amikacin
- once daily: 15 mg/kg IV every 24 hours
- multiple dose daily: 7.5 mg/kg every 12 hours
- tobramycin
- once daily: 5.1 mg/kg IV (7 if critically ill) every 24 hours
- multiple dose daily: 2 mg/kg load, then 1.7 mg/kg every 8 hours
- gentamycin
- once daily: 5.1 mg/kg IV (7 if critically ill) every 24 hours
- multiple dose daily: 2 mg/kg load, then 1.7 mg/kg every 8 hours
Neutropenic (absolute neutrophil count < 500mm3) adult with sepsis (agents of most concern are gram-negative bacilli; also Staphylococcus aureus, Streptococci viridans, and others):
Standard management of these
patients has included admission and broad spectrum antibiotics. A new
trend is risk-based therapy, wherein neutropenic patients with fever
are differentiated into low, moderate, and high-risk groups. Low-risk
groups are treated as outpatients with PO or IV antibiotics; moderate
risk groups are initially admitted for IV antibiotics with early
discharge on oral therapy; high-risk groups are treated the standard
way.8
Note: fungi are sometimes a cause of the primary infection but
more likely the cause of a secondary infection due to prior use of
broad-spectrum antibiotics in these patients. Fungal treatment is not
covered here.
Management considerations9:
- Patients who can’t mount the usual response to infection are hard to diagnose: a meticulous exam is indicated, along with liberal testing.
- Promptly culture for bacteria and fungi, paying particular attention to indwelling catheters and devices. Vascular access devices (such as a Hickman) can generally be left in place while evaluating the initial response to antibiotic therapy. Consult with a specialist on this topic.10
Adjunctive treatment considerations11:
- Routine antiviral drugs are not recommended unless evidence of infection exists.
- Granulocyte transfusions are not routinely used.
- Colony-stimulating factors are not routinely used but are considered in selected cases. See reference for guidance.12
Antibiotic considerations13,14:
monotherapy (not full coverage) in patients with suspected bacteremia
who do not appear too ill; use one of the following:
- ceftazidime: 2 g IV every 8 hours
- cefepime: 2 g IV every 8 hours
- imipenem: 0.5 g IV every 6 hours
- meropenem: 1 g IV every 8 hours
duo therapy (broader coverage) in patients who are sicker/suspected sepsis; one of the following (see above dosing):
- ceftazidime plus aminoglycoside
- cefepime plus aminoglycoside
- imipenem plus aminoglycoside
- meropenem plus aminoglycoside
- ticarcillin/clavulanate: 3.1 g every 4 hours IV plus aminoglycoside
- piperacillin/tazobactam : 3.375 g IV every 4 h IV plus aminoglycoside
Add vancomycin 1g every 12 hours IV if any of the following apply:
- hypotensive patient
- IV catheter infection
- current or recent antibiotic prophylaxis with fluroquinolone
- suspected methicillin-resistant Staphylococcus aureus
- suspected penicillin-resistant Streptococci viridans
- suspected drug-resistant Streptococcus pneumoniae
- severe mucous membrane damage present from chemo
References
- American College of Chest Physicians-Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-875.
- Rangel-Frausto M, Pittet D, et al. The natural history of the systemic inflammatory response syndrome (SIRS). JAMA. 1995;273(2):117-123.
- Wheeler A, Bernard G. Treating patients with severe sepsis. N Engl J Med. 1999;340(3):207-213.
- Wheeler et al.
- Wheeler et al.
- Bernard G, Vincent J-L, et al. Efficacy and safety of recombinant human activated protein c for severe sepsis. N Engl J Med. 2001;344(10):699-709.
- Gilbert D, Moellering R, Sande M. The Sanford Guide to Antimicrobial Therapy, 32nd Ed. 2002.
- Rolston K. New trends in patient management: risk-based therapy for febrile patients with neutropenia. CID 1999;29(Sept):515-21.
- Hughes WT, Armstrong D, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis.2002. Mar 15;34(6):730-51.
- Mermel LA, Farr BM, et al. Guidelines for the management of intravascular catheter-related infection. Clin Infect Dis. 2001;32:1249-72.
- Hughes WT et al.
- Ozer H, Armitage JO, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 2000; 18:355885.
- Gilbert D, Moellering R, Sande M. The Sanford Guide to Antimicrobial Therapy, 32nd Ed. 2002.
- The Medical Letter. Vol 43 2001. Issue 1111-1112.
Sepsis Guidelines *
Sepsis Criteria Identified:
|
Guiding Principles:
|
| If patient on general care floor, call rapid response team. |
| 1.
Give appropriate
antibiotics 2. Check labs 3. Give full bolus crystalloid 20 mL/kg over 30 minutes |
Sepsis
Severe Sepsis
Antibiotic Selection for Sepsis Protocol
| Site | Suggested Antibiotics | Potential Medications with Dosages |
| Urinary
Tract |
Zosyn
+ (levofloxacin OR gentamicin) + vancomycin. If PCN allergic, use aztreonam in place of Zosyn |
Zosyn
4.5 g IV q6h Levofloxacin 750 mg q24h Gentamicin 2 mg/kg IV q8h Vancomycin 1 g IV q12h Aztreonam 2 g IV q8h |
| Skin
and Soft Tissue Infections |
Zosyn
(+ levofloxacin if gram- negative organisms suspected) + vancomycin. Add clindamycin if risk of toxin release.Toxin release strongly suggests surgical disease, eg, necrotizing fasciitis, gangrene, abscess. |
Zosyn
4.5g IV q6h Levofloxacin 750 mg IV q24h Vancomycin 1 g IV q12h Clindamycin 900 mg IV q8h |
| Respiratory | Use Community Acquired Pneumonia (CAP) border set, with the addition of vancomycin for patients where MRSA risk possible and Linezolid for patients where MRSA is likely or strongly suspected. | See
CAP antibiotic selection guideline. |
| Vascular
Device Infection |
Zosyn
and Vancomycin. If PCN allergic, Aztreonam in
place of Zosyn. One blood
culture from catheter, one blood culture peripherally. |
Zosyn
4.5 g IV q6h Levofloxacin 750 mg IV q24h Vancomycin 1 g IV q12h Clindamycin 900 mg IV q8h |
| Bacteremia/ Unknown Source |
Zosyn
+ vancomycin. If
PCN allergy, aztreonam + metronidazole in place of Zosyn. (If gram-negative organisms suspected consider double covering with levofloxacin or gentamicin) |
Zosyn
4.5 g IV q6h Vancomycin 1 g IV q12h Aztreonam 2 g IV q8h Metronidazole 500 mg IV q6h |
| Abdominal | Zosyn
+ vancomycin.
If PCN allergy, aztreonam + metronidazole in place of Zosyn. |
Zosyn
4.5 g IV q6h Levofloxacin 750 mg IV q24h Vancomycin 1 g IV q12h Aztreonam 2 g IV q8h Metronidazole 500 mg IV q6h |
| Neurological | Meningitis/encephalitis: Ceftriaxone + vancomycin +/- ampicillin (if risk of Listeria) + dexamethasone (preferably given prior to antibiotics). |
Dexamethasone
10 mg
IV q6h X 2-4days Ceftriaxone 2 g IV q12h Vancomycin 1 g IV q12h Ampicillin 2 g IV q4h |
| Neurological | Abscess/Meningitis
w/hardware: meropenem + vancomycin |
Meropenem
2 g IV q8h Vancomycin 1 g IV q12h |
| Febrile
Neutropenia |
Vancomycin
+ Zosyn +
Levofloxacin or Gentamycin. Typical etiology is gram- negative flora. |
Vancomycin
1 g IV q12h Zosyn 4.5 g IV q6h Aztreonam (if PCN allergic) 2 g IV q8h Levofloxacin 750 mg IV q24h Gentamycin 2 mg/kg IV q8h |
| Diarrhea
(Acute Syndrome) |
Metronidazole
+ PO vancomycin. Vancomycin enema if oral vancomycin not possible |
Metronidazole
500 mg IV q6h Metronidazole 500 mg PO q6h Vancomycin oral solution 250 mg PO q6h Vancomycin enema 1 g/500mL rectally q8h |
Community Acquired Pneumonia Guideline
| Physician Orders | Nursing Guidelines/Orders |
Routine
patient orders: oxygen, cardiac |
|
Labs:
|
|
| Diagnostic
Testing: ECG 12-lead; Chest X-ray PA and lateral (portable if critical patient) |
If patient is monitored, the RN will accompany to x-ray. |
| Respiratory
Medications: Albuterol nebulizer treatment Ipratropium nebulizer treatment |
Obtain peak flow before and after administering nebulizer treatments. |
| Antipyretics: APAP or ibuprofen for temp > 101.5ºF |
|
|
Antibiotics:
For patients to be discharged: Discharge prescriptions: |
Infuse azithromycin over 60 min via infusion pump.
Antibiotics need to be started within 4 hours of arrival. |
| Admission: Admit to the hospitalist service in either medical or telemetry bed unless patient is in critical condition. | Complete admission note before transport. |
Severe Sepsis Protocol Checklist
Based on the
Evaluation for Severe Sepsis Screening Tool
□ Does patient history suggest a new infection? If yes,
□ Does patient present with 2 or more new signs or symptoms of
infection? If yes,
□ Does the patient have evidence of organ dysfunction due to the
infection?
If answers to
ALL screening elements are YES, initiate Severe Sepsis
Protocol.
□
Determine time of presentation, which is equal to ED triage time or
documentation (date/time) supporting diagnosis of severe sepsis in
progress notes for non-ED admissions.
Quality Indicators to Measure
Sepsis
Resuscitation Bundle—The goal is to perform all indicated tasks 100% of
the time within the first 6 hours of identification of severe sepsis.
□ Measure serum lactate.
□ Obtain blood cultures prior to antibiotic administration.
□ Administer broad-spectrum antibiotic within 3 hours of ED admission
and within 1 hour of non-ED admission.
Admission
In the event of
hypotension and/or a serum lactate > 4 mmol/L
□ Deliver an initial minimum of 20 mL/kg crystalloid or an equivalent
□
Apply vasopressors for hypotension not responding to initial fluid
resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg
In the event of
persistent hypotension despite fluid resuscitation
(septic shock) and/or lactate > 4 mmol/L
□ Achieve a central venous pressure (CVP) ≥ 8 mm Hg
□ Achieve a central venous oxygen saturation (SvcO2) ≥ 70% or mixed
venous oxygen saturation (SvO2) ≥ 65%.
Sepsis
Management Bundle
Begin
efforts to accomplish these goals immediately, but these items may be
completed within 24 hours of presentation for patients with severe
sepsis or septic shock:
□ Administer low-dose steroids for septic
shock in accordance with a standardized ICU policy. If not
administered, document why the patient did not qualify for low-dose
steroids based upon the standardized protocol.
□ Administer
recombinant human activated protein C (rhAPC ) according to
standardized ICU policy. If not administered, document why patient did
not qualify for rhAPC.
□ Maintain glucose control ≥ 70, but < 150 mg/dL
□ Maintain a median inspiratory plateau pressure (IPP) < 30 cm
H2O for mechanically ventilated patients.