Critical Care Combined

T/F: critically ill patients are at higher risk of treatment failure and adverse effects of antibiotics

true

describe pharmacodynamics for antibiotics:

what the drug does to the bacteria (efficacy)

what are the important PKPD parameters for infectious disease in the ICU?

peak concentration (Cmax), trough concentration (Cmin), total drug exposure (AUC), and MIC

what are the caveats of MIC?

Can give an idea of how susceptible a bacteria is to an antibiotic — is organism and drug specific so you cannot compare between drugs and just pick the lowest number!

Often not 100% reproducible (± at least 1 dilution) and accuracy depends on the method used to measure them

role of MICS in the ICU

MIC90 in the ICU setting is 2-4 times higher than other settings and as a result dosing regimens that are used to treat infections in non-ICU patients have a lower probability of attaining PK targets

what is MIC90?

the lowest concentration that will inhibit 90% of isolates

what are the PKPD targets of different antibiotic classes?

time dependent, concentration dependent, and exposure dependent

How is efficacy optimized for time dependent antibiotics?

by maximizing the amount of time the free drug concentration is over the MIC of the target organism at the site of infection

examples of time dependent antibiotics:

beta-lactams and linezolid

how do you optimize regimens for time dependent antibiotics?

Increasing total daily dose increases time over MIC

Increasing the frequency of doses increases time over MIC

Increasing duration of infusion increases time over MIC (3–4-hour infusion times) —- pip/taz, cefepime, meropenem, cefiderocol, ceftolozane/tazobactam

how is efficacy optimized for concentration dependent antibiotics?

greater microbial killing is observed as the concentration increased further with respect to the MIC of the organism (PK parameter is Cmax/MIC)

which type of antibiotics have prolonged post-antibiotic effects where the bacterial killing continues after concentration is below MIC?

concentration dependent antibiotics

examples of antibiotics that are concentration dependent

aminoglycosides

how to optimize regimens for concentration dependent antibiotics

high initial doses to maximize peak concentration and less frequent dosing (low trough concentrations improve tolerability)

describe the PK parameter for exposure dependent antibiotics?

the ratio of total exposure (AUC) over a certain period of time (usually expressed over 24 hours) to the MIC of the organism

which antibiotics are exposure dependent?

vancomycin, FQ, daptomycin, tetracyclines

what are important PK variables?

volume of distribution (Vd) and clearance (CL)

why does absorption of oral medications change in critical illness?

changes to gastric pH (higher or lower), continuous enteral feeding, GI transit time (increased or decreased), reduced blood flow to GI tract

T/F: many oral beta-lactam agents have poor bioavailability

true

T/F: IV antibiotics are usually preferred in critically ill patients at least up front

true

when can oral antibiotic step down be considered in critically ill patients?

when they are hemodynamically stable

how can we overcome absorption challenges?

use IV antibiotics up front in hemodynamically unstable pts, hold enteral tube feeds prior to giving relevant antibiotic if switching to PO (FQ, tetracycline), and choose antibiotics with high bioavailability if using PO

What is Vd?

a constant that relates the administered dose of a medication to the systemic concentration — represents the apparent volume of fluid the drug distributes into in the body to equal its plasma concentration

lipophilic antimicrobials tend to have ______ volume of distribution

higher

hydrophilic antimicrobials tend to have ____________ volume of distribution

smaller

where are hydrophilic meds mostly concentrated?

in the plasma

PK characteristics for hydrophilic meds:

Small volume of distribution, primarily eliminated by kidneys, low intracellular and tissue penetration, higher serum concentrations

examples of hydrophilic antimicrobials

aminoglycosides, beta-lactams, daptomycin, fluconazole, glycopeptides

PK characteristics for lipophilic meds

Large volume of distribution, primarily eliminated by liver, higher intracellular and tissue penetration, lower serum concentrations

examples of antimicrobials that are lipophilic

FQs, lincosamides, macrolides, metronidazole, oxazolidinones, tetracyclines

what are the alterations to distribution seen in the ICU?

increased capillary permeability in sepsis, ICU care itself can also increase Vd for hydrophilic antibiotics, hypoalbuminemia increases Vd for protein bound drugs, Vd can increase up to 2-fold in critically ill patients for hydrophilic antibiotics (results in reduced serum concentrations)

what are the effects from increased capillary permeability in sepsis?

causes fluid shift from intra-vascular to interstitial space and increases Vd

what ICU care increased Vd for hydrophilic antibiotics?

IV fluids, mechanical ventilation, and TPN

How can you overcome distribution challenges?

give loading doses (aminoglycosides, vancomycin), use highest safe dose of beta-lactams, TDM/PK based dosing, highly protein bound drugs should be dosed high or avoided in hypoalbuminemia

what is the loading dose for vancomycin?

20-25 mg/kg

examples of antibiotics changes in patients with hypoalbuminemia

give ceftriaxone 2-gram daily or 2-gram BID, consider meropenem over ertapenem until stable

T/F: metabolism is less affected than other PK components in the ICU

true

T/F: antibiotics with extensive hepatic metabolism will accumulate over time and may need adjustment in ICU patients

true

which antimicrobials have extensive hepatic metabolism?

macrolides, metronidazole, tigecycline

How can you overcome metabolism challenges?

can consider dose adjustment if long term — DO NOT DOSE ADJUST UP FRONT, can consider alternative agents with less hepatic metabolism

define clearance

the theoretical volume of serum that is completely cleared of drug over a time period (most commonly L/hr)

T/F: a patient’s clearance can increase or decrease in critical illness

true

T/F: AKI is common among critically ill patients

true

which ICU interventions can increase clearance?

intermittent hemodialysis, continuous renal replacement therapy, ECMO

what is augmented renal clearance (ARC)?

an increase in renal clearance which can occur in critical illness; increased cardiac output leads to increased renal perfusion which leads to increased drug clearance

what CrCl defines augmented renal clearance?

> 130 mL/min/1.73m2

how can augmented renal clearance be accurately measured?

actual measurement of urine creatinine — does not correlate well with the usual equations

what can ARC lead to?

subtherapeutic antibiotic dosing (esp in drugs like vancomycin, beta-lactams, FQ, and aminoglycosides)

ARC risk factors

younger patients, male, fewer comorbidities prior to critical illness, trauma/burn, surgery/neurosurgery, CF

how can ARC challenges be overcome?

Index of suspicion should be high in patients at risk (confirm with 8 or 24 hr urine creatinine if feasible)

Use the maximum safe dosing regimen (optimize duration of infusion for beta lactams)

TDM/PK dosing (vancomycin, aminoglycosides)

Use a different drug (ex: linezolid instead of vanc)

T/F: AKI can develop/resolve quickly in patients with septic shock

true

facts regarding AKI in sepsis patients

over 50% of episodes of sepsis related AKI resolve within 24 hours, SCr is a lagging indicator of renal function

How can PK challenges in AKI be overcome?

Delay dose adjustments for beta-lactams by 48 hours! Dose adjustments at 24-48 hours if AKI does not resolve.

Consider antibiotics that are less renally cleared/have larger therapeutic window (ex linezolid over vanco)

TDM/PK

what drug properties make something more dialyzable?

hydrophilic, smaller Vd, low protein binding

when is intermittent hemodialysis used?

in more stable patients — sessions may be as needed or scheduled on certain days of the week

what is continuous renal replacement therapy?

used for hemodynamically unstable patients — different types of CRRT will clear antibiotics to a different extent

what are the intermittent HD considerations?

residual renal function, timing of sessions, length of session, filter type

how to overcome intermittent HD challenges

Schedule doses of hydrophilic antibiotics after HD sessions

Daily checks for HD plan

TDM when available (vancomycin, aminoglycosides, β-lactams, linezolid)

Account for residual renal function when choosing dose

Consider alternative agents

CRRT considerations:

Hydrophilic antibiotics/antifungals may be extensively cleared (β-lactams, vancomycin, daptomycin, aminoglycosides)

Amount removed varies based on type of CRRT

Despite the name is not always continuous (requires vigilance for interruptions)

how to overcome CRRT challenges:

Dose adjustments (β-lactams, fluconazole, aminoglycosides, FQ)

Residual renal function

How continuous is the “CRRT”

Consider alternative agents (linezolid over vancomycin)

TDM/PK

what are the indications for neuromuscular blockers (NMB)?

facilitate mechanical ventilation, minimize oxygen consumption (ARDS), increased muscle activity (tetany, neuroleptic malignant syndrome, anti-shivering agent), increased intracranial pressures or intra-abdominal pressures, surgical procedures, rapid sequence intubation

which NMB are non-depolarizing agents (acetylcholine antagonists)?

cisatracurium, rocuronium, vecuronium

how is cisatracurium eliminated?

Hoffman (avoids kidney and liver)

onset of cisatracurium

2-5 minutes

duration of cisatracurium

is dose-dependent —- 30-90 minutes

how is rocuronium eliminated?

50% biliary and renal

onset of rocuronium

1-2 minutes

duration of rocuronium

30-60 minutes

how is vecuronium eliminated?

biliary and renal

onset of vecuronium

3-5 minutes

duration of vecuronium

45-60 minutes

which NMBs are depolarizing agents (bind and active acetylcholine to keep membrane depolarized)?

succinylcholine

how is succinylcholine eliminated

plasma pseudo-cholinesterase

onset of succinylcholine

30-60 seconds

duration of succinylcholine

5-10 minutes

precautions with succinylcholine

malignant hyperthermia and hyperkalemia

how are patients monitored when using NMBs?

train of four using a peripheral nerve stimulator with a goal of 2 twitches (80-90% blockage)

advantages of NMB

inhibit diaphragmatic function and reduce chest wall rigidity, reduces oxygen consumption, eliminates work of breathing

disadvantages of NMBs

patients cannot communicate, no analgesic or sedative properties (need RASS -4 to -5 before using), increased risk of DVT and skin breakdown, corneal abrasion risk, critical illness polyneuropathy

what is step 1 for rapid-sequence intubation?

preparation — assemble ass necessary equipment and drugs

what is step 2 for rapid-sequence intubation?

Preoxygenation —- replace the nitrogen in the patient’s functional reserve with oxygen (“nitrogen wash out - oxygen wash in”)

what is step 3 for rapid-sequence intubation?

Pretreatment — administer ancillary medications to mitigate adverse physiological consequences of intubation

what is step 4 for rapid-sequence intubation?

paralysis with induction — administer sedative induction agent via IV push followed immediately by administration of paralytic via IV push

what is step 5 for rapid-sequence intubation?

protection and positioning — position patient for optimal laryngoscopy; Sellick’s maneuver if desired, is applied now

what is step 6 for rapid-sequence intubation?

placement with proof — assess mandible for flaccidity; perform intubation, and confirm placement.

what is step 7 for rapid-sequence intubation?

postintubation management — long-term sedation, analgesia, or paralysis as indicated

which medications are used for pretreatment in rapid-sequence intubation?

lidocaine 1-1.5 mg/kg

fentanyl 50-100 mcg

midazolam 2-4 mg

which medications are used for induction in rapid-sequence intubation?

midazolam 0.2 - 0.3 mg/kg

etomidate 0.3 mg/kg

ketamine 1.5-2 mg/kg

propofol 1.5-2 mg/kg

which medications are used for paralysis in rapid-sequence intubation?

rocuronium 1-1.5 mg/kg

vecuronium 0.1-0.2 mg/kg

succinylcholine 1-1.5 mg/kg

MOA of etomidate

non-barbiturate general anesthetic believed to interact with gamma-Aminobutyric acid type A (GABA) receptors

onset of etomidate

30-60 seconds

duration of etomidate

2-5 minutes but is dose dependent

metabolism of etomidate

hepatic and plasma esterase

dosing of etomidate

0.3 mg/kg IV bolus

benefits of etomidate

has rapid onset, short duration, hemodynamic stability, simple dose regimen

what are the drawbacks of etomidate?

pain with injection, relative adrenal insufficiency within first 24 hours

when you drink alcohol acutely i.e. on a Friday night what happens to your NTs?

GABA is increased (creates imbalance between GABA and NMDA)

when you use alcohol chronically what happens to your NTs?

since you are constantly increasing GABA there is down regulation of the GABA receptors and NMDA increases to create balance

what happens to NTs in alcohol withdrawal?

the NMDA stays at the elevated point, but GABA is severely depleted