CONTENTS

• Rapid Reference 🚀
• Definitions of septic shock
• Diagnosis & evaluation
  • Clinical Presentations
  • Biomarkers:
    • NLR
    • Procalcitonin & CRP ➡️
  • Evaluation for the source
  • Sepsis mimics
• Treatment
  • Vasopressors
  • Source control
  • Fluid
  • Steroid
  • DVT prophylaxis with heparin
  • REFRACTORY SHOCK
    • Methylene blue
• Resuscitative endpoints
  • MAP
  • Heart rate
  • Urine output
  • Fluid balance
  • Lactate
  • Skin perfusion
• Interventions of no real value
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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#1/2: initial resuscitation 

investigations

• Labs:
  • Peripheral blood culture x2, culture of any line in place >48 hours.
  • Urinalysis and culture.
  • Lactate.
  • If not definitively sepsis: procalcitonin (+/- CRP in renal failure).
• Imaging:
  • Chest X-ray.
  • Consider CT abdomen/pelvis if no definite source (especially in obtunded/elderly patients).
• Additional tests as warranted (more on source evaluation: 📖).

antibiotics

• Review prior cultures & antibiotic exposure data (if available).
• Start with a solid beta-lactam backbone (e.g., piperacillin-tazobactam 💉, meropenem 💉, or cefepime 💉).
• Consider selectively adding MRSA coverage if there is a soft tissue infection, line infection, nosocomial infection, or for selected pneumonia patients. 📖
• Consider additional antibiotics depending on source, e.g.:
  • Community-acquired pneumonia:  Azithromycin or doxycycline.
  • Possible tick-borne illness:  Doxycycline.
  • Possible C. difficile:  oral vancomycin +/- IV metronidazole.

source control 📖

• Consider hardware removal (e.g., port, tunneled line, central line).
• Other drainage/debridement (e.g., decompress hydronephrosis, ERCP for cholangitis, abscess drainage).

hemodynamics

• Early peripheral vasopressors to maintain MAP >65. 📖

adjunctive therapies

• Hydrocortisone 50 mg IV q6hr, unless contraindicated. 📖
• DVT prophylaxis with low molecular weight heparin (if GFR >30 ml/min) or otherwise unfractionated heparin. 📖

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#2/2:  secondary survey 

correct diagnosis?

• Review imaging and lab data.
• Is further investigation needed to identify the source? 📖
• If no clear infection, consider sepsis mimics. 📖

review medications

• Have antibiotics been administered?
• Are antibiotics scheduled and dosed optimally?
• Review the medication list (e.g., discontinue antihypertensives and nephrotoxins as able).

basic hemodynamic targets

• MAP 📖
  • The initial MAP target is generally >65 mm.
  • For patients with chronic HTN and poor urine output, consider increasing the MAP target to >80 mm to see if this improves urine output (vasopressor challenge).
  • Following initial resuscitation, consider reducing the MAP goal to >60 mm (with monitoring of perfusion).
• Heart Rate 📖
  • Heart rate <~80 b/m: Consider epinephrine challenge 📖.
  • Heart rate >~140 b/m: Consider switch to vasopressors without beta-agonist activity (e.g., phenylephrine, vasopressin).

perfusion targets

• Skin perfusion 📖
  • Evaluate for:
    • (1) Mottling.
    • (2) Cool extremities.
    • (3) Capillary refill.
  • Poor perfusion despite adequate MAP may reflect excess vasoconstrictors (and possible benefit from an epinephrine challenge 📖).
• Urine output 📖
  • Falling urine output is concerning regarding hypoperfusion. However, this is nonspecific (may reflect either hypoperfusion or intrinsic renal failure).

repeat lactate 📖

• Rising lactate should prompt global re-evaluation of the patient.
• ⚠️ Epinephrine infusions will increase lactate, making lactate measurements meaningless in such patients.

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definitions of septic shock

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The consensus definition of septic shock was updated from Sepsis-II to Sepsis-III recently. These definitions may be summarized as follows:

• Sepsis II definition of septic shock: Infection causing persistent hypotension, despite fluid resuscitation.
• Sepsis III definition of septic shock: Infection causing vasopressor requirement to maintain a MAP > 65 mm (despite fluid resuscitation) plus a serum lactate >2 mM.

Neither of these definitions is perfect, but they focus our attention on two key bits that together help delineate septic shock:

• Bit #1: Overt hypotension.
• Bit #2: Hyperlactatemia – this is generally a reflection of aerobic lactate production due to endogenous epinephrine. It may be grossly conceptualized here as a measurement of the patient's endogenous epinephrine release.

Sepsis III requires both bits, which is a mistake because they measure different things:

Lactate is not specific to septic shock. Lactate may be elevated by a panoply of conditions (including any shock state, physiologic stress, beta-agonists, seizure, or hepatic dysfunction – more on this here). Elevated lactate does often identify patients who are at increased risk of mortality, who require more intensive investigation and treatment.

Ultimately, formal definitions are more relevant to clinical trials than bedside management of individual patients. These blunt tools are inadequate to direct patient management. Instead, a diagnosis of septic shock should be made carefully on an individual basis, using clinical judgement and consideration of the following factors:

• (1) Type of underlying infection:
  • Some infections (e.g. necrotizing fasciitis, ascending cholangitis) are more likely to cause septic shock. There should be a lower threshold to diagnose septic shock and initiate aggressive management in these patients.
• (2) Degree of hemodynamic instability:
  • Shock index (heart rate / systolic blood pressure)
  • Blood pressure, compared to patient's baseline pressure
  • Vasopressor requirement
  • Evidence of end-organ hypoperfusion (e.g. urine output, skin perfusion)
• (3) Degree of hyperlactatemia:
  • Presence of other factors which may increase lactate levels (e.g. albuterol, hepatic dysfunction).
  • Lactate >4 mM suggests a significant mortality. (28248722)
• (4) Other end-organ failures (e.g. delirium, shock liver)

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clinical presentations

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Septic shock encompasses a broad range of infections in a diverse range of patients. The table below shows common signs and symptoms of sepsis. This can be a difficult diagnosis, because different patients will present with different constellations of these findings.

In many cases, septic shock may be suspected before the underlying infection is definitively diagnosed. In such cases, it is generally best to empirically treat as if the patient has septic shock, while obtaining additional information (e.g., culture data, definitive CT imaging).

• For patients who are clinically in shock with no obvious cause (despite evaluation of history, physical exam, and echocardiography), there should be a high index of suspicion for septic shock.
  • 💡Echocardiography will identify most non-distributive causes of shock (e.g., RV dysfunction, LV dysfunction, pericardial tamponade, frank hypovolemia). If a patient is in shock with a normal-looking echocardiogram then they likely have distributive shock. The most common cause of distributive shock is septic shock.

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neutrophil/lymphocyte ratio (NLR)

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basics of the NLR

• The NLR is the ratio of neutrophils/lymphocytes. This is easily calculated from any differential cell count, making it readily available for most patients.
• Physiologic stress increases neutrophil count and reduces lymphocyte count, causing the NLR to increase. This likely involves some combination of endogenous cortisol and catecholamine secretion. Sepsis stimulates lymphocyte apoptosis, so this may cause especially dramatic elevation of the NLR compared to other forms of physiologic stress.(32148922)
• NLR elevates rapidly following physiologic stress (within <6 hours), often earlier than other indices such as the white blood cell count.(11723675)

utility of the NLR

• NLR may be helpful in sorting out patients with systemic illness versus patients with milder illness (i.e., “sick versus not sick”).
• NLR is not helpful in sorting out the precise etiology of the patient's illness (e.g., sterile pancreatitis versus bacteremia).

rough interpretation of the NLR

• Some very rough numbers:
  • ~1-3 is normal.
  • ~6-10 suggests mild stress (e.g., uncomplicated appendicitis).
  • ~10-15 suggests moderate stress (e.g., most critically ill patients).
  • >15 suggests severe stress (e.g., sepsis with gram negative bacteremia).
• The table below compares procalcitonin values with C-reactive protein and NLR among patients with suspected infection.(25341467) This may help provide a general concept of how these indices compare with one another:

use of the NLR in a patient with suspected sepsis

• NLR <3:
  • This should cast some doubt on the diagnosis of sepsis (>95% of septic patients will have an NLR above three).(28727802)
  • One driver of NLR elevation is cortisol. Therefore, an unexpectedly low NLR in the context of definite septic shock may suggest the possibility of adrenal insufficiency.
• NLR >10:
  • Higher NLR values support the diagnosis of septic shock.

pitfalls of the NLR

• Exogenous steroid may increase the NLR.
• Active hematologic disorder may affect the NLR (e.g., leukemia, cytotoxic chemotherapy, granulocyte colony stimulating factor).
• HIV patients have generally been excluded from studies of the NLR.

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common sources & evaluation of source

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common sources of septic shock

• Meningitis (more)
  • Clues: Nuchal rigidity, altered mental status.
  • Test: Lumbar puncture.
• Pneumonia (more)
  • Clues: Respiratory symptoms.
  • Test: CXR, lung POCUS (Note: if imaging findings are equivocal then look further for an alternative source. Patients with sepsis due to pneumonia should have an obvious pneumonia.)
• Endocarditis (more)
  • Clues: Murmur, embolic phenomena, history of valvular disease.
  • Test: Echocardiogram, blood cultures.
• Line infection (more)
  • Clues: Erythema/warmth at central line or port, line dysfunctional.
  • Test: Paired blood cultures from line and peripheral cultures.
• Cholecystitis (more)
  • Clues: Right upper quadrant or epigastric pain, nausea/vomiting.
  • Test: Ultrasound/CT findings may include gallbladder distension, sonographic Murphy's.
• Ascending cholangitis (more)
  • Clues: Right upper quadrant or epigastric pain, jaundice, rigors, gram negative bacteremia.
  • Test: Elevated bilirubin, ultrasound/CT shows dilated common bile duct.
• C. Difficile (more)
  • Clues: Recent antibiotic exposure, diarrhea, abdominal tenderness.
  • Test: Stool for C. difficile, CT shows pancolitis.
• Other abdominal sepsis (e.g., appendicitis, diverticulitis, obstruction, perforation)
  • Clues: May include pain, distension, nausea, vomiting, recent surgical procedure.
  • Test: CT scan, ultrasonography.
• Urosepsis (more)
  • Clues: Dysuria/frequency, flank pain.
  • Test: Abnormal urinalysis, positive urine culture, perinephric fat stranding on CT scan.
• Streptococcal cellulitis with toxic shock (more)
  • Clues: Classic appearance of cellulitis, but patient also has sepsis. Erythroderma can be seen in some cases.
  • Test: Blood cultures may be positive.
• Necrotizing fasciitis (more)
  • Clues: Pain out of proportion to examination; necrosis/bullae formation.
  • Test: CT scan, surgical exploration.

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sepsis mimics

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With increased focus on sepsis and septic shock, other disorders are increasingly likely to be misdiagnosed as septic shock.(27692840) A mimic of septic shock may be suspected in the absence of a clear focus or infection, or if the procalcitonin is unexpectedly low. Common mimics include:

infectious mimics

• Endocarditis causing valve failure (more)
  • Test: complete echocardiogram.
• Tick-borne illness, especially anaplasmosis (more)
  • Potential clues: Exposure, thrombocytopenia, skin rash, hemolysis.
  • Test: PCR for anaplasmosis, blood smear for babesiosis (will vary geographically)
• Candida septicemia (more)
  • Clues: Ongoing critical illness, central line, colonization, immunosuppression, GI surg/perf, parenteral nutrition.
  • Test: Blood cultures, beta-D-glucan level.
• Invasive aspergillus (more)
  • Clues: Prolonged neutropenia, hematologic malignancy, prolonged or high-dose steroid use, pneumonia, hemoptysis.
  • Tests: Beta-D-glucan level, galactomannan level, sputum culture.
• PJP pneumonia (more)
  • Clues: Diffuse pneumonia, immunosuppression (HIV, chronic steroid use, TNF-inhibitor, malignancy).
  • Tests: Beta-D-glucan level, induced sputum PCR.

endocrine mimics

• Adrenal crisis (more)
  • Clues: Recently discontinued steroid therapy, history of adrenal insufficiency, normal or elevated eosinophil count, vasopressor-refractory “septic shock.” May cause abdominal pain and nausea/vomiting, leading to confusion with abdominal sepsis.
  • Test: Cortisol level (obtained before steroid therapy).
• Thyroid storm (more)
  • Clues: Tremors, thyromegaly, tachycardia, encephalopathy.
  • Test: TSH, free T4.
• Diabetic ketoacidosis (DKA) (more)
  • Clues: Diabetes, hyperglycemia, anion gap inexplicably large. Note that DKA and septic shock often coexist, so diagnosing the patient with DKA doesn't exclude simultaneous sepsis!
  • Test: Ketones in urinalysis, preferred test is elevated beta-hydroxybutyrate level (>3 mM).

gastrointestinal mimics

• Acute mesenteric ischemia
  • Clues: Atrial fibrillation, vasculopathy, pain out of proportion to exam.
  • Test: CT angiography of the abdomen/pelvis.
• Bowel obstruction
  • Test: CT abdomen/pelvis.
• Pancreatitis (more)
  • Clues: Epigastric pain, nausea/vomiting.
  • Tests: Lipase level, CT abdomen/pelvis.
• Fulminant hepatic failure (more)
  • Tests: Liver function tests.
• Decompensated cirrhosis (more)
  • Clues: Chronic hypotension, elevated INR, thrombocytopenia.
  • Tests: Liver function tests and ultrasonography may show signs of cirrhosis. However, note that even if the patient has cirrhosis this doesn't exclude simultaneous septic shock as well.

toxicological mimics

• Salicylate intoxication (more)
  • Clues: History of salicylate use, tachypnea, delirium, inexplicably elevated anion gap.
  • Test: Salicylate level.
• Beta blocker or calcium channel blocker intoxication (more)
  • Clues: Disproportionate bradycardia, exposure history.
• Carbon monoxide poisoning (more)
  • Clues: Exposure (often winter), household members ill.
  • Test: Carboxyhemoglobin level.
• Metformin (more)
  • Clues: Exposure history, disproportionately severe hyperlactatemia, lactate level stable.

miscellaneous mimics

• Anaphylaxis (more)
  • Clues: Rapid onset following trigger, hives, pruritus, bronchospasm, angioedema, gastrointestinal manifestations.
  • Test: When in doubt treat for both processes (e.g., antibiotics, steroid, and epinephrine infusion). Follow the disease course over time. Patients with anaphylaxis will recover within hours (faster than septic patients) and their infectious evaluation will be negative.
• Hemophagocytic lymphohistiocytosis (more)
  • Clues: Cytopenias, hepatosplenomegaly, high fevers, delirium, elevated liver function tests.
  • Test: Elevated ferritin level.
• Dermatologic (very severe DRESS or AGEP)
  • Clues: Skin exam, review of active medications.
  • Test: Consult dermatology for skin biopsy.
• Aspiration pneumonitis
  • Clue: Rapid onset and often rapid recovery (faster than true bacterial pneumonia).

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vasopressors

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initial pressor: there is no universal first-line agent

• Traditional dogma favors a specific sequence of vasopressors for all patients (typically beginning with norepinephrine, then with sequential addition of vasopressin, and finally epinephrine). Evidence doesn't really support this:(31990655)
  • Initial vasopressor support with vasopressin was potentially beneficial in the VANISH trial.(27483065) This shows that a pure vasoconstrictor can be used as a front-line pressor for septic shock.
  • Epinephrine was shown to yield similar results to norepinephrine in the CAT trial 😺.(18654759)
  • The only prospective study comparing norepinephrine to phenylephrine found nearly identical hemodynamic responses.(19017409)
• For most patients, norepinephrine is a good choice. However, the selection of pressors may be individualized based on patient physiology, as shown below.
• The only pressor which shouldn't be used is dopamine (based on evidence of harm in prospective RCTs).(20200382, 26323041)

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peripheral vasopressors

• The main concern with peripheral vasopressor infusion is extravasation into the skin leading to necrosis. Fortunately, this is rare. Overall, the risk of skin necrosis should never be prioritized over the risk of systemic hypoperfusion and death.
  • Skin necrosis is both less common and less important than mortality and systemic hypoperfusion.
• Norepinephrine is safe for peripheral infusion, but the risk of extravasation does increase if infusions are used for prolonged periods of time.(25669592) Peripheral norepinephrine has been validated in a medical ICU with a rigorous protocol for placing IV lines and monitoring their function closely. (26014852)
• Phenylephrine or epinephrine are the safest agents to use peripherally. Both agents have been administered via a subcutaneous route intentionally in the past. There appear to be no reports in the literature of these agents' causing skin necrosis. It's sensible to avoid infusion into the wrist or hand, but overall these agents are unlikely to cause necrosis if extravasation occurs.
  • Note that phenylephrine infusion is physiologically very similar to norepinephrine.
• Vasopressin administration peripherally should probably be avoided. If vasopressin extravasates, there is no way to counteract its effect (unlike catecholamine extravasation, which can be treated with local infiltration with phentolamine).

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vasopressin

drawbacks of vasopressin

• Vasopressin is hard to titrate (half-life of ~30 minutes, so it will take a long time to reach steady state). Vasopressin can be used as a titratable pressor at doses ranging from 0-0.06 U/min, but don't expect dose adjustments to have an immediate effect.(27483065)
• ⚠️ The combination of vasopressin plus norepinephrine can cause excessive vasoconstriction, leading to digital ischemia and necrosis.
• Vasopressin shouldn't be given via peripheral infusion, as discussed above.

advantages of vasopressin

• Vasopressin may improve renal function.
• Vasopressin may be useful in patients with excessive tachycardia or tachyarrhythmias.
• Vasopressin causes pulmonary vasodilation, so it may be the preferred vasoconstrictor among patients with pulmonary hypertension (either acute or chronic).

how to use vasopressin?

• Vasopressin is best for patients with warm extremities (vasodilatory shock).  Alternatively, vasopressin should be avoided in patients with evidence of reduced cardiac output.
• Monitor extremity perfusion and stop vasopressin immediately if digital ischemia occurs (e.g., fingertips are turning blue).
• Consider combining vasopressin with epinephrine (rather than norepinephrine). This may allow taking advantage of the renal-perfusion benefits of vasopressin while avoiding excessive vasoconstriction.

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epinephrine might be the preferred inotrope for septic shock

• Traditionally, there has been a preference for catecholamine inotrophes that selectively affect the beta-1 receptor. This is based on the following two concepts, which are both wrong:
  • (1) The heart has only beta-1 receptors (Actually, the heart has both beta-1 and beta-2 receptors).(2876788)
  • (2) Elevation of lactate levels is harmful (Actually, lactate may serve as a bioenergetic fuel for the heart, improving cardiac function).(24666826)
• Epinephrine may actually have advantages over dobutamine:
  • (1) Epinephrine may have greater efficacy as an inotrope (figure below).
  • (2) Dobutamine causes vasodilation, which may decrease the blood pressure and exacerbate vasodilatory shock. This can cause problems if the dobutamine isn't titrated very thoughtfully. In contrast, epinephrine contains alpha-adrenergic stimulation which prevents it from having a net vasodilatory effect.

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multi-pressor titration

• Titration of multiple vasopressors involves avoiding excessive vasoconstriction or excessive inotropy (figure below). The optimal balance will vary between patients.
• When in doubt, the best approach is often to empirically up- and down-titrate pressors in order to sort out what the various agents are doing.
  • If a patient strongly responds to up/down titration of an agent, that drug is more likely to be causing benefit.
  • If a patient has no/minimal response to adjusting the dose of an agent, that drug probably isn't helping much (and may be causing harm).
• Norepinephrine down-titration: In addition to adding pressors, it's also useful to down-titrate pressors which aren't helping. Sometimes norepinephrine may over-constrict patients, leading to excessive afterload and a drop in ejection fraction (the heart is unable to tolerate the excessive afterload). If adjusting the norepinephrine dose doesn't affect blood pressure much, that suggests that the norepinephrine dose is excessive. The goal should always be to use the minimal dose of vasopressor(s) necessary to achieve hemodynamic targets.

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epinephrine challenge

indications for epinephrine challenge

• (1) Hypoperfusion (e.g. poor urine output, cold extremities, mottling, poor capillary refill).
• -plus, ideally-
• (2) Some indicator that epinephrine might help, for example:
  • POCUS shows a reduced ejection fraction.
  • Heart rate is inappropriately slow or normal (e.g. <80 b/m)
  • Lactate is inappropriately low relative to the severity of illness (inappropriate normolactatemia, suggesting inadequate endogenous epinephrine release).

contraindications to epinephrine challenge:

• Significant tachycardia (e.g. heart rate >120 b/m)
• Echocardiography shows the left ventricle is already hyperkinetic.

how to perform the epinephrine challenge

• Start an epinephrine infusion at ~4-5 mcg/min.
• Judge the response:
  • Effect on skin perfusion (e.g. capillary refill time, mottling, and temperature).
  • Effect on blood pressure. On average, epinephrine has a relatively equivalent effect on blood pressure compared to norepinephrine (e.g. 1 mcg/min epinephrine ~ 1 mcg/min norepinephrine). If the epinephrine has a considerably greater effect on blood pressure than norepinephrine, this suggests that it's helping (e.g. adding 4 mcg/min epinephrine allows the norepinephrine dose to be decreased by >>4 mcg/min).
  • Effect on heart rate – an excessive tachycardic response to epinephrine may be harmful.

follow-up:

• If the patient responds well to epinephrine, then this should be continued. In many cases, other vasopressors may be down-titrated (try to achieve MAP and perfusion targets with the minimal cumulative dose of vasopressor).
• If the patient responds poorly to epinephrine, then stop it.

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source control

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Failure to achieve source control might be the most common cause of death from septic shock within a modern healthcare system.  All other interventions described in this chapter will often fail if there is inadequate procedural source control.

common examples of source control

• Infected hardware (e.g. catheter) may need to be removed.
• Nephrolithiasis causing obstruction and infection may require decompression.
• Ascending cholangitis requires ERCP or percutaneous intervention for decompression.
• Perforated or obstructed bowel requires surgical repair.
• Necrotizing fasciitis may require debridement.

investigation regarding possible need for source control 

• Ensure that the source has been fully investigated (e.g. a patient with urosepsis should be imaged to exclude obstruction).
• For patients in whom no infection is identified, aggressive imaging may be helpful to search for the source (e.g. CT abdomen/pelvis).

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fluid

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Rivers of ink have been spilled discussing the optimal strategy for fluid administration in septic shock. However, there's little evidence that fluid administration is truly beneficial. Excessive fixation on fluid status may serve to divert attention from other more important aspects of care.

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basic concepts of fluid management in septic shock

1. The primary physiologic problems in septic shock are vasodilation and maldistribution of blood to organs (sometimes with cardiac dysfunction as well). None of these problems can be solved with fluid administration.
2. There is no high-quality evidence that large-volume fluid resuscitation is beneficial in septic shock.
3. A low central venous pressure and collapsed inferior vena cava may result from vasodilation and distribution of blood out of the central veins (rather than true hypovolemia). 🌊 Therefore, a collapsed IVC shouldn't be interpreted as an indication to give fluid. Furthermore, a low central venous pressure may facilitate tissue perfusion by increasing the pressure gradient across the tissues (which is equal to MAP-CVP).
4. A traditional concept is that septic patients should initially be volume overloaded, and subsequently diuresed during their recovery (“you need to swell to get well, you need to pee to be free”). There is no evidence to support this concept. Volume overload isn't a viable therapeutic strategy. A better strategy seems to be targeting euvolemia and then keeping patients there.
5. Fluid bolus therapy isn't evidence-based and should arguably be avoided when possible. The vast majority of crystalloid administered will leak out of vasculature into the interstitial tissue (for example, 95% in some studies of fluid boluses).(22165353)  Further discussion here: 🌊
6. Avoid the fluid-responsiveness trap. Measuring fluid responsiveness has never been shown to improve clinical outcomes in septic shock. Serial assessment of fluid responsiveness may lead to a vicious cycle of perpetual fluid administration (figure below).

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one reasonable approach

initial resuscitation

• For the majority of patients without any major fluid losses, a moderate amount of fluid is reasonable.
• Rare patients may present with a history of substantial volume losses (e.g., nausea, vomiting, diarrhea, poor PO intake).  Such patients may benefit from larger volume fluid resuscitation.
• For patients with pneumonia and mild hypotension, their primary physiological problem is often hypoxemia. If you're concerned primarily about pulmonary decompensation then fluid won't help – such patients may benefit from vasopressor support rather than fluids.
• Type of fluid may be selected based on the principles of pH-guided resuscitation (discussed further here: 📖)
  • Albumin administration is evidence-based for patients with spontaneous bacterial peritonitis, hepatorenal syndrome, and perhaps underlying cirrhosis.

then stop giving fluid

• Unless the patient has substantial ongoing fluid losses (e.g. severe diarrhea), it's usually wise to stop giving additional crystalloid following the initial resuscitation.
• Most patients will receive ~1.5 liters per day of fluid along with various infusions and antibiotics. The addition of enteral nutrition will often increase this to >2-3 liters per day. This fluid alone is already excessive (without the use of any additional crystalloid).
  • 💡 Keep careful track of the patient's net fluid balance (inputs – outputs). In the absence of marked hypovolemia prior to admission, it's probably wise to avoid allowing the patient to run more than ~4-5 liters net positive.

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steroid

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risk of steroid

• Stress-dose steroid (50 mg hydrocortisone IV q6hr) is equivalent to 50 mg prednisone daily. This dose of steroid is routinely used for outpatients with a myriad of diagnoses, without much fuss (e.g. asthma or COPD exacerbation).
• Stress-dose steroid doesn't increase the risk of superinfection. This concept was promoted by inappropriate interpretation of secondary outcomes in the CORTIUS trial.(18184957) This fear has been debunked in meta-analyses, as well as in the much larger ADRENAL trial.(19489712, 29347874)
• Large RCTs haven't detected a risk of steroid-induced myopathy. However, such a risk may exist in patients who are undergoing therapeutic paralysis.
• Steroid does increase the rate of hyperglycemia (shown in numerous RCTs above).

benefit of steroid

• Both the meta-analysis and ADRENAL trial show that steroid reduces the time on vasopressors, the duration of intubation, and the length of ICU stay.(29347874, 29761216) These are important outcomes which may hasten recovery, avoid iatrogenic harms, and reduce costs.
• A potential mortality benefit of steroid is debated. It's possible that one may exist, if steroid is initiated early and in the sickest patients.(29490185) Logistically, it is nearly impossible to prove whether such a mortality benefit exists, so this may be the wrong question to fixate upon.

rationale for early steroid administration

• (1) For years, it was believed that a subset of patients with pressor-refractory shock would experience a mortality benefit from steroid, based on subgroup analysis within the Annane 2002 trial.(12186604) This suggested that only the sickest subset of patients would benefit from steroid. However, the more recent ADRENAL trial showed that patients on any dose of vasopressor could benefit (as discussed above). This suggests that steroid therapy may be used more broadly.
• (2) The entire concept of sepsis resuscitation is to proactively support the patient and prevent further deterioration – not to wait for the patient to deteriorate further before trying to salvage them in a reactive fashion. This is why every single therapy in sepsis care is instituted rapidly – ideally including steroid.
• (3) Starting steroid immediately eliminates the decision about when to start steroids, shifting greater focus on other issues.
• (4) Immediately initiating maximal medical therapy can help rapidly clarify whether the patient can respond to medical therapy. This may expedite decisions about whether to move to a more aggressive surgical procedure for source control.
• (5) Antibiotics often cause bacterial cell lysis, which releases bacterial products into the bloodstream, causing clinical deterioration (Jarisch-Herxheimer reaction). Front-loaded steroid therapy could theoretically blunt this phenomenon.

one possible approach

• Above is one potential approach to steroid in septic shock. This strategy prioritizes liberation from pressors and ventilation over the risk of hyperglycemia.
• Please note that patients with known adrenal insufficiency or chronic steroid use should definitely be treated with stress-dose steroid.

steroid dose in septic shock

• The best studied dose of steroid in septic shock is 200 mg hydrocortisone total daily.
• Clinical studies often use a continuous infusion of hydrocortisone. However, in clinical practice the use of divided IV doses (50 mg IV q6hr) has the following advantages:
  • (1) Immediately establishes effective drug level (rather than an infusion that takes time to reach steady state).
  • (2) Doesn't tie up an intravenous line, making it easier to administer.
  • (3) One small RCT demonstrated that intermittent administration of hydrocortisone resulted in improved shock resolution compared to a continuous infusion. (30628950)
• If hydrocortisone isn't immediately available, any equivalent dose of steroid may be used. A nice option is methylprednisolone 40 mg IV daily, because this is widely available in emergency departments.

fludrocortisone is unnecessary

• The APROCHSS trial used a combination of hydrocortisone and fludrocortisone. This has led some to question the value of adding fludrocortisone on top of hydrocortisone.
• Using fludrocortisone currently doesn't seem justified for several reasons:
  • (1) Hydrocortisone itself has mineralocorticoid effects, making the addition of fludrocortisone unnecessary.
  • (2) Fludrocortisone administration to critically ill patients often fails to achieve a measurable serum drug level – so it's probably not doing much.(27416887)
  • (3) The ADRENAL trial demonstrated numerous benefits of steroid – without fludrocortisone administration.
  • (4) Septic patients are typically treated with an excessive quantity of exogenous sodium, making fludrocortisone-induced sodium retention unnecessary.

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DVT prophylaxis with heparin

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heparin may protect the endothelial glycocalyx

• The endothelial glycocalyx is composed of heparinoids, which have a similar molecular structure compared to exogenous heparin. This raises the possibility that exogenous heparin could potentially inhibit the activity of endogenous heparinase enzymes that degrade the endothelial glycocalyx (thereby protecting the glycocalyx). Some laboratory studies suggest that low molecular-weight heparin may protect the endothelial glycocalyx.(28347755, 30046671, 22507823, 22310127) Benefits from heparin may extend beyond this, to include immunomodulation as well.(28832958)
• Patients with septic shock are at high risk of deep vein thrombosis (DVT), so they merit treatment for DVT regardless of the above data. A potential benefit of heparin in septic shock argues for initiating this therapy sooner rather than later.

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refractory shock

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earlier considerations

• Placement of a central arterial line (femoral or axillary).
  • Radial arterial lines may underestimate blood pressure. 🌊
• Transition to more hemodynamically stable analgosedative regimen
  • Propofol or dexmedetomidine are excellent sedatives, but they do tend to reduce the blood pressure.
  • In the face of refractory shock, more hemodynamically stable agents may be preferable (e.g., ketamine infusion).
• Trial of various different pressor agents (e.g. epinephrine challenge, addition of vasopressin).
  • Vasopressin has been demonstrated to be safe at doses of 0.06 U/min and could likely be titrated higher.(18305265)
  • High-dose norepinephrine (there is no maximal dose 🌊).
• For patients with right ventricular dysfunction and hypoxemia on mechanical ventilation, inhaled pulmonary vasodilators could be trialed (e.g., inhaled epoprostanol).

later considerations

• Methylene blue:
  • Consider for refractory vasodilatory shock.
  • Further discussion of methylene blue in the section below.
• Intravenous calcium:
  • Consider for patients with ionized calcium <0.8 – 0.9 mM.
  • Further discussion of calcium infusions for refractory shock: 📖
• Reducing MAP target:
  • If very high doses of norepinephrine are required to achieve a MAP >65 mm (e.g. >1 ug/kg/min), this may be causing more harm than good. Reducing the MAP target to >55 or >60 could potentially represent a more beneficial balance of vasopressor benefit vs harm.
• Angiotensin II may be considered (if your hospital has this).
• Hydroxocobalamin:
  • Dose: 5 grams IV x1.
  • Avoid if possible (in one RCT, inhibition of nitric oxide increased mortality).(14707556)

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methylene blue (MB)

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contraindications to MB

• ⚠️ Risk of serotonin syndrome (e.g., recent use of selective serotonin reuptake inhibitors, high-dose fentanyl). (28655448)
  • Medications that can cause serotonin syndrome are listed here: 📖
  • Best approach: prior to using MB, look for any potential drug-drug interactions using a drug-interaction program (e.g., Medscape 🌊).
• ⚠️ G6PD deficiency (glucose-6-phosphate dehydrogenase deficiency) – either personal or family history.
• ⚠️ Hemodynamics:
  • Severe pulmonary hypertension (MB will increase the pulmonary vascular resistance).
  • Cardiogenic shock (increased afterload may promote pulmonary edema).
  • Hypovolemic shock (excessive afterload could reduce cardiac output).
• ⚠️ Continuous renal replacement therapy: Methylene blue can cause some hemodialysis machines to malfunction.
• ⚠️ Poor IV access: extravasation of methylene blue may cause tissue necrosis.
• ⚠️ Pregnancy: NO expression in the placenta may place the fetus at risk of hypoxia due to methylene blue administration. (32705530)

dose of MB

• Usual dose is 1-2 mg/kg (e.g., 100 mg). This may be infused over a variable time frame (from 5 minutes to six hours, depending on patient acuity). The largest RCT investigating methylene blue in septic shock utilized 100 mg doses diluted in 500 ml saline that were infused over 6 hours every day, for a total of three days. (36915146) 
  • ⚠️ If administered rapidly, methylene blue will temporarily cause spuriously low pulse oximetry results.
  • ⚠️ Methylene blue can cause tissue necrosis if it extravasates. Ideally MB should be infused via a central line. Dilution in larger volumes of carrier solution might also reduce this risk (e.g., 100 mg diluted in 500 ml saline).
• Doses >7 mg/kg may cause numerous side-effects (nausea, vomiting, confusion, dyspnea, tremulousness, diaphoresis, methemoglobinemia, hemolytic anemia).
• Hepatic and/or renal dysfunction: patients may metabolize methylene blue slowly, so exercise caution with repeated doses or continuous infusions.

pharmacology of MB

• Half-life may range from ~5-24 hours depending on the formulation used. (32145658)
• Methylene blue is mostly metabolized by the liver (CYP 1A2, 2C19, and 2D6), but ~40% is excreted unchanged in the urine.

role of MB in therapy for septic shock

• MB was historically utilized as a salvage therapy for patients refractory to all other treatments. However, a recent meta-analysis of RCTs found a mortality benefit from methylene blue (when combining patients with septic shock and patients with post-surgical vasoplegia). (37880041) A single-center RCT found that early MB administration accelerated shock resolution, with subsequent reduction in ICU length of stay. (36915146) These studies suggest that earlier introduction of MB into therapy could be reasonable. However, MB has yet to demonstrate efficacy in a large, multi-center randomized controlled trial.
• MB seems to be a fairly safe therapy if appropriate caution is utilized surrounding drug-drug interactions, contraindications (listed above), and cumulative dose (ideally maintained below ~5 mg/kg and spread out over time). Extravasation with skin necrosis does remain a concern, even at lower doses. Consequently, it might be reasonable to consider MB for patients who are failing to respond well to vasopressors and have central vascular access.

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resuscitative endpoints: general philosophy

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Resuscitative endpoints are targets which we would ideally like our patients to reach. The evidentiary basis for most resuscitative endpoints can be summarized roughly as follows:

• There is usually excellent retrospective evidence that a resuscitative endpoint correlates with improved outcomes.
• There is usually minimal prospective RCT evidence that tailoring resuscitation to intentionally reach a specific endpoint improves outcomes.

Prospective RCTs tend to compare different resuscitative endpoints, which is extremely murky (because none of these endpoints is supported by any hard data). These studies often build upon one another, with an exquisitely shaky foundation. For example:

1. The Rivers trial used resuscitative endpoints including central venous pressure (CVP) and mixed venous oxygen saturation. However, this is a profoundly flawed trial which at this point has been largely disproven.
2. The Jones trial showed equivalence between mixed venous oxygen saturation and lactate. This is establishes the equivalence of two awful resuscitative endpoints.(20179283)
3. The ANDROMEDA-SHOCK trial suggested that capillary refill could be superior to using lactate as a resuscitation target.(30772908) Given the lack of evidence supporting lactate as an endpoint, this trial is nearly impossible to interpret. It's possible that this trial reveals more about the harm of chasing lactate than the benefit of chasing capillary refill.

how to use resuscitative endpoints wisely?

• (1) Using resuscitative endpoints as a trigger for fluid administration is generally not a good idea. 📖
• (2) Resuscitative endpoints may be most useful for titrating vasopressors and inotropes.
  • Exactly how patients will respond to vasopressors or inotropes may be impossible to predict from an initial echocardiogram (which represents a snapshot of cardiac function in time).
  • The optimal hemodynamic targets (e.g., MAP goal) may vary between patients.
  • The best way to determine the optimal MAP goal and vasopressor dose for any specific patient may be empiric titration with close observation of the effects.
• (3) Failure to meet resuscitative endpoints should prompt overall re-evaluation of the patient, for example:
  • Is there a failure to achieve source control?
  • Are the antibiotics appropriate and dosed correctly?

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resus targets: MAP

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why MAP is generally the most useful blood pressure parameter:

• MAP is the mean pressure driving perfusion.
• MAP is what noninvasive oscillometric blood pressure cuffs actually measure.
• MAP is the most reproducible parameter when measured in different locations and via different techniques (e.g. noninvasive vs. invasive monitoring).
• Septic patients with vasodilation often have low diastolic blood pressure – so an adequate systolic blood pressure may be falsely reassuring.

conventional MAP target (>65 mm)

• MAP >65mm is the usual initial target.
• This is generally a reasonable place to start – particularly in an undifferentiated patient whose baseline hemodynamics are unclear.

higher MAP targets (>80 mm)

• The SEPSISPAM trial showed that a MAP goal of >80-85 mm improved renal function in the subset of patients with chronic hypertension, but higher MAP targets were associated with increased risk of atrial fibrillation.(24635770)
• Higher MAP targets may be trialed in patients with chronic hypertension and poor urine output. If there is an improvement in urine output at higher MAP, then this strategy may be continued; otherwise, the MAP target may be decreased (vasopressor challenge).
• Patients with cirrhosis and renal failure who have a component of hepatorenal syndrome might benefit from higher MAP targets.

lower MAP targets (e.g., >60 mm)

• Situations where lower MAP targets may be especially sensible:
  • Patients with chronic hypotension (e.g. younger women, patients with cirrhosis without hepatorenal syndrome, systolic heart failure).(31990655)
  • Patients with end-stage renal failure on hemodialysis (the primary concern with low MAP is renal injury, which isn't an issue here).
• The 65-TRIAL compared targeting a MAP >60 mm versus >65 mm among patients >65 years old with vasodilatory shock. Targeting a lower MAP (>60 mm) allowed slightly faster weaning of vasopressors, without any difference in other endpoints.(32049269)
• When lowering the MAP target, ensure that the patient remains adequately perfused.

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resus targets: heart rate

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optimal heart rate?

• Septic patients should have a bit of tachycardia. This is a compensatory response that improves cardiac output.
  • Remember: Cardiac Output = (Heart Rate)(Stroke Volume)
• The optimal heart rate for a patient with septic shock is unknown, and may vary between patients (e.g. patients with diastolic dysfunction could do better with a slightly slower heart rate). In general, a mild degree of tachycardia might be optimal for most patients.

management of bradycardia or “inappropriate normocardia” (e.g. <80 b/m) with systemic hypoperfusion

• If systemic perfusion is inadequate, a normal heart rate is usually not ideal.
• Epinephrine may be trialed in this situation, to determine if it could improve the heart rate and cardiac output (see above: epinephrine challenge).
• For patients with permanent pacemakers, pacemaker rate may be increased.

management of excessive tachycardia (e.g. heart rate >140 b/m)

• Excessive tachycardia probably isn't great either:
  • May impair ventricular filling (especially with diastolic dysfunction).
  • Over time, may increase the risk of stress cardiomyopathy.
• Potential interventions which may be considered:
  • Transition to vasopressors with less beta-adrenergic stimulation (e.g. vasopressin or phenylephrine).
  • Digoxin initiation in patients with chronic atrial fibrillation.
  • Removal of other stimuli which may be driving tachycardia (e.g. under-treated agitation, pain, or withdrawal).
  • Esmolol infusion was found to be beneficial in one study, but generalization from that study is impossible (because patients were on high-dose pressors and often levosemindan).(24108526) It's possible that the benefit from esmolol reflected excessive beta-adrenergic administration. Esmolol infusion in septic shock generally isn't generally recommended.

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resus targets: urine output

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typical urine output

• The usual goal is >0.3-0.5 cc/kg/hr ideal body weight.
• There is no single, specific cutoff rate for the urine output. The risk of renal failure increases based on how low the urine output is, and how long oliguria persists. For example:
  • Urine output 0.4 cc/kg for an hour with subsequent improvement is probably fine.
  • Urine output <0.3 cc/kg for several hours suggests an increased risk of renal failure.

good urine output is generally reassuring

• Some factors may falsely elevate urine output: diuretics, severe hyperglycemia (osmotic diuresis), or hypothermia.
• In the absence of these factors, adequate urine output is strong evidence of adequate perfusion.

low urine output is nonspecific

• Rarely oliguria or anuria may be due to urinary obstruction (e.g. dysfunctional Foley catheter).
• Oliguria may represent acute-onset hypoperfusion (“pre-renal AKI”), which will respond to improved perfusion. However, oliguria often represents acute tubular necrosis (“intrinsic AKI”), which won't respond to hemodynamic manipulation. In this scenario, trying to increase the urine output will be futile and potentially harmful (especially if fluid is used).

potential approach to oliguria

• After the initial resuscitation, additional fluid boluses should be avoided unless there is compelling evidence of hypovolemia (e.g. fluid loss from diarrhea).
• Depending on the current hemodynamics, vasopressor or inotrope challenges may be useful. If there is evidence of systemic congestion or a high suspicion for intrinsic renal failure, a furosemide stress test may be performed.
  • This is discussed further in the chapter on acute kidney injury.

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resus targets: fluid balance

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• Keep track of the net fluid balance of the patient, which includes the volume of crystalloid given, as well as the volume of antibiotics and other infusions.
• Very high fluid balance correlates with increased mortality. (28130687) Unless there is strong evidence of pre-existing hypovolemia, avoid running the fluid balance above ~5 liters positive.
• More on fluid management above.

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resus targets: lactate

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general philosophy on lactate

• Lactate is not an indicator of perfusion, systemic oxygenation, organ failure, or anaerobic metabolism. In most cases lactate serves as an index of endogenous epinephrine production.
• Cycling the lactate and trying to “normalize” it isn't evidence-based (for more on this, see Myth #3 here).
• Following the lactate is reasonable until it falls, but this data should be used in an intelligent and thoughtful fashion.

following lactate in patients not on epinephrine

• If the lactate is continuing to increase, this may be a sign of “missed injury.”
  • Undrained source of infection.
  • Inappropriate antibiotic selection.
  • Incorrect diagnosis entirely.
• A rising lactate isn't an indication to blindly give fluid or inotropes, but rather should be a sign that something is wrong and the entire patient needs to be reconsidered carefully.

following lactate in patient on epinephrine

• Epinephrine should cause the lactate to increase. In fact, rising lactate following initiation of epinephrine is generally a positive prognostic sign! (20016405)
• However, if the lactate increases to very high levels (e.g., >10 mM), then the epinephrine infusion should be down-titrated (and replaced by dobutamine if an inotropic agent remains necessary).

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resus targets: skin perfusion

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multidimensional assessment of skin perfusion:

• Mottling
  • Mottling refers to excessive vasoconstriction of cutaneous blood vessels, which creates a patchwork appearance (skin areas with very poor perfusion will appear violaceous).
  • Mottling has been linked to mortality in several studies. Patients with mottling are extremely sick and should be taken very seriously.
• Capillary refill time
  • The ideal technique may be to compress the fingertip using a slide with enough pressure to cause blanching for ten seconds. Any clear surface can also be used, such as a plastic urine specimen container.(27908340) Normal capillary refill time is <3-4 seconds, whereas >5 seconds indicates delayed capillary refill.
  • Normal capillary refill time (e.g., <3 seconds) suggests adequate perfusion. Such patients may be harmed by ongoing fluid resuscitation.(33852500; 30772908)
• Skin temperature
  • Warmth of extremities may be used as an indirect measurement of cardiac output.
  • Septic shock is often initially associated with a hyperdynamic state, which is associated with warm extremities and elevated cardiac output (“warm shock”). Some patients may subsequently transition to a state of reduced cardiac output (e.g. due to septic cardiomyopathy). One sign of this transition may be the development of cold extremities (“cold shock”).

skin perfusion as a resuscitation target

• The above signs of skin perfusion generally trend together (especially temperature and capillary refill). If all signs are consistent with one another, then this is more likely to be accurate.
• Management of poor skin perfusion:
  • (1) Signs of skin hypoperfusion may reflect excessive vasoconstriction. In some patients, these will improve with a shift towards use of an inotrope (e.g., epinephrine).
  • (2) Vasopressin down-titration: One of the most feared complications of using vasopressin is digital ischemia, which may lead to necrosis and digit loss. Cool digits may be a sign of excess vasoconstriction and the need to down-titrate vasopressin. Digital ischemia (e.g. blue fingers) should be an indication to immediately stop vasopressin.
• Adequate peripheral perfusion may identify patients who won't benefit from more aggressive resuscitation.(33852500)

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interventions of no real value

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central venous pressure (CVP) transduction

• Central venous pressure is an extremely complex variable, which reflects a nexus of volume status, cardiac function, and vascular tone.
• The concept that central venous pressure reflects volume status has been thoroughly debunked.(18628220)
• Measuring the central venous pressure should be avoided, as this value will almost invariably be misinterpreted.

mixed venous oxygen saturation (%svcO2)

• Similar to central venous pressure, the mixed venous oxygen saturation is a highly complex variable which reflects numerous contributing factors.
• Based on the number of factors affecting svcO2%, there is a dramatic error range in the value.
• Measurement of mixed venous oxygen saturation should be avoided because it is extremely complex, subject to considerable random error, and easily misinterpreted. Furthermore, numerous RCTs revealed that measuring svcO2% didn't improve outcomes compared to conventional therapy (the PROCESS, PROMISE, and ARISE trials).

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Inadequate focus on antibiotic selection and source control. Failure of either of these is most likely to cause morbidity or mortality.
• Delaying the initiation of vasopressors while waiting to see if fluid-loading works. If the patient is really in septic shock, delaying hemodynamic stabilization isn't advisable.
• Incorrect diagnosis of sepsis due to pneumonia (in response to minor CXR abnormalities from atelectasis) or urosepsis (due to UA abnormalities reflecting asymptomatic bactiuria). CXR and UA are often abnormal, so be careful of premature diagnostic closure based solely on these tests.
• Inadequate diagnostic investigation (e.g., for patients with an unknown or unclear source of sepsis, get a CT abdomen/pelvis).
• Excessive bombardment of all septic patients with vancomycin. In particular, patients with urosepsis or community-acquired abdominal sepsis won't benefit from vancomycin – all vancomycin will achieve is nephrotoxicity.
• Antibiotics should always be ordered first dose now, STAT. Beware of electronic medical record systems which will auto-schedule antibiotics to start hours in the future.

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• = Link to IBCC section about a drug.
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