[187] WE#1 Considerations P1

Dimension

\[Reason why critical care is unique]

multi-organ, inter-related, requires treatment of both primary and secondary insult

Challenges

\[Reason why critical care is unique]

acceptability of practices, ethical issues

Consequences

\[Reason why critical care is unique]

post-ICU syndrome (PICS), long-term complications

Time-dependence

\[Reason why critical care is unique]

small window period for optimal diagnosis and therapy, very dynamic

Resuscitation, Organ support (Optimization), Stabilization, Evacuation (De-escalation)

Phases of Critical Care

Poor perfusion

\[Rescue Phase - determine pathophysiology of PK/PD changes]

decreased absorption via non-IV routes

Capillary leak

\[Rescue Phase - determine pathophysiology of PK/PD changes]

Expanded Vd

Hypoalbuminemia

\[Rescue Phase - determine pathophysiology of PK/PD changes]

Decreased plasma protein binding

Fluid resuscitation

\[Rescue Phase - determine management given based on of PK/PD changes]

Expanded Vd

Loading dose

given to ensure that hydrophilic drugs become therapeutic despite the increase in Vd

Decreases

If Vd increases/expands, plasma concentration of hydrophilic drugs (increase/decrease).

vancomycin, daptomycin,
aminoglycosides, beta-lactams,
Morphine

Examples of hydrophilic drugs

Target organ support (hemodialysis, ECMO)

\[Rescue Phase - determine management given based on PK/PD changes]

Increased clearance of drugs

Vasoactive Agents

\[Rescue Phase - determine management given based on PK/PD changes]

Decreased absorption via non-IV routes

Adjustment of timing, top-up doses

strategies done to compensate for increased clearance of drugs due to use of target organ support (hemodialysis, ECMO)

Inflammation progress

\[Optimization/Stabilization Phase - determine pathophysiology of PK/PD changes]

Decreased absorption via non-IV routes

Capillary Leak

\[Optimization/Stabilization Phase - determine pathophysiology of PK/PD changes]

Expanded Vd

Hypoalbuminemia

\[Optimization/Stabilization Phase - determine pathophysiology of PK/PD changes]

decreased plasma protein

End-organ dysfunction

\[Optimization/Stabilization Phase - determine pathophysiology of PK/PD changes]

Changes in metabolism and clearance of drugs, possible toxicity

Liver, Kidneys

End-organ dysfunction typically affects which organs?

Fluid management/replacement (fluid therapy from rescue phase is adjusted as needed)

\[Optimization/Stabilization Phase - determine management given based on PK/PD changes]

Expanded Vd

Vasoactive agents (continued and adjusted)

\[Optimization/Stabilization Phase - determine management given based on PK/PD changes]

Decreased absorption via non-IV routes

PO, IM, SQ

(vasoactive agents decrease absorption via non-IV routes; best avoid these routes and stick with IV)

Routes of administration that should be avoided due to effect of vasoactive agents

Albumin correction

\[Optimization/Stabilization Phase - determine management given based on PK/PD changes]

Decreased plasma protein binding

Drug level monitoring, Shift to alternative meds (not affected by pathophysiology or management)

strategies done to ensure therapeutic effect of drugs despite PK/PD changes caused by critical illness

Target organ support therapies

\[Optimization/Stabilization Phase - determine management given based on PK/PD changes]

Changes in Metabolism and Clearance, possible Toxicity

renal/hepatic dosing adjustment, adjust timing or top-up dose

strategies done to compensate for changes in metabolism and clearance and avoid possible toxicities after use of target organ support therapies

Normalization of tissue perfusion

\[Evacuation/De-escalation Phase - determine pathophysiology of PK/PD changes]

Improved PO, SQ, IM absorption

Fluid resorption

\[Evacuation/De-escalation Phase - determine pathophysiology of PK/PD changes]

Decrease in Vd

Improving organ function

\[Evacuation/De-escalation Phase - determine pathophysiology of PK/PD changes]

better metabolism and clearance

Normalization of albumin

\[Evacuation/De-escalation Phase - determine pathophysiology of PK/PD changes]

improved protein binding

Discontinuation of IV fluid

\[Evacuation/De-escalation Phase - determine management given based on PK/PD changes]

Decreased Vd

Adjust dose back to standard dosing

done after Vd has decreased

Tapering off of vasoactive agents

\[Evacuation/De-escalation Phase - determine management given based on PK/PD changes]

Better absorption via non-IV routes

shift from IV to enteral or SQ (but rarely IM)

done once there is better absorption via non-IV

Target organ support

\[Evacuation/De-escalation Phase - determine management based on PK/PD changes]

Increased clearance of drugs

shift back of renal adjusted doses to standard doses

done once there is improvement in renal clearance of drugs

Vancomycin

example of hydrophilic drug whose loading dose should be increased when Vd is expanded or increased

Argatroban

example of a drug whose dose is adjusted for acute liver failure

Cefepime

example of a drug that is renally cleared thus requires renal dose adjustment

Bioavailable, Fast Acting, Safe, Titratable

Characteristics of Ideal ICU medication

Warfarin

Heparin can be rapidly titrated. It can be used as an alternative to what drug?

Glargine

Regular insulin can be rapidly titrated. It can be used as an alternative to what drug?

Altered bioavailability, Vd changes, Drug Elimination Effects

Therapeutic failures or unintended toxicities in critically ill patients may be due to these PK/PD changes

Bioavailability

Main drug factor that affect absorption

bioavailability,
drug size,
lipophilicity,
water solubility,
ionization,
dissociation constant,
presence of chelators and binders,
first pass metabolism

Drug factors that affect absorption

Gastric pH,
GI motility,
Regional blood flow,
Peripheral gut edema

Patent factors that affect absorption

Bioavailability, Tmax, Cmax

Absorption Parameters

Tmax

Time to maximum concentration

1/rate of absorption

Slower

A higher Tmax would mean that the drug has (slower/faster) onset of action and absorption

Cmax, AUC

extent of absorption
refers to overall bioavailability

more clinically impactful than bioavailability

enteral, IM, SQ

Route of Administration that is decreased in critical illness

Perfusion deficits,
Delayed gastric emptying or dysmotility,
Loss of bowel integrity (perforations),
Surgical alteration in the anatomy,
Altered pH,
Medications adhere to NGT tubes

Factors that could affect enteral absorption of drugs in critically ill patients

Vasopressors

Drugs used to restore macro-circulation by increasing the Mean arterial pressure thus increased perfusion

Microcirculatory Failure

This persists despite the increase in Mean arterial pressure caused by administration of vasopressors

Gut

commonly affected when there is failure in the microcirculatory system

Acetaminophen

When there are perfusion deficits, this drug has increased Tmax and decreased Cmax. Despite this, pain scores are still similar between shock and non-shock patients.

False

\[True/False] A decrease in absorption always translates to clinical impacts.

Non-ionized

Form of drug that the body is able to absorb

PPI, antacids, H2-blockers

Drugs that could precipitate alteration in gastric pH due to frequent use in the ICU

acidic

the acidic environment in the stomach promotes the retention of the non-ionized form of weakly (acidic/basic) drugs

Stress ulcer prophylaxis

usually given to ICU patients because they are prone to gastritis and bleeding in the stomach

Part of the ventilator-association pneumonia bundles

Antifungals, antivirals, tyrosine kinase inhibitors

examples of drugs whose absorption is affected by alteration of pH in the stomach

Acute and Chronic diseases,
Mechanical Ventilation,
Electrolyte imbalance,
Surgery,
Cytokines

factors that could cause a delay in gastric emptying or could cause dysmotility

Sepsis,
Burns,
Increased intracranial pressure,
Volume overload,
Shock

Examples of acute and chronic diseases that could cause delayed gastric emptying or dysmotility

HYPOkalemia, HYPOcalcemia

Electrolyte imbalances that may cause delayed gastric emptying and dysmotility

Post-operative ileus

caused by surgery;
occurs 24-48 hours (small intestine and stomach) & 72 hours (colon) after surgery or before normal peristalsis is regained

IL2, IL6, substance P, neurokinin

Pro-inflammatory cytokines that cause dysmotility

Vasopressors,
Opioids,
Sedatives,
Anticholinergics (esp 1st gen),
Calcium channel blockers

Types of drugs that cause delayed gastric emptying and dysmotility

Vasopressors

catecholamine that has a sympathetic effect that overides the vagal tone. It has an anti-effect to cholinergic effects such as peristalsis thus leading to dysmotility.

Opioids

activate mu receptors to cause analgesia and sedation; causes constipation

Benzodiazepines, barbiturates

Example of sedatives that cause dysmotility

Dexmedetomidine

sedative that may be considered due to less chance of dysmotility

Diphenhydramine

examples of 1st gen H1-blockers (anticholinergic) that causes dysmotility

Amiodarone,
Carbamazepine,
Ciprofloxacin,
Phenytoin,
Fluconazole,
Digoxin

Drugs that have decreased absorption with food

1 - 2 hr

strategies to avoid decreased absorption due to enteral feeding include pausing tube feeds in \___ intervals with drug administration

Adjust tube feeding rates

When implementing 1-2hr tube feeding intervals with drug administration, you have to \_______ to ensure that the patient still receives adequate calories

Immediate (due to immediate effect, faster onset, and rapid titration)

Which is more preferred for enteral feeding? Immediate or extended release?

reduced peripheral perfusion from vasopressors,
increased peripheral edema

Factors that could affect SC and IM absorption of drugs in critically ill patients

Anascara

A serious condition in which there is a generalized accumulation of fluid in the interstitial space

SC heparin

drug (and RoA) used to treat DVT --\> continuous use causes increased risk for clot because peak anti-Xa levels are not achieved

IV

RoA preferred for acutely ill or hemodynamically unstable patients

limit cost,
avoid excess fluid,
decreased need for sustained IV access

Reasons why it is recommended to transition to enteral drug delivery once px is stabilized

perfusion abnormalities,
decreased GI motility,
altered gastric pH,
bowel wall edema,
Drug-nutrient interactions

Etiologies of decreased absorption

Itraconazole

example of a drug that required acidic pH to be absorbed by the body --\> less absorption if pH is altered

Antifungals (itraconazole),
SQ enoxaparin,
Vasopressors,
Phenytoin-dextrose containing solutions

drugs affected by etiologies causing decreased absorption

Volume of distribution (Vd)

propensity of a drug to leave the plasma

High

if Vd is __, plasma concentration is low

Low

drugs are more likely to stay in the plasma (high plasma concentration) when Vd is __

Blood flow,
Body composition,
Protein concentration

distribution is highly dependent on these patient factors

Protein binding affinity, MW, pKa

distribution is highly dependent on these drug factors

Hydrophilic

\[Hydrophilic / Lipophilic]

Small Vd --\> drug is more likely to stay in the plasma

Hydrophilic

\[Hydrophilic / Lipophilic]

Dependent on tissue perfusion

Hydrophilic

\[Hydrophilic / Lipophilic]

Tissue penetration is dependent on Blood flow

Lipophilic

\[Hydrophilic / Lipophilic]

high Vd --\> more likely to go to the tissues

Lipophilic

\[Hydrophilic / Lipophilic]

Independent of tissue perfusion

Lipophilic

\[Hydrophilic / Lipophilic]

has good tissue perfusion

Diazepam, midazolam,
Fentanyl, propofol,
macrolides, fluoroquinolones

Examples of Lipophilic drugs

Large volume resuscitation,
Capillary leak syndrome,
Ascites,
Mechanical ventilation

4 causes of increased Vd in the ICU for HYDROphilic drugs

Loading dose

strategy done for hydrophilic drugs when there is increased Vd