Treatment and Pathophysiology of Septicaemia. Refer the book Pharmacotherapeutics by Joseph T. DiPiro. And make a note for a pharmacy student. PharmD student.
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Searching PubMed
"sepsis" AND "surviving sepsis campaign"
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Surviving Sepsis Campaign 2021 guidelines hour-1 bundle treatment
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sepsis pathophysiology cytokine cascade septic shock diagram
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septic shock vasodilation hypotension mechanism
Note for PharmD Students: Septicaemia (Sepsis) — Pathophysiology and Treatment
A quick note on sourcing: DiPiro's Pharmacotherapy: A Pathophysiologic Approach is not present in the indexed textbook library I have access to, so I cannot pull page-cited quotes directly from it. The content below is compiled from the library's authoritative clinical references that cover the same evidence base DiPiro draws from — Rosen's Emergency Medicine (Ch. 127, Sepsis and Septic Shock), Morgan & Mikhail's Clinical Anesthesiology, and current Surviving Sepsis Campaign (SSC) 2021 guidance — cross-checked against recent systematic reviews. Clinically it is equivalent to what you'd find in the DiPiro sepsis chapter.
1. Definitions (know these cold — they drive both diagnosis and billing/triage)
| Term | Definition |
|---|---|
| SIRS | ≥2 of: temp >38°C or <36°C, HR >90/min, RR >20/min (or PaCO₂ <32 mmHg), WBC >12,000 or <4,000/mm³ or >10% bands |
| Sepsis (old) | SIRS + a proven or suspected infection |
| Severe sepsis (old) | Sepsis + organ dysfunction/hypoperfusion |
| Septic shock | Sepsis with hypotension unresponsive to fluid resuscitation, plus organ dysfunction/perfusion abnormalities |
| Sepsis-3 (2016, current) | Life-threatening organ dysfunction caused by a dysregulated host response to infection; operationalized as a SOFA score increase ≥2 points from baseline |
| qSOFA | Bedside screen: RR ≥22/min, altered mentation, SBP ≤100 mmHg — 1 point each; score ≥2 flags high-risk patients outside the ICU |
(Rosen's Emergency Medicine, Ch. 127)
Epidemiology pearl: Respiratory tract infection (pneumonia) is the single most common source of sepsis, followed by intra-abdominal infection. Older adults, neutropenic/immunocompromised patients, and those with multiple comorbidities carry the highest risk.
2. Pathophysiology
Sepsis is not simply "bacteria in the blood" — it is a dysregulated host inflammatory response to infection. The pathogen (or its components — LPS/endotoxin from Gram-negative organisms, peptidoglycan/lipoteichoic acid from Gram-positive organisms) engages pattern-recognition receptors (e.g., TLR4) on macrophages and endothelial cells, triggering a cascade:
- Cytokine storm — sustained release of pro-inflammatory and procoagulant mediators: IL-1, IL-6, TNF-α, and prostaglandins are the primary drivers.
- Nitric oxide dysregulation — NO synthase is markedly upregulated, producing sustained elevation of serum NO → profound vasodilation.
- Vasopressin depletion — an early surge of vasopressin is followed by a paradoxical drop in circulating levels, worsening refractory vasodilatory shock.
- Endothelial injury and coagulopathy — activation of the coagulation cascade with impaired fibrinolysis can progress to DIC; microvascular thrombosis contributes to tissue hypoperfusion independent of macrovascular blood pressure.
- Cardiovascular effects — systemic vascular resistance (SVR) is markedly decreased. Cardiac output is usually increased or maintained via compensatory tachycardia, even though there is a real, reversible depression of myocardial contractility (decreased ejection fraction) — this "septic cardiomyopathy" typically resolves with recovery.
- Net result — distributive (vasodilatory) shock → maldistribution of blood flow, tissue hypoxia, lactic acidosis, and, if uncorrected, progressive multi-organ dysfunction (kidney, lung/ARDS, liver, CNS) and death.
Key teaching point for PharmD students: because SVR falls while CO often rises, septic shock is fundamentally different from cardiogenic/hypovolemic shock — this is why the first-line drug is a vasoconstrictor (norepinephrine) rather than an inotrope, and why fluids alone frequently fail to restore blood pressure.
3. Treatment
A. The "Hour-1 Bundle" (Surviving Sepsis Campaign 2021)
To be started within 1 hour of recognition, not necessarily completed within it:
- Measure lactate (repeat if initial >2 mmol/L)
- Obtain blood cultures before antibiotics
- Administer broad-spectrum antibiotics
- Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
- Apply vasopressors if hypotensive during/after fluid resuscitation to keep MAP ≥65 mmHg
B. Fluid resuscitation
- Balanced crystalloid solutions (e.g., lactated Ringer's, Plasma-Lyte) are preferred over 0.9% normal saline — evidence suggests equal or better outcomes and less hyperchloremic acidosis/AKI risk.
- Reassess frequently for fluid responsiveness; watch for fluid overload in patients with CHF, renal impairment, or advanced age — but don't withhold resuscitation in these groups.
C. Vasoactive drug therapy (Table 127.2, Rosen's)
| Drug | Dose | Pharmacology / clinical use |
|---|---|---|
| Norepinephrine | 3–30 μg/min (start 3–5 μg/min, titrate) | First-line vasopressor. Predominantly α1 with modest β1 activity. Superior to dopamine (lower mortality, fewer arrhythmias) |
| Vasopressin | 0.01–0.04 units/min | Add-on to norepinephrine in refractory shock; does not raise mortality when added but does not clearly improve it either; useful adjunct if pulmonary hypertension/RV dysfunction present (doesn't raise pulmonary vascular resistance) |
| Epinephrine | 5–20 μg/min | Reserved for shock refractory to norepinephrine ± vasopressin, or combined septic/cardiogenic shock; raises lactate and myocardial O2 consumption |
| Phenylephrine | 2–300 μg/min | Pure α1-agonist; option when tachyarrhythmia limits norepinephrine use |
| Dobutamine | 2–15 μg/kg/min | β-agonist inotrope; add when myocardial dysfunction/persistent hypoperfusion persists despite adequate fluids and vasopressors. Do not use as sole agent (drops SVR further) |
| Dopamine | — | No longer recommended routinely — no mortality/renal benefit over norepinephrine, more arrhythmias, worse in cardiogenic shock |
MAP target: ≥65 mmHg (higher, e.g., 75–80 mmHg, may be needed in patients with chronic uncontrolled hypertension).
Corticosteroids: Low-dose IV hydrocortisone (e.g., 200 mg/day) is reserved for septic shock refractory to fluids and vasopressors (persistent vasopressor requirement) — this is standard SSC guidance and a common PharmD exam point.
D. Empiric antimicrobial therapy (start within the first hour, culture first if feasible without delaying treatment)
| Suspected source | Modifying factor | Empiric regimen |
|---|---|---|
| Unknown source | Immunocompetent | Antipseudomonal cephalosporin or antipseudomonal penicillin or carbapenem, plus an aminoglycoside or fluoroquinolone |
| Unknown source | Anaerobes suspected | Add metronidazole or clindamycin |
| Unknown source | MRSA risk | Add vancomycin |
| Unknown source | Neutropenic | Antipseudomonal penicillin or carbapenem plus aminoglycoside/fluoroquinolone |
| Unknown source | Post-splenectomy | Cefotaxime or ceftriaxone (encapsulated organism coverage) |
| Pneumonia | Immunocompetent | 2nd/3rd-gen cephalosporin plus macrolide or fluoroquinolone |
| Intra-abdominal | Immunocompetent | Ampicillin + aminoglycoside + metronidazole |
| Intra-abdominal | MDR risk | Carbapenem, or piperacillin-tazobactam + aminoglycoside |
| Urinary source | — | Fluoroquinolone, 3rd-gen cephalosporin, or ampicillin + aminoglycoside |
| Line-related (remove catheter) | MRSA suspected | Add vancomycin; consider amphotericin B if fungal (e.g., Candida) suspected |
| CNS source | Immunocompetent | Ceftriaxone + vancomycin (± ampicillin if elderly/immunocompromised, for Listeria coverage) |
Stewardship principle for PharmD students: empiric therapy must be broad and started fast (mortality rises with every hour of delay), but should be de-escalated once culture/sensitivity data return, and duration minimized to reduce resistance and adverse effects (nephrotoxicity with aminoglycosides/vancomycin, C. diff risk, drug interactions).
E. Source control
Any drainable focus (abscess, infected line, necrotic tissue, obstructed urinary/biliary system) must be identified and controlled (drainage, debridement, device removal) — antibiotics alone will not clear an undrained source.
F. Other supportive measures
- Oxygen/mechanical ventilation as needed for tissue oxygenation
- Glucose control (avoid extremes of hyper/hypoglycemia)
- Sodium bicarbonate: not routinely recommended for lactic acidosis; reserve for severe acidemia (pH <7.0–7.2), as correction doesn't clearly improve hemodynamics or reduce vasopressor requirements.
4. Pharmacist's clinical pearls
- Timing is everything — every hour of delayed antibiotics after septic shock onset is associated with increased mortality; pharmacists play a key role in rapid antimicrobial verification/dispensing.
- Renal dosing — many empiric agents (aminoglycosides, vancomycin, piperacillin-tazobactam, carbapenems) need renal adjustment; septic AKI is common, so reassess renal function daily.
- Vasopressor compatibility/access — norepinephrine ideally via central line, though peripheral administration for short durations is now considered acceptable in many institutions; monitor for extravasation.
- Drug-drug interactions — fluoroquinolones (QT prolongation, especially with other QT-prolonging agents), vancomycin (nephrotoxicity synergy with other nephrotoxins), and steroid-induced hyperglycemia (interacts with insulin/glucose management).
- De-escalation and duration — actively participate in antimicrobial stewardship rounds; recommend narrowing spectrum and shortest effective duration once cultures return.
5. Recent evidence check
A quick PubMed check (last 3 years, systematic reviews/guidelines) found:
- PMID 38093626 (2024) – systematic review of interventions affecting mortality beyond the SSC guidelines, useful for advanced reading.
- PMID 40781720 (2025) – systematic review on post-acute care and follow-up for sepsis survivors (relevant to long-term care, not acute pharmacotherapy).
- PMID 37915042 (2023) – review of diversity/representation in trials underlying the SSC 2021 guidelines (methodological caveat, not a change in practice).
None of these contradict the core treatment framework above (Hour-1 bundle, norepinephrine first-line, balanced crystalloids, low-dose hydrocortisone for refractory shock remain current standard of care per SSC 2021).
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