1.3 Resuscitation Pharmacology, Pharmacokinetics & Vascular Access

1.3 Resuscitation Pharmacology, Pharmacokinetics & Vascular Access

Altered Pharmacokinetics in Critical Illness and Resuscitation

During cardiac arrest, hemorrhagic shock, and severe distributive shock, profound circulatory failure disrupts the fundamental principles of absorption, distribution, metabolism, and elimination. Standard pharmacokinetic parameters derived from healthy volunteers do not apply.

                    PHARMACOKINETIC SHIFTS IN CRITICAL RESUSCITATION
  ┌─────────────────────────────────────────────────────────────────────────────┐
  │ 1. Organ Hypoperfusion & Impaired Clearance                                │
  │    - CPR produces only 10%–30% of normal cardiac output.                    │
  │    - Hepatic blood flow drops -> flow-limited drug clearance falls sharply  │
  │      (lidocaine, fentanyl, morphine accumulate rapidly).                   │
  ├─────────────────────────────────────────────────────────────────────────────┤
  │ 2. Severe Acidemia & Altered Ionization                                     │
  │    - Tissue hypoxia -> profound lactic acidosis (pH < 7.15).                │
  │    - Alters weak acid/base ionization and drug-receptor binding.            │
  │    - Blunts alpha-1 and beta-1 catecholamine receptor responsiveness.       │
  ├─────────────────────────────────────────────────────────────────────────────┤
  │ 3. Expanded Volume of Distribution (Vd)                                     │
  │    - Capillary leak + fluid loading -> expanded extracellular fluid.        │
  │    - Hydrophilic drugs diluted -> REQUIRES LARGER INITIAL LOADING DOSES     │
  │      (beta-lactams, vancomycin, aminoglycosides, rocuronium).               │
  ├─────────────────────────────────────────────────────────────────────────────┤
  │ 4. Protein Binding Shifts & Free Drug Fractions                             │
  │    - Acute hypoalbuminemia + endogenous acid displacement.                  │
  │    - Free (active) drug fraction surges (phenytoin, ceftriaxone, warfarin). │
  │    - Total serum drug levels understate free clinical drug activity.        │
  └─────────────────────────────────────────────────────────────────────────────┘

1. Organ Hypoperfusion & Impaired Clearance

In cardiac arrest, high-quality closed-chest CPR generates only 10% to 30% of normal baseline cardiac output, preferentially shunting blood to coronary and cerebral vessels while splanchnic, renal, and peripheral circulation ceases. In cardiogenic and hypovolemic shock, intense compensatory vasoconstriction similarly collapses visceral perfusion.

• Flow-Dependent Drug Clearance: Medications cleared primarily by hepatic metabolism with high hepatic extraction ratios ($>0.7$, such as lidocaine, morphine, fentanyl, and propranolol) depend strictly on hepatic blood flow. When hepatic perfusion plunges, their clearance falls proportionally. Repeated boluses or continuous infusions rapidly accumulate to toxic concentrations.
• Organ Dysfunction: Acute tubular necrosis and renal hypoperfusion abolish glomerular filtration, necessitating extended dosing intervals for renally eliminated medications once initial loading is complete.

2. Severe Acidemia & Receptor Responsiveness

Cellular hypoperfusion produces rapid accumulation of lactic acid, while respiratory failure leads to hypercapnia, driving arterial pH below 7.15. Severe acidemia exerts major pharmacologic consequences:

• Ionization Shifts: Weak bases become increasingly protonated (ionized) in acidemic environments, preventing lipid-membrane penetration, while weak acids shift toward their un-ionized, lipophilic state, altering tissue distribution.
• Blunted Adrenergic Responsiveness: Severe acidosis alters the tertiary conformation of alpha-1 and beta-1 adrenergic receptors on vascular smooth muscle and myocardium. The inotropic and vasopressor potency of endogenous and exogenous catecholamines (epinephrine, norepinephrine, dopamine) is markedly blunted at pH $<7.15$. Higher doses or restoration of physiological pH (via ventilation and underlying shock reversal) are required to restore vascular tone.

3. Expanded Volume of Distribution ($V_d$)

Endothelial glycocalyx disruption in sepsis, burns, and trauma induces massive capillary leak. When combined with crystalloid fluid resuscitation, the extracellular fluid compartment expands by 30% to 50% or more.

• Hydrophilic Drugs: Agents with small baseline distribution volumes ($V_d < 0.6$ L/kg) that distribute primarily into extracellular water (e.g., beta-lactam antibiotics, vancomycin, aminoglycosides, and neuromuscular blockers such as rocuronium and succinylcholine) experience dramatic dilution.
• Clinical Practice: Initial loading doses of hydrophilic medications must be increased regardless of renal function to achieve therapeutic peak concentrations ($C_{max}$). For example, cefepime 2 g, meropenem 2 g, vancomycin 25–30 mg/kg, and rocuronium 1.2–1.6 mg/kg must be administered to achieve target receptor saturation.

4. Protein Binding Shifts & Free Drug Fractions

Critical illness rapidly lowers circulating serum albumin through reduced hepatic transcription and transcapillary extravasation. Simultaneously, circulating uremic acids, bilirubin, and free fatty acids compete for binding sites on albumin.

• Surge in Free Drug Fraction: For highly protein-bound drugs ($>90\%$, such as phenytoin, ceftriaxone, warfarin, and valproic acid), displacement dramatically increases the unbound, pharmacologically active fraction. Total serum concentration assays understate drug exposure; therapeutic drug monitoring must evaluate unbound (free) concentrations or use corrected equations.

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Vascular Access Routes in Resuscitation

Selecting the appropriate route of drug administration during resuscitation depends on urgency, hemodynamic status, drug properties, and anatomical access.

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Intraosseous (IO) Access: Anatomy, Technique & Pharmacology

The intraosseous space is an uncollapsible, rigid venous plexus located within the medullary cavity of long and flat bones. Non-collapsible sinusoids drain directly into central venous circulation via medullary emissary veins, providing absorption kinetics identical to central venous administration.

Anatomical Insertion Sites

1. Proximal Humerus (Humeral Head):
   • Landmark: Greater tubercle of the proximal humerus, 1 cm superior to the surgical neck.
   • Flow Rate: Delivers the highest IO flow rate—up to 5,000 mL/hr (5 L/hr) under 300 mmHg pressure.
   • Transit Time: Drugs reach the right atrium in 3 to 5 seconds due to close proximity to the superior vena cava.
   • Pain Profile: Less painful during infusion than tibial sites in awake patients, but requires limb immobilization to prevent needle dislodgement during chest compressions or patient repositioning.
2. Proximal Tibia:
   • Landmark: Anteromedial flat surface of the tibia, 2 cm medial to the tibial tuberosity (and 1–2 cm proximal in infants, 1–2 cm distal in adults).
   • Flow Rate: Delivers approximately 1,000 mL/hr (1 L/hr) under 300 mmHg pressure.
   • Clinical Utility: Rapidly accessible landmark during active chest compressions without interfering with CPR or airway management; stable fixation; contraindicated in the presence of ipsilateral fracture, severe orthopedic trauma, or prior knee arthroplasty.
3. Distal Tibia: Alternative landmark located 2 cm proximal to the prominence of the medial malleolus.
4. Sternum (FAST1): Utilized primarily in tactical and military combat settings; contraindicated in traumatic sternal fractures or during active closed-chest CPR.

The Mandatory Initial Flush Mechanism

Unlike an intravenous vein where fluid flows spontaneously upon cannulation, bone marrow is packed with a dense gelatinous meshwork of hematopoietic cells, adipose tissue, and fibrin trabeculae.

• Immediately following IO needle insertion and stylet removal, a rapid, forceful manual syringe flush of 5 to 10 mL normal saline (2 to 5 mL in pediatric patients) must be pushed.
• This high-pressure bolus physically fractures the medullary meshwork, opening sinusoids into emissary veins.
• Without an immediate rapid manual flush, gravity drips and infusion pumps will fail to flow.
• Continuous fluid infusions require pressure infuser bags inflated to 300 mmHg.

Pain Management in Conscious Patients

While needle penetration through the periosteum causes brief discomfort, the high-pressure fluid infusion against intramedullary pressure sensors causes excruciating pain in conscious patients.

• Premedication Protocol: Administer preservative-free 2% lidocaine (cardiac lidocaine) into the IO needle prior to the initial flush.
• Adult Dosing: 40 mg (2 mL of 2% lidocaine) infused slowly over about 120 seconds. Allow the lidocaine to dwell in the marrow space for 45 to 60 seconds to anesthetize intramedullary nerve fibers, then administer the 5–10 mL saline flush.
• Pediatric Dosing: 0.5 mg/kg (maximum 40 mg) administered slowly over 1 to 2 minutes, followed by dwell time and flush.

Medication Compatibility & Diagnostic Sampling

• Universal Compatibility: ANY medication, crystalloid, colloid, or blood product (including packed red blood cells, whole blood, platelets, and plasma) that can be administered via peripheral or central IV can be administered via IO at the exact same doses and concentrations.
• Laboratory Diagnostics: Bone marrow blood may be aspirated for point-of-care blood gas analysis, typing and crossmatching, electrolytes, and basic chemistry. However, marrow must be aspirated BEFORE the initial saline flush. White blood cell counts, differential, and platelet counts from marrow aspirate are clinically invalid due to hematopoietic precursors.

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Access Hierarchy in Cardiac Arrest (2025 AHA Guidelines)

The 2025 AHA Adult Advanced Life Support guidelines set a clear order for drug access during cardiac arrest:

1. Peripheral IV first (Class 1). Recent trials comparing first-attempt IV with first-attempt IO access in out-of-hospital arrest found no survival advantage for IO.
2. Intraosseous access is reasonable if IV attempts fail or are not feasible (Class 2a).
3. Central venous access may be considered by trained clinicians if IV and IO both fail (Class 2b).
4. Endotracheal drug delivery has been removed from the adult guidelines because it produces low, unpredictable blood levels.

You may still meet the older "NAVEL" teaching (naloxone, atropine, vasopressin, epinephrine, lidocaine at 2 to 2.5 times the IV dose, diluted in 5 to 10 mL). Know it as history, not as a recommended route. On the exam, the answer to "no IV access during arrest" is intraosseous access, not the endotracheal tube.

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Push-Dose Pressors & Bedside Compounding

Push-dose pressors provide immediate, titratable adrenergic vascular support to bridge transient, life-threatening hypotension during rapid sequence intubation (peri-intubation collapse), acute procedural sedation vasodilation, or profound distributive vasoplegia while continuous infusions are prepared.

                         PUSH-DOSE PRESSOR COMPOUNDING GUIDE
  ┌─────────────────────────────────────────────────────────────────────────────┐
  │ PUSH-DOSE PHENYLEPHRINE (Final Concentration: 100 mcg/mL)                   │
  │ Method A: Add 1 mL (10 mg/mL = 10,000 mcg) to a 100 mL NS bag               │
  │           -> Yields 100 mcg/mL. Draw directly from bag.                     │
  │ Method B: Draw 1 mL (10 mg/mL) into a 10 mL syringe, dilute with 9 mL NS    │
  │           (1 mg/mL = 1,000 mcg/mL). Discard 9 mL. Add 9 mL NS to remaining   │
  │           1 mL -> Yields 100 mcg/mL.                                        │
  │ Dose: 50–200 mcg (0.5–2 mL) IV every 2–5 minutes.                           │
  ├─────────────────────────────────────────────────────────────────────────────┤
  │ PUSH-DOSE EPINEPHRINE (Final Concentration: 10 mcg/mL)                      │
  │ Compounding: Take a 10 mL syringe containing 9 mL of normal saline.         │
  │              Draw 1 mL of "cardiac" epinephrine (0.1 mg/mL = 100 mcg/mL)    │
  │              into the syringe. Total volume = 10 mL (100 mcg / 10 mL).      │
  │              -> Yields 10 mcg/mL.                                           │
  │ Dose: 5–20 mcg (0.5–2 mL) IV every 2–5 minutes.                             │
  └─────────────────────────────────────────────────────────────────────────────┘

Clinical Selection & Hemodynamic Profiles

• Push-Dose Phenylephrine (100 mcg/mL):
  • Receptor Profile: Pure $\alpha_1$-adrenergic agonist. Causes arterial vasoconstriction and increases systemic vascular resistance (SVR) and mean arterial pressure (MAP) without direct inotropic or chronotropic activity.
  • Hemodynamic Effect: May induce a mild vagally mediated reflex bradycardia.
  • Ideal Scenario: Hypotension in the setting of preserved cardiac output or tachycardia (e.g., septic shock with HR $>120$ beats/min, atrial fibrillation with RVR and hypotension, or peri-intubation vasoplegia in a tachycardic patient).
• Push-Dose Epinephrine (10 mcg/mL):
  • Receptor Profile: Potent $\alpha_1, \beta_1,$ and $\beta_2$-adrenergic agonist. Provides potent inotropic (increased myocardial contractility), chronotropic (increased heart rate), and peripheral vasoconstrictive support.
  • Hemodynamic Effect: Increases cardiac output, stroke volume, and MAP.
  • Ideal Scenario: Hypotension accompanied by bradycardia (e.g., neurogenic shock, post-resuscitation myocardial dysfunction, peri-intubation collapse in an acidemic patient, or refractory anaphylaxis).

Safety Guardrails & Error Prevention