Topic Discussion During Critical Care Rotation

1. 1
Infection
Inflmmatory
response
Hyperocagulability
Organ
Damage
Hypoperfusion and Organ
Damage
Endothelial
dysfunction
Vasodilation
Platelet-fibrin
clots and
microthrombi
Tissue factor
TNF, IL-6
Lactate
ANG II
receptor
Pathophysiology: An interplay between Inflammatory and hemostatic processes
Cortisol
 Life-threatening organ damage resulting
from dysregulated host response to an
infection
 Septic shock: Sepsis+ circulatory
compromise+ metabolic and cellular
abnormalities
o Higher mortality
 ~30 million affected
o ~6 million deaths annually
 > $20 million healthcare cost in 2011
Sepsis and Septic Shock
Anna Sandler
PharmD Candidate, 2023
Background: The highest healthcare expense
Vaso-
pressin
Vaso-
pressin
Other
noteworthy
culprits
ANG: Angiotensin; TNF: Tissue necrosis factor

2. 2
qSOFA SOFA
Altered mental status Low PaO2
RR ≥ 22 Hypotension
SBP ≤ 100 Low platelets, high bilirubin
AKI
Low Glasgow Coma Scale
Common Offenders
Escherichia coli
MSSA
Streptococcus spp.
S. pneumoniae
MRSA
Pseudomonas aeruginosa
Enterobacter spp.
Suspect
• Fever
• Elevated WBC
• Positive cultures
• Anion gap metabolic acidosis
Screen • qSOFA or SIRS
• ≥ 2 points
Confirm • SOFA
• ≥ 2 points baseline increase=
organ dysfunction
Presentation, Diagnosis, Goals of Treatment
Goals of
treatment
Time
Minimize
ADRs
Septic Shock
MAP < 65
mmHg
Infection
Control
Lactate >
2 mmol/L
Infection
Control
Preserve
organ
function
MAP: mean arterial pressure; MSSA: methicillin susceptible staphylococcus aureus; MRSA: methicillin
resistant s. aureus; qSOFA: Quick Sequential Organ Failure Assessment; RR: Respiration rate; SIRS: Systemic
inflammatory response syndrome; SPP: species; WBC: white blood cell count

3. 3
Pressor Receptors Effect
NE α1++
β1+
Increased venous and
arterial tone
Epinephrine α1+++
β1+++
β2+++
Tachycardia
Lactic acidosis
Hyperglycemia
Peripheral ischemia
Vasopressin V1a Peripheral ischemia
Cardiac arrhythmia
Norepinephirne
Vasopressin
Epinephrine
Therapies
 Vasopressors
o First-line: Norepinephrine (NE)
o Inadequate MAP with NE: vasopressin
Dose
 NE: 0.05-0.15 mcg/kg/minute
 Vasopressin: 0.01-0.04 units/minute
Monitoring: Intravascular volume and organ perfusion
 MAP
 Arrhythmias
 Splanchnic and digital ischemia
Treatment: Fluid Resuscitation immediately upon suspicion of sepsis or septic shock
Treatment: Hemodynamic management after fluid resuscitation
Therapies
 Crystalloids > colloids
o 0.9% NaCl (NS)
o Lactated Ringers (LR), “Balanced”
 Increasing use of balanced solutions/ “chloride-
restrictive”
o Hyperchloremic metabolic acidosis
o AKI
Dose
 Initial: 30 mL/kg
 Subsequent: Guided by patient assessment
Monitoring: Intravascular volume and organ perfusion
 MAP
 Fluid challenges
 Capillary refill time
 Extremity temperature
Goal time: Within
first 3 hours
AKI: Acute Kidney Injury
What about IV corticosteroids?
 If fluids and vasopressors are insufficient to
restore hemodnyamic stability
o IV Hydrocortisone 200mg/day
Steroids?

4. 4
MRSA
coverage
Other
commonly
used
agents
Pseudomonas
Vancomycin
Daptomycin
Linezolid
Ceftriaxone
Cefepime
Cefotaxime
Cefepime
Ceftazidime
Meropenem
Imipenem
Agent Utility Recommendation/evidence
ANG II Vasoconstrictive effects for
hemodynamics
Potential adjunctive vasopressor therapy
Low quality evidence
VTE prophylaxis Prevent clots LMWH > Heparin
IV Vitamin C Potential anti-
inflammatory properties
Guidelines suggest AGAINST
Bicarbonate Acidosis treatement Potentially if severe metabolic acidemia is
present
Additional considerations and recommendations
Treatment: Anti-infectives-early administration is a very effective intervention
Empiric coverage: Broad and IV
 Based on guidelines for infection source
 MRSA
o Only those at high-risk
o ONLY High-risk of MDROs
 Double gram-negative
coverage
MRSA
coverage
Other
commonly
used agents
Pseudomonas
Vancomycin
Daptomycin
Linezolid
Ceftriaxone
Cefepime
Cefotaxime
Cefepime
Ceftazidime
Meropenem
Imipenem
 Initiate regardless of procalcitonin level
 General concept: Broad and IV
Empiric coverage
 Based on guidelines for infection source
 MRSA
o Only those at high-risk
o ONLY High-risk of MDROs
 Double gram-negative
coverage
 De-escalate once causative
pathogen and
susceptibilities are known
Pharmacokinetics
 Optimizing PK/PD parameters
o Prolonged beta-lactam infusions
Goal times
Goal times
1 hour
1 hour
3 hours
3 hours
Recognition
Recognition
Probable sepsis
+/- shock
Probable sepsis
+/- shock
Possible sepsis +
shock
Possible sepsis +
shock
Possible sepsis -
shock
Possible sepsis -
shock
0 hour
Pharmacokinetics
 Optimizing PK/PD parameters
o Prolonged beta-lactam infusions
Other considerations
 Source control
 De-escalation
 Fungal coverage in those with risk
factors
Other considerations
 Source control
 De-escalation
 Fungal coverage in those with risk
factors
MDRO: Multi-drug resistant organism
Anti-fungal
agents only in
high-risk patients
DDD: Don’t forget:
Daily evaluation
+De-Escalation

5. 5
Drug MOA-class/Coverage Sepsis Dosing ADRs, Monitoring,
Warnings
Normal Saline 30 mL/kg within first hour Hyperchloremic
metabolic acidosis
AKI
Fluid overload
Lactated Ringer’s 30 mL/kg within first hour Hyperkalemia
Monitoring: K, Cl, Ca,
osmolarity
Calcium in LR binds to
ceftriaxone CI in
neonates requiring LR;
flush lines between
administration in older
adults
Norepinephrine
(Levophed)
α1>β1 activity
Vasoconstriction with
some ionotropic and
chronotropic effects
5-15 mcg/min (0.05-0.15
mcg/kg/minute)
Extravasation-infuse into
large, central vein if
possible
Vasopressin (Vasostrict) Pure vasoconstrictor
Stimulates V1 receptor
and increases systemic
vascular resistance
0.01-0.04 unites/minute Non-titrating drip
Epinephrine (adrenaline) Potent α1 and β1agonist 1-15 mcg/min (0.01-0.2
mcg/kg/minute)
Tachycardia
Tachyarrhythmias
Extravasation
Increased lactate
Hydrocortisone Cortisol replacement
Anti-inflammatory
50 mg bolus every 6 hours
or 200 mg/dayhyd
Hyperglycemia
Vancomycin (Vancocin) Glycopeptide antibiotic
G+, MRSA,
15-20 mg/kg/dose every
8-12 hours or per hospital
protocol
Loading dose
recommended
Renally dose adjusted
Monitor target trough
levels
ADRs: Injection site
reactions,
nephrotoxicity,
ototoxicity, Red man
syndrome
Piperacillin-Tazobactam
(Zosyn)
Beta lactam-Beta
lactamase inhibitor, G+,
EB, PsA, anaerobes
4.5 g IV every 6 hours Renally dose adjusted
ADRs: Diarrhea, flushing,
thrombophlebitis,
anaphylaxis

6. 6
Drug MOA-
class/Coverage
Sepsis Dosing ADRs, Monitoring,
Warnings
Cefepime (Maxipime) Fourth generation
cephalosporin/G+,
EB, PsA
2 g IV every 8 hours Renally dose adjusted
ADRs: Injection site
reactions, skin rash, D/N/V
Ceftriaxone/Rocephin Third generation
cephalosporin/
G+, EB
Based on source of infection Not renally dose adjusted
DO NOT use in
hyperbilirubinemic
neonates
DO NOT coadminister
with calcium-containing
solutions
ADRs: Injection site
reaction, pruritis, skin
rash, flushing, anemia,
thrombocytopenia,
increased LFTs
Meropenem (Merrem) Carbapenem/ G+,
EB, PsA.
anaerobes
1-2 g IV every 8 hours Renally dose adjusted
DDI with valproic acid
decreased levels+
increased risk of seizures
ADRs: skin rash, diarrhea,
flatulence, anemia,
injection site reaction,
seizures,
Linezolid (Zyvox) Oxazolidinone
G+, MRSA,
Based on source of infection Not renally dose adjusted
ADRs: Thrombocytopenia,
rare peripheral or optical
neuropathy
EB: Enterobacter; G+: Gram positive, generally includes streptococcus, methicillin-susceptible Staphylococcus aureus (MSSA) , and
enterococci; note, all cephalosporins lack coverage against enterococci; PsA: Pseudomonas Aeruginosa, V1: Arginine vasopressin 1a (AVP1a)
receptor

7. 7
Picture links:
https://www.nidirect.gov.uk/news/recognising-signs-and-symptoms-sepsis
https://www.amenclinics.com/blog/mold-affect-brain/
https://www.svhlunghealth.com.au/conditions/ards-acute-respiratory-distress-syndrome
https://www.shutterstock.com/search/liver
https://www.healthline.com/health/lactated-ringers
https://www.uptodate.com/contents/image?imageKey=PULM%2F99963
References
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