“Pressors” in Distributive Shock in Adults

“Pressors” in Distributive Shock in Adults

Thank you, Dr Dastmalchi, for requesting this POTD. I will review “pressors” for cardiogenic shock separately

• Vasopressors- Pure vasoconstriction without any inotropy eg Phenylephrine and Vasopressin

• Inotrope- Increase cardiac contractility à improving SV and cardiac output without any vasoconstriction eg Milrinone

• Inopressors - a combination of vasopressors and inotropes, because they lead to both increased cardiac contractility and increased peripheral vasoconstriction eg Norepinephrine, Epinephrine and Dopamine

Norepinephrine- Inopressor

• First line vasopressor in septic shock per Surviving Sepsis Guidelines

• Less arrhythmogenic than Epinephrine and Dopamine

Mechanism of action

• Stimulates alpha-1 and alpha-2 receptors

• Small amount of beta-1 agonist- modest inotropic effect

• Increased coronary blood flow and afterload

• Increases venous tone and return with resultant increased preload

Adverse effects

• Norepinephrine is considered safer than both Epinephrine and Dopamine.

• ARR of 11% compared to dopamine with NNT 9

• NE superior in improving CVP, urinary output, and arterial lactate levels compared to Epinephrine, Phenylephrine, and Vasopressin.

Indications

• First-line pressor choice in distributive shock, including both neurogenic and septic shock

• Norepinephrine as the only first-line pressor per SSC guidelines

Dosing

• Use weight-based dosing to avoid the adverse effects associated with norepinephrine use

• Weight-based dosing is based on GFR

• Norepinephrine has a rapid onset of action (minutes) and can be titrated every 2-5 minutes

Epinephrine- Inopressor

Mechanism of action

• Beta-1 and beta-2 receptors agonism à more inotropic effects than norepinephrine

• Epinephrine greatly increases chronotropy (heart rate) and thus stroke volume

• Some stimulatory effect on alpha-1 receptors

• Lower doses (1-10 mcg/min) à a beta-1 agonist

• Higher doses (greater than 10 mcg/min) à an alpha-1 agonist

Adverse effects

• Associated with an increased risk of tachycardia and lactic acidosis

• Hyperglycemia

• Increased incidence of arrhythmogenic events associated with epinephrine

• More difficult use lactate as a marker of the patient’s response to treatment

Indications

• SSC guidelines recommend epinephrine as a second-line agent, after norepinephrine

• “push-dose pressor”

• Due to beta-2 receptors agonism causing bronchodilation, epinephrine is first-line agent for anaphylactic shock

Dosing

• Guidelines for anaphylactic shock recommend an initial bolus of 0.1 mg (1:10,000) over 5 minutes, followed by an infusion of 2-15 mcg/min however associated with adverse cardiovascular events

• For septic shock start epinephrine at 0.05 mcg/kg/min (generally 3-5 mcg/min) and titrate by 0.05 to 0.2 mcg/kg/min every 10 minutes. maximum drip rate is 2 mcg/kg/min

Dopamine- Inopressor

• Fallen out of favor

• Associated with higher arrhythmogenic events

Mechanism of action

• Effects are dose-dependent

• Low doses à dopaminergic receptors à leads to renal vasodilation à increased renal blood flow and GFR although studies failed to demonstrate improved renal function with dopamine use clinically

• Moderate doses à beta-1 agonism à increased cardiac contractility and heart rate

• High doses à alpha-1 adrenergic effects à arterial vasoconstriction and increased blood pressure

Adverse Effects

• Several large, multi-center studies that demonstrate increased morbidity associated with its use

• Significantly higher rates of dysrhythmias à NNH 9

Indications

• Rescue medication when shock is refractory to other medications

Dosing

• Start at 2 mcg/kg/min and titrate to a maximum dose of 20 mcg/kg/min.

• Less than < 5 mcg/kg/min à vasodilation in the renal vasculature

• 5-10mcg/kg/min à beta-1 agonism

• 10 mcg/kg/min à alpha-1 adrenergic

Vasopressin- Vasopressor

• Add vasopressin (doses up to 0.04 units/min) to norepinephrine to help achieve MAP target or decrease norepinephrine dosage

• Restore catecholamine receptor responsiveness, particularly in cases of severe metabolic acidosis.

• pH independent

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

Mechanism of action

• At low doses (< 0.04 units/min) à increases vascular resistance (V1)

• No effect on heart rate and cardiac contractility

Adverse Effects

• Vasopressin has been shown to be as safe as norepinephrine at lower doses

• Increases SVR and afterload and decreases cardiac output although unclear if effect significant at lower doses

Indications

• Second line vasopressors per SSC guidelines for septic shock

• pH independent- Vasopressin in combination with epinephrine demonstrated improved ROSC in cardiac arrest patients with initial arterial pH <7.2 compared with epinephrine alone

Dosing

• Steady dose at 0.03-0.04 units/min

• Vasopressin is not titrated to clinical effect as are other vasopressors

• Think about it more as a replacement therapy and treatment of relative vasopressin deficiency

Phenylephrine- Vasopressor

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

• SSC guidelines does not make rated recommendations on Phenylephrine

• Limited clinical trial data

Mechanism of action

α1 agonism with peripheral vasoconstriction

Adverse Effects

• Bradycardia - decrease in heart rate mediated by the carotid baroreceptor reflex 2/2 increase in SVR

• Increases SVR and afterload and decreases cardiac output

Indications

• Patients that are susceptible to beta-adrenergic generated arrhythmia

• Push dose formulation

• Refractory shock

Dosing

0.1-2mcg/kg/min (onset: minutes, duration: up to ~20 minutes)

References:

Emdocs

LITFL

Pollard, Sacha, Stephanie B. Edwin, and Cesar Alaniz. "Vasopressor and inotropic management of patients with septic shock." Pharmacy and Therapeutics 40.7 (2015): 438.

Amlal, Hassane, Sulaiman Sheriff, and Manoocher Soleimani. "Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin." American Journal of Physiology-Cell Physiology 286.5 (2004): C1019-C1030.

Khanna, Ashish, and Nicholas A. Peters. "The Vasopressor Toolbox for Defending Blood Pressure."

Turner, DeAnna W., Rebecca L. Attridge, and Darrel W. Hughes. "Vasopressin associated with an increase in return of spontaneous circulation in acidotic cardiopulmonary arrest patients." Annals of Pharmacotherapy 48.8 (2014): 986-991.

Targeted Temperature Management

Great job on resuscitating that V fib cardiac arrest and achieving sustained ROSC. 

Now what? Cool them!

Whether you cool them or not could determine whether your patient goes into multisystem organ failure in the ICU or walks out of the hospital few weeks later.

What:

Targeted temperature management (TTM) to improve survival and neurological outcomes among comatose survivors of patients with cardiac arrest

Who:

Adults with out-of-hospital cardiac arrest with an initial shockable rhythm and nonshockable rhythm

Inclusion criteria (must meet all criteria)

• Postcardiac arrest status (any rhythm as a cause of arrest is eligible)

• ROSC < 30 minutes from EMS/code team arrival

• Time at induction < 6 hours from ROSC

• Comatose status (patient does not follow commands)

• MAP ≥ 65 mm Hg (may include use of vasopressor drugs)

Exclusions may include

• DNR advanced directive, MOLST, poor baseline status, or terminal disease

• Traumatic etiology for the arrest

• Active bleeding or known intracranial bleeding (relative)

• Cryoglobulinemia (relative)

• Pregnancy (relative; consider obstetrician/gynecologist consultation)

• Recent major surgical procedure (relative)

• Severe sepsis/septic shock as cause of arrest (relative)

Why:

• Decreased fever-related tissue injury

• Reduction in ischemic-reperfusion injury

• Cerebral metabolic rate decreases by a 6-7% for every 1ºC drop in body temperature which reducing oxygen demand, preserving phosphate compounds and preventing lactate production and acidosis

• Bernard, et al (2002) found an Absolute Risk Reduction (ARR) for death or severe disability of 23%, NNT was 4.5

• The Hypothermia After Cardiac Arrest (HACA) Group (2002) found an ARR for unfavourable neurological outcome of 24%, and NNT of 4

How:

• IV cold saline 2-3 mL/kg

• Cooling vest and cooling machine- Arctic Sun

• If shivering does not occur, do not use neuromuscular blockade

• If paralysis employed, titrate to degree of shivering- do not need train-of-four monitoring

• Sedation of choice is institution dependent (MMC CICU uses Fentanyl and Midazolam)

When:

Initiation of TTM within122 minutesof hospital admission was associated with improved survival.
Most guidelines recommend initiation within6 hours

What temperature should be targeted:

This remains controversial, with guidelines accepting a range of temperature targets from 33-36C. Available evidence shows no benefit to hypothermia (33C) compared to normothermia (36C). In the absence of evidence, targeting 36C is prudent

• TTM36 is more hemodynamically stable than TTM33, which is relevant because these are often very unstable patients.

• TTM36 avoids electrolytic shifts associated with raising and lowering the temperature.

• Hypothermia at 33C suppresses immune function and associates with increased rates of pneumonia.

• TM33 will induce bradycardia, which is dangerous in patients with underlying torsades de pointes.

References

Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63. PMID 11856794

Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56. PMID 11856793

Nielsen N et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013; 369: 2197-206. PMID 24237006

Stanger, Dylan, et al. "Door‐to‐targeted temperature management initiation time and outcomes in out‐of‐hospital cardiac arrest: insights from the Continuous Chest Compressions Trial." Journal of the American Heart Association 8.9 (2019): e012001.

Donnino, Michael W., et al. "Temperature management after cardiac arrest: an advisory statement by the advanced life support task force of the international liaison committee on resuscitation and the American Heart Association emergency cardiovascular care committee and the council on cardiopulmonary, critical care, Perioperative and Resuscitation." Circulation 132.25 (2015): 2448-2456.

REBEL EM
LITFL
EB Medicine
Mayo Clinic Florida TTM Guideline

POTD: Pulmonary Embolism Decision Rules - Beyond the Basics

Special thanks to Dr. Errel Khordipour for giving this amazing review and Dr. Anna Bona for taking meticulous notes during this talk!

TL;DR

• PE carries an 8% 30-day mortality after diagnosis (some studies higher)

• CTA has a very high false positive rate

• Step 1: based on the patient's history and presentation, do you think the patient has a PE? If yes, proceed. If no, STOP

  • Read more below for nuances re: features that makes a patient risky for PE

• Step 2: Using your clinical decision rules (Well's, Geneva, or clinical gestalt), is the patient low, medium, or high risk?

  • Low risk: PERC

  • Medium: D-dimer --> then CTA if positive

    • Age adjust your d-dimer if possible

  • High Risk: CTA

• Step 3: Treat! (or don't treat!)

  • Unstable --> tPA and MICU

  • Stable --> get labs, echo

    • Labs abnormal or echo w/ RV strain --> heparin +/- half-tPA

    • Labs/echo normal --> determine the pt's PESI score

      • High --> heparin

      • Low --> lovenox and discharge

• Subsegmental PEs in patients < 50 with stable vitals have a very low risk of adverse outcome

  • May consider discharging without anticoagulation if no DVT is present and there are no risk factors for recurrence

• If the study is inadequate, refer to the d-dimer

  • If d-dimer positive, get bilateral lower extremity dopplers

    • Discharge if negative

    • If positive, consider anticoagulation based on risk factors and labs and f/u with PMD for repeat doppler in 3-7 days. 

Interested? Let's get more specific!

Let’s consider a patient that rolls into your emergency department. They’re complaining of chest pain and shortness of breath. You’re working with a medical student and they list pulmonary embolism as a differential diagnosis. How do we risk stratify our patients using our decision making tools.

Background
First off, why do we care? First off, PE is a very much-feared missed diagnosis, which carries an 8% 30-day mortality** after diagnosis (this was much lower than I expected, to put this into context, hemorrhagic strokes carry a 25-40% mortality depending on your source and hip fractures carry a 4-10% mortality rate depending on your source).

**some studies show a 30% mortality, however those were autopsy studies, so it is unknown whether the patients died with a PE or as a result of a PE.

That being said, our testing methods are very much imperfect! The false positive rate on CTA for segmental PE is 25% and even scarier, the false positive rate for subsegmental PEs is 60%!! Not a great test! Plus, a CTA is not a benign test. Contrast can cause anaphylactoid reactions and lifetime risk of malignancy increases with each CT. Plus, once a patient is labeled as having a PE (even subsegmental), they’re much more likely to get scanned in the future.

So let’s talk about how we can determine who is high risk and who is low risk.

Step 1: Consider the patient’s presentation and history

Vital signs:

Risk Factors: 

Prior VTE (PE/DVT): Was the last PE/DVT unprovoked or provoked? More concerning if the last PE/DVT was unprovoked (e.g. the patient was not immobilized for a long period of time). This does not change if testing for hypercoagulability was negative. If provoked, this is less concerning.

Malignancy History: Higher risk with active cancer. This either means active treatment within the last 6 months or metastatic disease. Chemotherapy patients are also more at risk. Not all malignancies are created equal, though! Your risk is even higher with pancreatic cancer, multiple myeloma, colon cancer, glioblastoma, and melanoma.

Immobility: certain types of immobility are higher risk than others! Examples: patients in casts, hospitalized trauma patients (others not at higher risk). Surgical patients are higher risk if they were intubated, received general anesthesia, or received an epidural (e.g. knee surgery, abdominal surgery, neurological surgery). Being in a continuous seated position for > 6 hours might be a risk factor.

OCPs: estrogen of any form increases risk (e.g. OCPs, estrogen replacement, intra-vaginal estrogen). For transgendered patients, more study is needed to determine increased risk.

Pregnancy: Highest risk 2 weeks postpartum. If a patient is pregnant and symptomatic, they have a 70% risk of PE.

Increased risk at age 50: Risk of PE perpetually increases with age. 

Symptoms:

Chest pain: pleuritic chest pain suggest peripheral PE (65%)

Hemoptysis: more indicative of pulmonary hemorrhage, not infarct

Exertional Dyspnea: concerning! You do not need to have chest pain to have a PE!! There is a syndrome that consists of subacute dyspnea that gets worse over days that is predictive of central PE.

Calf pain/Calf swelling: unilateral calf pain (the symptom) and calf swelling (the physical exam finding) are both concerning.

Syncope: corresponds to a large clot burden, but syncope  (likely does not confer an increased likelihood of PE)

Anticoagulation: if they are compliant with anticoagulation, they are less likely to have PE. While this is definitely true with NOACs, with Coumadin, it’s less certain because levels will vary regardless of compliance with medication. Symptoms that are not significant: orthopnea, palpitations, anxiety, dizziness 

Physical Exam Findings:

Abnormal pulmonary exam - decreases likelihood of PE

Clinical signs of DVT - such as calf swelling, redness, etc. increases likelihood 

STEP 1 (cont): Do you, based on the information above, feel that a PE is possible? Meaning, it is ABOVE the 2% threshold for PE. 

Professional recommendation: if the patient has risk factors in 2 or more of the above categories (e.g. vital sign and risk factors, or risk factors and exam findings), and there is no alternative explanation for the patient's presentation, you can say adequately that you have suspicion for PE. 

If you have less than a 2% clinical suspicion for PE, STOP. You do NOT think there is a PE and you do not evaluate further. I repeat - STOP! Evaluate for other suspected pathologies). ACEP Guidelines: 2% is an acceptable cutoff recognizing limitations of testing and risk of false positives (in latest NSTEMI guidelines) Now that you truly think your differential should include PE...  

STEP 2: RISK STRATIFY

It doesn't matter if you use Well's Score vs. Geneva vs. Gestalt; all have been shown to be equal. Keep in mind these decision tools SHOULD NOT used to rule out. They are only to RISK STRATIFY. Meaning that you clinically have a suspicion of said disease before you use them. This means you should NEVER document "Well's score low, not likely PE". 

 High risk: get a CTA! May consider empiric heparin before or after CTA.  

Moderate: D-dimer. 

• In general, you should use age adjusted cutoffs for patients > 50. The conversion depends on which unit you use. 

  • FEU (fibrinogen unit, cutoff usually ~ 500): add the age x 10

  • DDU (d-dimer unit, cutoff usually ~ 250): add the age x 5

Low: PERC

STEP 3: Further Management

Ever get a reading that said "evaluation for sub-segmental suboptimal due to motion artifact? What do you do? (Only if vital signs are stable)

• Get a d-dimer (if not already obtained)

• Positive --> LE dopplers

  • Yes DVT: anticoagulate!

  • No DVT: discharge with or without anticoagulation based on risk factors and lab values; follow-up with PMD for repeat surveillance ultrasound in 3-7 days. 

• Negative -->  Discharge 

Now let's go over what you do if a PE is found...

Disposition: depends on if the patient is stable or unstable

Unstable: hypotensive, signs of shock, etc

• Give tPa and admit to MICU

Stable: labs (BNP, troponin), echo

• If the patient as abnormal labs or right heart strain, give heparin +/- half-dose tPA and admit to ICU/tele

• If normal, determine the patient's PESI Score

  • High PESI score --> give heparin and admit to floor

  • Low PESI score --> give lovenox** and discharge

** There inadequate evidence and no FDA approval for NOACs at this time
  Subsegmental PEs in patients < 50 with stable vitals have a very low risk of adverse outcome, so you may consider discharging without anticoagulation if no DVT is present and there are no risk factors for recurrence and have the patient f/u with PMD for surveillance of PE symptoms.