Vasopressors/Sedatives

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    Source:  Various sources, UNVERIFIED

     

     

     

     

     

     

     

     

     

     

     

    Introduction

    • Generally:

     

    • Receptor Location Effect Example Agonists Example Antagonists
      α1 Peripheral Peripheral Vasoconstriction

      Phenylephrine (pure α1)

      Epinephrine (β + α​)
      Norepinephrine (α1 > β1)

      Clonidine (α2)

       

      Tamsulosin (α1)

      Terazosin

      Phentolamine (a1 + a2)

      α2 CNS outflow

      CNS symphathetic outflow

      (i.e. Preganglionic neurons communicate with

      post-synaptic neurons via α2 receptors),

      causing generally peripheral vasoconstriction

      β1 Heart

      Increases cardiac contractility (inotropy)

      Increases cardiac rate (chronotropy)

       

      Isoproterenol (β1 ONLY)

      Dobutamine (β1>β2) 3:1

      Salbutamol (β2>>β1)

      Selective:

      Metoprolol (β2>β1)

      Bisoprolol  (β2>β1)

      Atenolol (β2>β1)

      Non-Selective

      Carvedilol (β2>β1α)

      Labetalol (β2>β1α)

      β2

      Lungs

      Liver

      Bronchodilator

      Glycogenolysis + Gluconeogenesis

          (I.e. K+ shifting, hypoglycemia)

       

     

    Vasopressors Summary

    Vasopressor Activity Dose Indications Side Effects / Cautions

    Norepinephrine

    (aka Levophed)

    α1 > β1 1-30 mcg/min

    - Septic Shock (1st line)

    - Cardiogenic Shock

    - Undifferentiated Shock

    Least arrhythmogenic

    Dopamine

    α1, β1, Dopa

    Low Dose: DA > β1

    Medium: β1 > β2

    High: α1 > β1

    1-20 mcg/kg/min

      (1-5 used to be renal dose,

      but disproven)

      3-10 mcg/kg/min "cardiac dose"

      Larger Inotropic effect.

      >10 = systemic vasoconstriction

    - Cardiogenic Shock

    - Septic Shock (1st or 2nd line)

    - Some inotropy (use if sepsis

       + LV dysfunction)

    CAUTION:

           MOST Arrhythmogenic

     (avoid in tachycardia)

    NOTE: "renal dosing" theory

                 disproven

    Vasopressin

    V1

    (vascular

    smooth muscle

    +antidiuretic effect)

    0.03-0.04 u/min --> 

    2.4 u/hr 

    (usually not titratable,
    either on or off)

    - Exclusively septic 

      shock (2nd line after 

      norepinephrine)

    - NO INDICATION for

      non-septic shock

    CAUTION: Coronary + 

      splanchnic vasoconstriction

    - Avoid in NSTEMI if

    troponin >10, or if risk of gut

    ischemia.

    Phenylephrine Pure α1

    20-300 mcg/min

    (10mg in 100 mL of NS/D5W

     100mcg/mL - give 200-300mcg)

    - Neurogenic Shock

          (1st line)

    - Septic Shock (3rd/4th line)

    - Milder shock states (least

      risky through peripheral IV)

    CAUTION: Heart Rate 

       neutral, can cause reflex
       brady

    - LOW risk of arrhythmia

    - Not as effective as others

    Dobutamine

    β1 >> β2

    (can counteract α1)

    2.5 - 20 mcg/kg/min

    (some texts 3-15 mcg/kg/min)

    - Cardiogenic Shock

    (Low output septic shock)

    - Often add a pressor for 

      α1 - i.e. phenyl/dopamine

    CAUTION: Tachyarrhythmias
    Epinephrine

    Low Dose:

         β1 > β2 >> α1

    High Dose: α1 = β1 

     

    - 2nd line for septic/cardiogenic

      shock or other refractory shock

    Moderate arrhythmia risk

    Moderate ischemia

    Milrinone

    Positive inotrope

    and lusitropic + 

    systemic vasodilat.

    50mcg/kg bolus then

    0.25-1 mcg/kg/min

    - Cardiogenic Shock

    - Unlike dobutamine, acts 

    independent of β1 receptors

    (Can use with B-Blockers)

     

     

    • Note: Higher doses of vasopressors can be used, but they stop being effective.
      • I.e. If patient is on levophed 18mcg/min, higher doses will not help shock  very much, so you must think about adding a second agent.
    • Note #2: Some pressors can be run peripherally.  I.e. Levophed can be run at an approximately maximum of 10-15 mcg/min peripherally, but preferred to run for short period of time to prevent peripheral ischemia and necrosis.

    Sedating Meds

    NOTE: Doses are ESTIMATES.  It's rarely dosed per kg because it varies so much.  

    Often make a judgement call based on:

    • Weight
    • Age***
    • Alcohol Use
    • etc..

    Notes

    • Examples to make you comfortable:
      • In anesthesia procedural sedation is typically: 
        • 2mg midazolam
        • 100mcg of fentanyl (given with midaz)
          ---- wait 1 minute ----
        • 50mg of propofol
          • + titrate propofol q30secs based on desired level of sedation.
          • If patient is too deep they will be apneic, and you have to bag-mask or will need LMA or intubate.
          • If patient is too light, they will breathe on their own, but will move around during sedation.
          • The art of procedural sedation rests with getting them into the "theraputic" level of consciousness where they are light enough to breathe and not require airway manipulation and deep enough to not feel pain and not move during the procedure.
      • Typical induction for intubation: (example, but highly varies based on anesthetist)
        • 2-4mg midazolam
        • 100mcg of fentanyl
        • 100mg of propofol
        • paralyze if needed (succicnyl choline - short acting/irreversible/hyperkalemia risk, or rocuronium longer acting, reversible w/ glycopyrrolate or neostigmine.)
          • CAREFUL WITH PARALYSIS: They will not be able to breathe spontaneously.  You must make sure you can bag-mask ventilate them beforehand.  If you paralyze and cannot get ET tube in, and cannot bag-mask, they will need a surgical airway or they will die!
      • Why is midazolam/fentanyl/propofol used in combo?
        • Different effects, different duration, synergy, minimize toxicity from using one.
        • i.e. if you use midazolam only - they will not have pain control, will last a long time, need high doses.  Synergistic with other agents (allows lower doses of all meds).
        • i.e. if you use fentanyl by itself - will require exremely high fentanyl doses >400mcg for adequate anesthesia, they will stop breathing (need airway), may drop BP, and will remember everything. (no amnestic properties)
        • i.e. if you use propofol by itself > 100 mg - very short acting, after 5 min they will wake up with no anxiolytics and no pain control. 
        • HENCE: They are all used in combination to achieve synergy, low doses, low toxicity.
           
      • In a code situation, you can usually intubate the person if they are not conscious (no drugs needed). 
      • If a person is conscious and require sintubation (i.e. asthma, COPD, etc..), they will require sedation.
        • Drug of choice for "crash intubations" is Ketamine.  I.e. 50-80mg IV push.
        • Ketamine is the drug of choice because:
          • Lasts 20 min (relatively short acting)
          • Does not drop BP **** --> this is KEY!
          • Bronchodilates**** --> also KEY!
          • Does not decrease drive to breathe --> most KEY of all!  If you fail intubation, they can still breathe spontaneously. 
        • Another drug that is often used in crash intubations is remifentanyl.  i.e. 50-80 mcg IV push. 
              Because:
          • Extremely short acting (minutes), much more short acting than fentanyl.  If cannot get airway in, they will resume breathing in a few minutes. 
          • Extremely potent (i.e. may not require paralysis)

     

    Intermittent

    Agent Dose Properties Notes

    Midazolam (Versed)

    (comes in 1mg/mL)

    1-5 mg IV

    (1mg = ~2 drinks, slightly sleepy)

    (2mg = ~4 drinks, sleepy, can sleep)

    -Onset (3min)

       Peaks in 20-30m.

    -Duration: 0.5-1h

    -Residual: up to 4h

    Relatively pressure neutral, good sedative/analgesic.

    - Anxiolytic, anti-epileptic.

    - Inject over 20s, evaluate effect
       & titrate q2-3min

    Fentanyl

    (comes in 50mcg/mL)

    50-100 mcg IV (~1mcg/kg)

    - Immediate onset

    -Duration: 0.5-1hr

    Relatively pressure neutral, but patient remembers!

    - Pain control, anxiolytic

    Propofol

    (comes in 10mg/mL)

    50-100mg IV (1-1.5 mg/kg)

    - Immediate onset

    - Duration: ~5min

    Hypotension, have phenylephrine ready.

    - Anxiolytic, NOT analgesic.

    Ketamine

    1-2 mg/kg (typical 50-100mg IV)

    Recommended influse rate:

       0.5mg/kg/min)

    Onset IV: 30s

    Duration 5-10min

    Dissociation can

    last ≥ 20min.

    Used strictly as an induction agent, some indications

    for pain control in small doses.

    - Slight analgesic.

    - KEY in crash/unstable sedation because it is BP 

      neutral, bronchodilator (asthma).

    - Problem: Emergence reactions, pts disoriented

      and confused on emergency(give with benzo

      such as diazepam or midazolam).

    - Dissociative anesthesia - eyes wide open, produces

     hallucinations etc..  

     

    Continuous

    Agent Dose Notes
    Midazolam (Versed) 1-4 mg/hr mild-moderate, 5-10 intense sedation Relatively pressure neutral, good sedative/analgesic.
    Fentanyl 25 mcg/hr (mild), 50-100 mcg/hr (mod), >100 (more intense) Relatively pressure neutral, but no amnestic property!
    Propofol

    Dosed mcg/kg/min, but often requires a bolus (~150)

    20-60 mcg/kg/min [Light Sedation (i.e. ventilator ICU) ]

    60-150 mcg/kg/min [Deep anesthesia in OR]

    Hypotension, have phenylephrine ready.

    Neuromuscular Blockers

    • Used most often to manage ventilated patients who are agitated and difficult to ventilate.
    • However, this is FROWNED UPON! (see below)
    • Mechanism:
      • Inhibit acetylcholine receptors on post-synaptic side of neuromuscular junction.
      • Two different modes of action:
        • Depolarizing Agents --> act like acetylcholine --> sustained depolarization
        • Nondepolarizing agents --> inhibit depolarization of post-synaptic membrane
    • Drugs

     

    Drug Dose Dose Adj. Duration Notes Disadvantages

    Pancuronium

    (Pavulon)

    0.1 mg/kg q1-2 hrs

    (usually bolus-dosing)

    (can infuse if needed)

    1-2 mcg/kg/min

    Renal 60-100min

    >35y of clinical use

    - Rarely used
    (cardiac effects + long duration)

    - Long duragion (>1-2hrs)

    - Tachycardia

    - Need renal dose adjustment.

    Rocuronium

    (Zemuron)

    Load: 0.6-1.0 mg/kg

    Infuse: 10-12 mcg/kg/min

    Hepatic 30-40min

    - Shorter acting,

    - no tachycardia s/e

    - Dose
    Atracurium       - NOT USED (cisatracurium is better)

    - generates metabolite laudanosine

    that causes neuroexcitation.

    Cisatracurium

    (Nimbex)

    Load: 0.1-0.2 mcg/kg

    Infuse: 2.5-3.0 mcg/kg/min

    NONE 35-50min

    - NO cardiac effects

    - NO need to

    renally/hepatic dose adjust

     

    Succinylcholine

    (Anectine)

    (Depolarizing)

    1-2 mg/kg

    - paralyzes in 60s

      5min

    - Ultra-short-acting depolarizing

    - Only used for intubation

    - Can raise K+ by 0.5 mEq/L

    - Life threatening hyperkalemia

     if denervation injury 

    (head/spinal injury), rhabdo, 

    hemorrhagic shock, thermal inj.

    chronic immobility


     

    • Monitoring:
      • 4 low-frequency (2Hz) electrical pulses to ulnar nerve on forearm --> observe thumb adduction.
      • Total absence of thumb abduction = excessive block.
      • Goal: 1-2 perceptible twitches  (adjust drug infusion)
    • Disadvantages:
      • Frightening/painful experience (heavily sedate!!!)
      • Hard to monitor adquacy of sedation (use bis monitoring)
      • Complications of long-term paralysis:
        • Critical illness myopathy
        • Pneumonia in dependent lung lesions (cannot clear secretions)
        • VTE
        • Pressure ulcers

    Ventilators

    Basic Modes

    • Step 1:
      • Spontaneous vs. Controlled (aka AC)
        • Spontaneous: patient initiating breaths.
          • Patient must be able to blow open a valve...you set what defines a triggered "breath".  Often you set "trigger flow", if inspiration flow opens the value, this triggers a breath with a defined support (volume or pressure).
          • Typically if apnea occurs, ventilator switches to control mode for 2 minutes.
            • Some ventilators (newer ones like Dragger) can have PC-PSV
              • PC-PSV (Pressure Control - Pressure Support Vent): can set a minimum rate.  If rate falls below minimum, so it triggers a pressure control breath, and allows pressure support to continue if patient can breathe.
        • Control:
          • Defined rate, patient cannot override.
          • Usually uncomfortable.
          • Preferred for paralyzed patients.
    • Step 2:
      • Pressure Guarantee vs. Volume Guarantee
      • Pressure Guarantee
        • Provides airway pressure to a set amount.
        • This is a "go-to" mode for most RT's... set pressure, and titrate airway pressures to reach an a certain tidal volume (usually 6-10cc/kg) ~400-500ccs
        • Usually good for COPD/Asthma because you can titrate deltaP. (see below)
        • I:E ratio --> Inspiration:Expiration.  (I is set)
          • I:E ratio is important for airway obstruction.  If COPD/Asthma patient has a short I:E ratio, they need long exhalation time.  If exhalation is not complete they will keep air in their lungs at the end of each breath, causing "PEEP" to build up (called auto-PEEP)
      • Volume Guarantee:
        • Less common, often used by anesthesia because people more healthy.
        • Set volume, and machine will determine airway pressures to achieve that volume.
        • Typically scary, make sure you keep a max pressure.  If patient obstructs, machine can generate high pressures and no volume.  Can cause pneumo etc.. 
      • PAV - Proportional Assist Ventilation
        • Gives proportional pressure assist.
        • Used to wean off of ventilator.
        • The idea is to work the diaphgram... some research into improving weaning off vents.
      • SIMV - Synchronized Intermittent Mandatory Ventilation
        • AC-PC mode, but allows you to breathe.
        • When takes spontaneous breath, machine resets and lets you take the breath.
      • IMV
        • Intermittent mandatory ventilation.
        • Patient discomfort - eg. inhales when vent exhales.
      • APRV (Aka Bi-Level)
        • Similar to BiPAP
        • ECHOR?  Extra-corporally
    • Lingo:
      • Spontaneous + Pressure Guarantee = Pressure Support
      • Controlled + Pressure Guarantee = Pressure Controlled (PCV)
      • etc..
    • Goals:
      • Clear CO2 at minimzied lung volumes
      • Barotrauma, hard to wean if keep on high lung volumes.

    Settings

    • PEEP - Positive End Expiratory Pressure
      • Regulates PaO2
      • Usual Settings: 6-12 mmH2O
        • Natural PEEP is up to 5 mmH2O
        • Use 6 for low PEEP (COPD for high deltaP)
        • Use 12 for high PEEP (CHF - push fluid into vasculature).
        • Or no PEEP if healthy.
    • Pressure Control
      • Starting: 6-12.
      • Titrate to tidal volumes of 6-8 cc/kg. (i.e. 80kg = 480cc's).  (8-10 possible, but considered high volumes).
    • Total Airway Pressure
      • For BiPAP maximum airway pressure is 20 --> if over 25, open cardiac esophageal sphincter. --> requires definitive airway.
      • Same for LMAs.
    • Plateau pressure:
      • Pressure you apply to small airways (causes baro trauma).
    • Peak Pressure:
      • Pressure applied to large airways.
      • In asthma: Plat (small airways) is low, and Peak pressure is high (airway obstruction).

     

    Adjusting Settings Based on ABG

    • If PaO2 is low: 
      • Either increase PEEP or increase FiO2  (and maybe Inspiratory:Expiratory ratio)
      • Typically increasing FiO2 >50% is less desirable due to toxic lung injury, so many anesthetists/RTs like to go up on the PEEP and keep FiO2 low.
    • If PaCO2 is high
      • Increase detaP  (= difference between PEEP and Peak Pressure) or increase respiratory rate.
      • i.e. in COPD who is accummulating CO2, make PEEP low and pressure support high.

    Note on BiPAP

    • Can they tolerate BiPAP?
      • Awake, alert, spontenously breathing.
      • Alert enough to say they are vomiting to take off mask.
      • Vomiting is a contraindication to BiPAP!
    • Contraindicatons:
      • Severe hemoptysis, cardiac arrest / MI, decreased LOC , vomiting risk, recent oropharyngeal or gastric surgery.
      • Non-cooperative, agitated, face trauma/surgery, facial deformity, upper airway obstruction.
    • Always for spontaneous ventilation.
    • IPAP and EPAP (inspiratory and expiratory).
      • (EPAP = PEEP) and (IPAP = total inspiratory pressure).
      • IPAP - EPAP = pressure support setting on intubation ventilator.
    • Starting pressures:
      • EPAP = 5-12 (increase if oxygenation issues)
        • Also depends on condition (i.e. 5 for CHF, 7 for COPD, 10 for ILD)
      • IPAP = 8-20  (increase if ventilation/pCO2 issues)
    • Limited by 20-25 mmH2O maximum airway pressures, as higher pressures open the cardiac esophageal sphincter causing stomach air entry, vomiting, aspiration.
      • If higher pressures needed --> intubate.
    • Often order "to keep pH > 7.3".
    • If cannot improve pH >7.25 in 2 hours --> INTUBATE
    • If O2 not improvement, and IPAP is up to 18-20 --> INTUBATE

     

    • Respond to blood gasses:
      • If CO2 is high = increase deltaP (difference between IPAP and EPAP)
      • if O2 is high = increase the EPAP (aka PEEP).
      • Titrate to NORMAL PH (not CO2) or rather titrate to their baseline CO2 (that is normally compensated)

    Extubation

    • Generally ventilator settings are down-titrated slowly, and when they are at minimal settings.. patient is extubated.
    • Several trials support the use of NIPPV post-extubation (reduced risk of re-intubation and shortened ICU stay, improved survival).
      • Not replicated in further studies, only done in specific populations.
      • Many trials, controversial.
    • Bottom line: Immediate NIPPV post-extubation should be done for patients with chronic lung disease and hypercapnia.

    CPAP vs. BiPAP

    • CPAP - For O2 problem (for oxygenation problem) (proven)
      • CHF
      • OSA
      • COPD exacerbation (if CO2 is not up)
      • Pneumonia
        • (Discouraged as can make them worse, pts less likely to cough.  Avoid unless think they will fail.)
      • Initial disease
    • BiPAP (for CO2 +/- O2 problem)
      • neuromuscular weakness (myasthenia gravis, GBS, ALS)
      • COPD exacerbation
    • Often  atelectasis in the lungs, the idea with PEEP or EPAP is keeping high pressures to keep alveoli open.
      • However if you remove all PEEP, alveoli will collapse again (because those airways don't have surfactant).
        • Need 24-48hrs to build up surfactant to keep airways open. (studies show if drop peep right away, there is no benefit, airways re-collapse)
      • However, with high PEEP there is a risk of barotrauma (popping alveoli) and compressing blood flow and converting shunt to dead sapce.
    • Rat Lungs recruitment with peep:
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