Management of Sepsis

Ian Jenkins, MD

Stefanos Parpos, MD

I: DEFINITIONS / INTRODUCTION

II: RECOGNITION:

III: TREATING THE INFLAMMATORY CASCADE:

A: FLUIDS: Don't write for an infusion and walk away; bolus, reassess, and rebolus until goals are met. While the novice is often hesitant to use much fluid, initial requirements may be >10 liters in the first day, and after capillary leak causes extravasation of much IVF, patients can end up dozens of liters up over a micu stay. The MUST protocol comes from the only hard data for fluid use—a study of protocol, goal driven therapy: 500cc NS boluses until CVP was 8-12, then pressors were added for a MAP >65, and if SVO2 was <70%, transfusion for to hct > 27 and dobutamine as needed were added to support O2 delivery. Mortality was 25.2 instead of 40.7%! The prudent MD will also consider HR, urine output, correction of hyperlactatemia, exam evidence of perfusion, or wedge pressure.

B: ANTIBIOTICS: Generally, you can go by Sanford for empiric therapy until you have culture data and sensitivities. Treat EARLY. Antibiotics for meningitis should NEVER wait for CT/LP, and yofor example. Culture and treat. Other:
1) Severe infection doesn't mean antibiotic resistance, but the cost of a mistake is higher. Therefore, it may be ok to treat mild strep pneumo pneumonia (in a healthy host with no risk factors for drug resistance) with penicillin, but if the infection is severe, be cautious—ceftriaxone has near certain coverage; some would add a second drug (respiratory quinolone) in the really sick. Have someone floridly septic from the UTI that was cultured 2 days ago? Their sensitive E coli may merit only cefazolin or ampicillin and when they're ready for discharge, bactrim.
2) Recognize the patient who needs broad spectrum coverage (nursing home, hospitalizations, ICU acquired infections putting them at risk for MRSA, dangerous GNRs). Look at prior culture data. You may find the patient failing levoflox for pneumonia had drug-resistant pseudomonas in prior sputa.
3) GNR sepsis, or what looks like it, is often double covered (best data for a B-lactam and aminoglycoside) to try to get synergistic killing and ensure at least one drug is active. The data that this is better than a 3rd generation cephalosporin or carbapenem alone is scant; in neutropenic fever for example, ceftaz or cefepime is equal to piperacillin and gent.
4) Vanco is overused. If you are worried about resistant pathogens, start it; if you have no cultures from the ET tube, or the blood, or the line after 3 days, try to stop it. Don't mistake spectrum for power. Vanco is often just static. For susceptible staph, naf and ox are stronger / cidal, cheaper, and reduce vanco resistance. That said, community acquired MRSA is becoming more common and if missed, is deadly.
5) Don't forget C diff. Even without diarrhea, and especially if there is ileus, abdominal distention or pain, high WBC, suspect it and treat it / rule it out. There are exotoxin B only C Diffs which will have (-) stool tests.
6) Some basics... CAP in the ICU can be treated with ceftriaxone + azithro. VAP needs MRSA (vanco) + GNR coverage (ceftaz / pip-tazo / carbapenem) until you have more data. Cholecystitis, cholangitis, diverticulitis and colonic perfs require gram (-), (+), and anaerobe coverage. Amp + gent + flagyl, amp-sulbactam or pip-tazo, or levo (suboptimal enteroccocus coverage) + flagyl are options.
7) Remove sources: antibiotics do not get into abscesses; drain them. Sources of toxic shock (wound packing, tampons), infected prosthetic devices and lines must be removed; a necrotic gallbladder, ischemic bowel, or colon with severe C diff may require surgery. If they have pneumonia, you can't remove it, but you can affect recurrence (or prevent) by keeping the head of bed elevated > / = 30 degrees.

C: PRESSORS AND INOTROPES: Know a few; the rest comes with practice. Don't memorize the dose yet; ask the RN, look it up. Remember, your objective is organ perfusion, NOT blood pressure. You can give a hypovolemic patient powerful pressors and get the BP up, but their toes will turn black from ischemia, and their kidneys, gut (leading to bacterial translocation), liver and other organs will suffer too. No good data to prefer one over another but there are some physiologic rationales:

D: ACTIVATED PROTEIN C (drotrecogin or Xigris): Seems counterintuitive, but the coagulation and inflammatory cascades are intertwined, and it has antiinflammatory and anti-DIC properties. A 96 hour infusion started within 24 hours of presentation reduced mortality from 30.8 to 24.7 among ~1700 patients, but caused a trend to more bleeding (sometimes fatal). It also costs $6,000+. Thus there are strict inclusion and exclusion criteria on the web (don't memorize them!). Briefly: known or suspected infection, 3 of 4 SIRS criteria, plus hypotension after fluids, oliguria, hypoxia, thrombocytopenia or acidosis, and NOT be under 18, pregnant, have plts < 30k, bleeding or predisposition (recent GIB, head trauma, surgery, diathesis), dialysis dependence, organ transplant, advanced AIDS, merely acute pancreatitis, moribund state, chronic liver disease, and most anticoagulants or procoagulant states). Had favorable cost-benefit ratio for patients with APACHE (an illness severity measure) scores > 25 (24k per year of life gained), and poor ratio for scores < 25 ($575k per year of life gained).

E: STEROIDS: A large study of severe sepsis patients found that a week of 50mg hydrocortisone IV Q6H + 50mcg fludrocortisone PO QD reduced morality from 63 to 53% (still a horrible outcome—sicker than the APC trial patients?). This was among only those who were adrenally insufficient (<10mcg/dl response to a 250mcg cosyntropin stimulation test); the few adrenally responsive patients trended to increased mortality on steroids. So cort-stim patients with severe sepsis and treat while results are pending and if (+).
If they are sick, give some Dexamethasone ASAP then test—it doesn't cross-react with the assay, but the others do. Don't miss adrenal crisis! $10 worth of steroids can save a critically ill patient in hours. It is miraculous to watch. Clues: hyponatremia, hyperkalemia, eosinophilia, no other cause seen, predisposition (other autoimmune disorders like type 1 diabetes, or known metastatic cancer, immunosuppression (infiltrative infections of the adrenals)).

F: INSULIN and NUTRITION and OTHER: In >1500 intubated patients, intensive (gtt) insulin therapy with a goal of 80-100 instead of 180-200 reduced SICU mortality from 8 to 4.6%, hospital mortality from 10.9 to 7.2%, with less bacteremia and polyneuropathy with a cost of more hypoglycemia. Glucose control improves acute outcomes (ie, immune function, wound healing, survival in MI) so it is plausible these benefits extend to MICU and not just SICU patients, but that needs to be confirmed. Also, providing nutrition supports albumin, immune function, and wound healing, and if enteral, you avoid line complications (mechanical, infection) and might decrease bacterial translocation across the guy by keeping it healthy. The exact best regimen is undetermined. Lastly, keep HOB > 30 degrees to avoid aspiration in all unless impossible; use daily, protocol-driven vent wean-ability assessments, and pay daily attention to GI / DVT prophylaxis and use of sedation.

IV: SUMMARY

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  Sepsis is common, dangerous, complicated and costly
  
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  Early sepsis is hard to recognize and easy to treat; late sepsis is easy to recognize and hard to treat
  
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  Aggressive bolus fluid resuscitation until goals are met (CVP 8-12)
  
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  AFTER volume, use norepinephrine, then dopamine and vasopressin as needed; phenylephrine is good when there are SVTs.
  
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  When MAP > 70, check SVO2, and if < 70, use transfusions for hct <27 and dobutamine for >27 and reassess.
  
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  Appropriate and early antibiotic therapy and removal of the source when possible
  
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  Does the patient fit all the inclusion and none of the exclusion factors for activate protein C?
  
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  Test for adrenal insufficiency and treat if positive (can cover with dexamethasone while testing)
  
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  Aim for normoglycemia, don’t forget nutrition, and think about other details of good care (daily reconsideration of sedation, vent weaning, prophylaxis, and semirecumbent position).
  

References:

 alpha 1: vasoconstrict peripheral arterioles

 cardiogenic:   PCWP increased; CO increased; SVR increased

 Sympathomimetic Rx:

 Phosphodiesterase Inhibitors:

 Vasodilators/Venodilators:

 1. DOPAMINE

 2 DOBUTAMINE

 3. ISOPROTERONOL

4. LEVOPHED

5. EPINEPHRINE

6. NEOSYNEPHRINE

7. MILRINONE