Sepsis and Septic Shock — Part 2: Initial Resuscitation & Hemodynamic Management

Hour-1 bundle components, fluid resuscitation strategy, crystalloid selection, fluid responsiveness assessment, vasopressor selection and dosing, inotrope use, hemodynamic monitoring, and lactate-guided resuscitation.

guidelines•Mar 2026•guidelines

1. The Hour-1 Resuscitation Bundle

In 2018, the international surviving sepsis working group consolidated the previous 3-hour and 6-hour bundles into a single hour-1 bundle, emphasizing that resuscitation should begin immediately upon sepsis recognition rather than being delayed by risk stratification or sequential assessments.1 2

1.1 Hour-1 Bundle Components

All five elements should be initiated within 1 hour of sepsis recognition. “Initiated” means that the process has begun — not necessarily completed — within the first hour.

Bundle ElementTargetNotes
1. Measure lactateObtain serum lactate levelRe-measure within 2–4 hours if initial lactate > 2 mmol/L
2. Obtain blood cultures≥ 2 sets (aerobic + anaerobic) before antibioticsDo NOT delay antibiotics if cultures cannot be obtained promptly
3. Administer broad-spectrum antibioticsWithin 1 hour of sepsis recognitionEmpiric therapy targeting suspected source
4. Begin rapid IV crystalloid infusion30 mL/kg for hypotension or lactate ≥ 4 mmol/LUse ideal body weight; reassess after each bolus
5. Apply vasopressorsTarget MAP ≥ 65 mmHgIf hypotension persists during or after fluid resuscitation

1.2 Evidence for the Hour-1 Bundle

  • Each hour of delay in antibiotic administration after the onset of sepsis-related hypotension has been associated with an approximately 4% increase in mortality in observational studies.3
  • Bundle compliance (completion of all elements) has been associated with a 15–25% relative reduction in mortality compared to non-compliance in large multicenter registry studies.4
  • The transition from the 3-hour/6-hour bundles to the hour-1 bundle was motivated by evidence that earlier initiation of treatment — particularly antibiotics and fluids — is associated with improved outcomes.1

1.3 Practical Implementation

  • Time zero is defined as the time of sepsis recognition, which may be the time of triage, the time of a positive sepsis screen, or the time a clinician first documents suspicion of sepsis.
  • Blood cultures should ideally be obtained before antibiotics, but antibiotic administration should NOT be delayed beyond 45 minutes to obtain cultures. If venipuncture or line access is difficult, administer antibiotics and obtain cultures as soon as possible thereafter.2
  • Peripheral vasopressor administration: Norepinephrine may be safely administered through a well-functioning peripheral IV (≥ 18 gauge, preferably in the antecubital fossa) for up to 2–4 hours while central venous access is being obtained.5 This removes the prior barrier of waiting for central access before initiating vasopressors.

2. Fluid Resuscitation

2.1 Initial Fluid Strategy

The 2021 international sepsis guidelines recommend:2

Recommendation: For adults with sepsis or septic shock, the panel suggests using at least 30 mL/kg of IV crystalloid fluid within the first 3 hours of resuscitation in patients with sepsis-induced hypoperfusion or septic shock.

Strength: Weak recommendation, low quality of evidence

Key points:

  • Volume calculation: Use ideal body weight rather than actual body weight, particularly in obese patients. For a 70 kg patient, 30 mL/kg = 2,100 mL.
  • Not a fixed target: The 30 mL/kg is a starting point, not a mandated total volume. Some patients will require more; others (especially those with heart failure, ESRD, or cirrhosis) may require less.
  • Individualized approach: The guidelines emphasize that fluid administration beyond the initial bolus should be guided by frequent reassessment of hemodynamic status and fluid responsiveness.
  • Speed of administration: The initial crystalloid should be administered as rapidly as possible (ideally within the first 1–3 hours), using pressure bags or rapid infusion devices when necessary.

2.2 Crystalloid Selection: Balanced Solutions vs. Normal Saline

Recommendation: For adults with sepsis or septic shock, the panel suggests using balanced crystalloids instead of normal saline for resuscitation.

Strength: Weak recommendation, low quality of evidence2

Comparison of Available Crystalloids

PropertyNormal Saline (0.9% NaCl)Lactated Ringer’s (LR)Plasma-LyteNormal Plasma
Sodium (mEq/L)154130140135–145
Chloride (mEq/L)1541099898–106
Potassium (mEq/L)0453.5–5.0
Calcium (mEq/L)0304.5–5.5
Magnesium (mEq/L)0031.5–2.0
BufferNoneLactate (28)Acetate (27), Gluconate (23)Bicarbonate (22–26)
Osmolarity (mOsm/L)308273294275–295
pH5.0–5.56.0–7.56.5–8.07.35–7.45

Key Evidence

  • SMART trial (2018): In a pragmatic single-center cluster-randomized trial of 15,802 critically ill adults, balanced crystalloids (LR or Plasma-Lyte) reduced the composite outcome of death, new renal replacement therapy, or persistent renal dysfunction (major adverse kidney events at 30 days [MAKE30]) compared with normal saline (14.3% vs. 15.4%; adjusted OR 0.90, 95% CI 0.82–0.99).6
  • PLUS trial (2022): In a multicenter, double-blind RCT of 5,037 ICU patients, Plasma-Lyte did NOT significantly reduce 90-day mortality compared with normal saline (21.8% vs. 22.0%; absolute difference −0.15%, 95% CI −2.66 to 2.36).7
  • BaSICS trial (2021): In a multicenter RCT of 10,520 ICU patients, balanced solutions (Plasma-Lyte) did NOT significantly reduce 90-day mortality compared with normal saline (26.4% vs. 27.2%; RR 0.97, 95% CI 0.90–1.05).8

Practical Recommendations

  • First choice: Balanced crystalloids (Lactated Ringer’s or Plasma-Lyte) — preferred in most clinical scenarios
  • When normal saline may be preferred: Hyperkalemia (K+ > 5.5 mEq/L), concern for cerebral edema (traumatic brain injury), and hypochloremic metabolic alkalosis
  • Avoid in sepsis: Hydroxyethyl starch (HES), gelatin-based colloids, and dextran — all associated with increased renal injury and/or mortality2
  • Albumin: The guidelines suggest using albumin in addition to crystalloids for patients who have received large volumes of crystalloid during initial resuscitation (weak recommendation, low quality evidence). The ALBIOS trial demonstrated no mortality benefit for albumin-targeted resuscitation in sepsis overall, though a post-hoc analysis suggested potential benefit in the septic shock subgroup.9

2.3 Fluid Responsiveness Assessment

After the initial resuscitation bolus, further fluid administration should be guided by assessment of fluid responsiveness — that is, whether additional fluid will meaningfully increase cardiac output and improve tissue perfusion.2

Recommendation: For adults with sepsis or septic shock, the panel suggests using dynamic measures to guide fluid resuscitation, over physical examination or static parameters alone.

Strength: Weak recommendation, very low quality of evidence

Dynamic vs. Static Measures

CategoryMeasureThresholdSensitivitySpecificityKey Conditions
DynamicPassive leg raise (PLR)Increase in CO or SV ≥ 10%85–90%90–95%Patient supine; must measure CO/SV (not just BP)
DynamicPulse pressure variation (PPV)> 12–13%85–90%85–90%Mechanically ventilated, tidal volume ≥ 8 mL/kg, sinus rhythm
DynamicStroke volume variation (SVV)> 10–12%80–85%85–90%Same conditions as PPV
DynamicIVC distensibility index (mechanically ventilated)> 18% (dIVC)75–85%80–90%Mechanically ventilated, adequate tidal volumes
DynamicIVC collapsibility index (spontaneous breathing)> 40–50% (cIVC)70–80%70–80%Less reliable than in mechanically ventilated patients
DynamicEnd-expiratory occlusion testIncrease in CO ≥ 5% after 15 sec hold85–95%85–95%Mechanically ventilated; cooperative or sedated
DynamicMini-fluid challenge (100 mL over 1 min)Increase in SV ≥ 6–10%80–85%85–90%Requires precise SV measurement
StaticCentral venous pressure (CVP)8–12 mmHg55–65%55–65%Poor predictor of fluid responsiveness
StaticScvO2> 70% (target)N/A (treatment target)N/AReflects global O2 supply-demand balance

Passive Leg Raise (PLR) — Technique

The PLR maneuver is the single best bedside test of fluid responsiveness in spontaneously breathing patients and is recommended as the first-line assessment.10

Technique:

  1. Start with the patient in a semi-recumbent position (head of bed at 45°)
  2. Lower the head of bed to 0° (flat) AND raise the legs to 45° simultaneously (this can be done by using the bed’s Trendelenburg function or by manually lifting the legs)
  3. This maneuver autotransfuses approximately 250–350 mL of blood from the lower extremities and splanchnic bed to the central circulation
  4. Measure the hemodynamic response within 30–90 seconds — the effect is transient
  5. Positive response: An increase in cardiac output or stroke volume of ≥ 10% indicates fluid responsiveness

Critical caveats:

  • Blood pressure changes alone are insufficient — must measure cardiac output or stroke volume (via pulse contour analysis, echocardiography, or esophageal Doppler)
  • False negatives may occur with intra-abdominal hypertension (abdominal compartment syndrome)
  • The PLR is a reversible test — if the patient does not respond, no harm has been done (unlike an actual fluid bolus)

2.4 When to Limit Fluids — Recognizing Fluid Overload

Emerging evidence suggests that excessive fluid administration in sepsis is associated with harm, including prolonged mechanical ventilation, increased ICU length of stay, and potentially increased mortality.11

Signs suggesting fluid overload / need to limit further fluids:

  • Negative fluid responsiveness on dynamic testing (PLR, PPV, SVV)
  • Rising CVP without corresponding improvement in hemodynamics
  • Worsening oxygenation (increasing FiO2 or PEEP requirements)
  • Development of pulmonary edema on chest X-ray or lung ultrasound (B-lines)
  • Increasing peripheral edema
  • Worsening intra-abdominal pressure
  • Cumulative fluid balance > 10% of body weight

3. Hemodynamic Targets

3.1 Mean Arterial Pressure (MAP)

Recommendation: For adults with septic shock on vasopressors, the panel recommends an initial target MAP of 65 mmHg over higher MAP targets.

Strength: Strong recommendation, moderate quality of evidence2

Evidence basis:

  • SEPSISPAM trial (2014): Randomized 776 patients with septic shock to high-MAP (80–85 mmHg) vs. low-MAP (65–70 mmHg) targets. No difference in 28-day or 90-day mortality. Patients with chronic hypertension in the high-MAP group had lower rates of RRT (31.7% vs. 42.2%, p = 0.046), but higher rates of atrial fibrillation.12
  • 65 trial (2020): Permissive hypotension (MAP 60–65 mmHg) in patients ≥ 65 years was non-inferior to usual care for 90-day mortality (41.0% vs. 43.8%) and was associated with lower vasopressor exposure.13

Clinical application:

  • Start with a MAP target of 65 mmHg for most patients
  • Consider targeting 80–85 mmHg in patients with chronic hypertension (pre-existing renal autoregulatory adaptation to higher pressures)
  • Consider accepting 60–65 mmHg in elderly patients (≥ 65 years) without evidence of end-organ hypoperfusion
  • Individualize based on clinical response: mental status, urine output, lactate clearance, skin perfusion

4. Vasopressor Therapy

4.1 Vasopressor Selection — Guideline Recommendations

Recommendation: For adults with septic shock, the panel recommends norepinephrine as the first-line vasopressor.

Strength: Strong recommendation, high quality of evidence2

Recommendation: For adults with septic shock on norepinephrine with inadequate MAP, the panel suggests adding vasopressin (up to 0.03 U/min) rather than further escalating norepinephrine.

Strength: Weak recommendation, moderate quality of evidence2

Recommendation: For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and MAP, the panel suggests adding dobutamine to norepinephrine or using epinephrine alone.

Strength: Weak recommendation, low quality of evidence2

Recommendation: For adults with septic shock, the panel suggests against using dopamine.

Strength: Weak recommendation, high quality of evidence2

4.2 Complete Vasopressor and Inotrope Dosing Reference

AgentMechanismStarting DoseTitration RangeMax DoseKey Receptor ActivityPrimary Indication in Septic Shock
Norepinephrineα1 » β10.01–0.05 μg/kg/minTitrate by 0.02–0.05 μg/kg/min every 5–15 min0.5–1.0 μg/kg/min (doses > 1.0 used in refractory shock)α1 (potent), β1 (moderate)First-line vasopressor
VasopressinV1 receptor agonist0.03 U/min (fixed dose)Usually fixed at 0.03 U/min; some protocols use 0.01–0.04 U/min0.04 U/minV1 (vascular), V2 (renal)Second-line — added when norepinephrine dose ≥ 0.25–0.5 μg/kg/min
Epinephrineα1 + β1 + β20.01–0.05 μg/kg/minTitrate by 0.02–0.05 μg/kg/min every 5–15 min0.5–1.0 μg/kg/minα1, β1, β2 (all potent)Second- or third-line vasopressor; preferred if concurrent cardiac dysfunction
PhenylephrinePure α1 agonist0.5–2.0 μg/kg/minTitrate by 0.5–1.0 μg/kg/min5–10 μg/kg/minα1 onlySalvage; use when tachyarrhythmias preclude other agents
DopamineDose-dependent: DA → β1 → α15–10 μg/kg/min (vasopressor range)Titrate by 2–5 μg/kg/min every 10–15 min20 μg/kg/minDA (1–5), β1 (5–10), α1 (>10)Not recommended — higher arrhythmia risk; use only if norepinephrine unavailable
Angiotensin IIAT1 receptor agonist20 ng/kg/minTitrate to MAP target; dose range 1.25–40 ng/kg/min40 ng/kg/min (80 ng/kg/min in first 3 hrs)AT1 (vascular)Rescue agent — refractory vasodilatory shock on high-dose vasopressors
Dobutamineβ1 » β2 (inotrope)2.5 μg/kg/minTitrate by 2.5 μg/kg/min every 10–15 min20 μg/kg/minβ1 (potent), β2 (moderate)Sepsis-induced myocardial dysfunction with low CO despite adequate MAP
MilrinonePDE-3 inhibitor (inodilator)0.125–0.25 μg/kg/minTitrate by 0.125 μg/kg/min0.75 μg/kg/minN/A (PDE-3)Alternative inotrope; caution — causes vasodilation; renally cleared

4.3 Vasopressor Initiation — Timing

Recommendation: For adults with septic shock, the panel suggests starting vasopressors peripherally to restore MAP rather than delaying vasopressor initiation until central venous access is secured.

Strength: Weak recommendation, very low quality of evidence2

Early vasopressor initiation (within 1 hour of hypotension recognition):

  • Multiple observational studies suggest that early vasopressor initiation (within the first 1–2 hours of sepsis-induced hypotension) is associated with improved outcomes compared to delayed initiation.14
  • The CENSER trial (2019) demonstrated that early norepinephrine administration (within 1 hour of septic shock recognition) was associated with higher rates of shock control at 6 hours compared with standard care (76.1% vs. 48.4%, p < 0.001).15
  • Peripheral vasopressor administration has been shown to be safe for short durations (< 12–24 hours) through well-functioning large-bore peripheral IVs, with extravasation rates of approximately 2%.5

4.4 Practical Vasopressor Algorithm

Step 1: Start norepinephrine at 0.05 μg/kg/min. Titrate every 5–10 minutes to MAP ≥ 65 mmHg.

Step 2: If norepinephrine reaches 0.25–0.5 μg/kg/min without achieving MAP target:

  • Add vasopressin at 0.03 U/min (fixed dose)
  • This allows for catecholamine sparing and may reduce norepinephrine requirements by 25–50%

Step 3: If MAP remains inadequate on norepinephrine + vasopressin:

  • If cardiac output is low (sepsis-induced cardiomyopathy): Add dobutamine 2.5–10 μg/kg/min OR switch to epinephrine 0.05–0.3 μg/kg/min
  • If cardiac output is adequate (pure vasodilatory shock): Increase norepinephrine; consider angiotensin II as a rescue agent

Step 4: Refractory shock (MAP not achieved despite maximal doses of norepinephrine + vasopressin + either epinephrine or dobutamine):

  • Reassess diagnosis: consider alternative shock etiologies (cardiogenic, obstructive, hemorrhagic)
  • Consider hydrocortisone 50 mg IV q6h (see Part 4)
  • Consider angiotensin II 20 ng/kg/min
  • Evaluate for ongoing source (undrained abscess, necrotic tissue, infected device)
  • Consider methylene blue (1–2 mg/kg IV bolus) as rescue in refractory vasodilatory shock (limited evidence)

4.5 Key Evidence for Vasopressor Selection

TrialYearComparisonKey Finding
De Backer et al.2010Dopamine vs. norepinephrine (n = 1,679)No mortality difference overall; dopamine associated with significantly more arrhythmias (24.1% vs. 12.4%, p < 0.001); subgroup analysis: dopamine associated with higher mortality in cardiogenic shock16
VASST2008Vasopressin + norepinephrine vs. norepinephrine alone (n = 778)No mortality difference overall (35.4% vs. 39.3%, p = 0.26); post-hoc: potential benefit in less severe shock (norepinephrine 5–14 μg/min)17
VANISH2016Early vasopressin vs. norepinephrine (n = 409)No difference in kidney failure-free days or mortality; vasopressin group required less RRT18
ATHOS-32017Angiotensin II vs. placebo in vasodilatory shock (n = 344)Angiotensin II increased MAP response rate at 3 hours (69.9% vs. 23.4%, p < 0.001)19

5. Hemodynamic Monitoring

5.1 Monitoring Recommendations

Recommendation: For adults with septic shock requiring vasopressors, the panel suggests placing an arterial catheter as soon as practical, rather than relying solely on non-invasive blood pressure monitoring.

Strength: Weak recommendation, very low quality of evidence2

5.2 Monitoring Modalities

ModalityWhat It MeasuresClinical Utility in SepsisRecommendation
Arterial lineContinuous invasive BP, waveform analysis, PPV/SVVGold standard for MAP monitoring; enables frequent ABGs; facilitates dynamic fluid responsiveness assessmentRecommended for all patients on vasopressors
Central venous catheterCVP, ScvO2 (if equipped), central drug deliveryEnables vasopressor infusion, ScvO2 monitoring; CVP is a poor predictor of fluid responsivenessIndicated for vasopressor administration and central venous access
ScvO2Central venous oxygen saturationTarget > 70%; low ScvO2 suggests inadequate oxygen delivery (low CO, anemia, or increased extraction); high ScvO2 (> 80%) may indicate mitochondrial dysfunction or AV shuntingCan guide fluid/inotrope management
Point-of-care echocardiographyLV/RV function, volume status, cardiac outputIdentifies sepsis-induced cardiomyopathy; guides fluid vs. vasopressor vs. inotrope decisions; evaluates IVC for fluid responsivenessStrongly encouraged; bedside FOCUS exam
Pulse contour cardiac output (PiCCO, FloTrac)Continuous cardiac output, SVV, extravascular lung waterAdvanced hemodynamic monitoring; identifies fluid responsiveness; quantifies pulmonary edemaConsider in complex/refractory shock
Pulmonary artery catheterCardiac output, PCWP, SVR, PVR, SvO2Comprehensive hemodynamic assessment; distinguishes distributive from cardiogenic shockReserved for complex cases; no routine use

5.3 Focused Cardiac Ultrasound (FOCUS) in Sepsis

A focused bedside echocardiographic examination should address the following questions in the septic patient:

  1. Is the left ventricle hyperdynamic or depressed?

    • Hyperdynamic LV (LVEF > 55%, hyperdynamic walls): Consistent with distributive shock; likely fluid and vasopressor responsive
    • Depressed LV (LVEF < 40%, global hypokinesis): Sepsis-induced cardiomyopathy (occurs in 20–40% of septic shock patients); consider inotrope support

  2. Is the right ventricle dilated or failing?

    • RV dilation (RV:LV ratio > 0.6–1.0): Consider right heart failure, pulmonary hypertension, ARDS-related RV dysfunction
    • May indicate need for RV-protective ventilation strategies and avoidance of excessive PEEP

  3. What is the IVC status?

    • Small, collapsing IVC (< 1.0–1.5 cm, > 50% respiratory variation in spontaneous breathing): Suggests fluid responsiveness
    • Distended, non-collapsing IVC (> 2.0–2.5 cm, < 15% respiratory variation): Suggests elevated right atrial pressure, fluid overload, or RV dysfunction

  4. Is there a pericardial effusion or tamponade?

    • Must be excluded in hemodynamically unstable patients

6. Lactate-Guided Resuscitation — Practical Protocol

Based on the 2021 international sepsis guideline recommendations and supporting evidence:2 20

Step 1: Measure initial serum lactate at the time of sepsis recognition.

Step 2: If lactate is elevated (> 2 mmol/L):

  • Initiate aggressive resuscitation (fluids, vasopressors, antibiotics as indicated)
  • Re-measure lactate every 2–4 hours

Step 3: Target lactate normalization OR lactate clearance ≥ 10–20% every 2 hours.

  • If lactate is clearing: Continue current management
  • If lactate is not clearing or is rising: Reassess for:
    • Ongoing source of infection
    • Inadequate resuscitation (hypovolemia)
    • Cardiac dysfunction requiring inotropic support
    • Ongoing tissue ischemia (mesenteric ischemia, limb ischemia)
    • Non-infectious causes of elevated lactate

Step 4: Continue serial lactate monitoring until lactate normalizes (< 2 mmol/L) or a plateau is reached.

6.2 Evidence for Lactate-Guided Resuscitation

  • Jansen et al. (2010): In a multicenter RCT (n = 348), lactate-guided resuscitation (targeting ≥ 20% reduction every 2 hours for the first 8 hours) resulted in lower hospital mortality (33.9% vs. 43.5%, adjusted HR 0.61, 95% CI 0.43–0.87, p = 0.006).20
  • Jones et al. (2010): In a randomized non-inferiority trial (n = 300), lactate clearance-guided resuscitation was non-inferior to ScvO2-guided resuscitation (mortality 17% vs. 23%, p = 0.067), suggesting that lactate clearance is at least as good as ScvO2 as a resuscitation endpoint.21

7. Colloids in Sepsis Resuscitation

7.1 Hydroxyethyl Starch (HES)

Recommendation: The panel recommends against using hydroxyethyl starch (HES) for intravascular volume replacement in patients with sepsis or septic shock.

Strength: Strong recommendation, high quality of evidence2

Evidence:

  • 6S trial (2012): HES 130/0.42 vs. Ringer’s acetate in severe sepsis (n = 798). HES was associated with higher 90-day mortality (51% vs. 43%, RR 1.17, p = 0.03) and significantly more renal replacement therapy (22% vs. 16%, RR 1.35, p = 0.04).22
  • CHEST trial (2012): HES vs. saline in ICU patients (n = 7,000). No difference in 90-day mortality but HES was associated with significantly more RRT (7.0% vs. 5.8%, RR 1.21, p = 0.04).23

7.2 Gelatin-Based Colloids

Recommendation: The panel suggests against using gelatin-based colloids for resuscitation in sepsis or septic shock.

Strength: Weak recommendation, low quality of evidence2

7.3 Albumin

Recommendation: For adults with sepsis or septic shock who have received large volumes of crystalloid, the panel suggests using albumin in addition to crystalloids.

Strength: Weak recommendation, low quality of evidence2

  • ALBIOS trial (2014): 20% albumin targeted to serum albumin ≥ 30 g/L vs. crystalloid alone in severe sepsis (n = 1,818). No difference in 28-day mortality (31.8% vs. 32.0%, RR 1.00, p = 0.94). Post-hoc analysis showed a potential mortality benefit in the septic shock subgroup (43.6% vs. 49.9%, RR 0.87, p = 0.03).9
  • SAFE study (2004): 4% albumin vs. saline in ICU patients (n = 6,997). No difference in 28-day mortality. Sepsis subgroup analysis suggested possible benefit with albumin (RR 0.87, 95% CI 0.74–1.02).24

References

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  2. Evans L, Rhodes A, Alhazzani W, et al. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.” Crit Care Med. 2021;49(11):e1063-e1143. DOI: 10.1097/CCM.0000000000005337 ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎

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  4. Levy MM, Rhodes A, Phillips GS, et al. “Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.” Crit Care Med. 2015;43(1):3-12. DOI: 10.1097/CCM.0000000000000723 ↩︎

  5. Cardenas-Garcia J, Schaub KF, Belchikov YG, et al. “Safety of peripheral intravenous administration of vasoactive medication.” J Hosp Med. 2015;10(9):581-585. DOI: 10.1002/jhm.2394 ↩︎ ↩︎

  6. Semler MW, Self WH, Wanderer JP, et al. “Balanced crystalloids versus saline in critically ill adults.” N Engl J Med. 2018;378(9):829-839. DOI: 10.1056/NEJMoa1711584 ↩︎

  7. Finfer S, Micallef S, Hammond N, et al. “Balanced multielectrolyte solution versus saline in critically ill adults.” N Engl J Med. 2022;386(9):815-826. DOI: 10.1056/NEJMoa2114464 ↩︎

  8. Zampieri FG, Machado FR, Biondi RS, et al. “Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial.” JAMA. 2021;326(9):818-829. DOI: 10.1001/jama.2021.11684 ↩︎

  9. Caironi P, Tognoni G, Masson S, et al. “Albumin replacement in patients with severe sepsis or septic shock.” N Engl J Med. 2014;370(15):1412-1421. DOI: 10.1056/NEJMoa1305727 ↩︎ ↩︎

  10. Monnet X, Marik P, Teboul JL. “Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis.” Intensive Care Med. 2016;42(12):1935-1947. DOI: 10.1007/s00134-015-4134-1 ↩︎

  11. Boyd JH, Forbes J, Nakada TA, et al. “Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality.” Crit Care Med. 2011;39(2):259-265. DOI: 10.1097/CCM.0b013e3181feeb15 ↩︎

  12. Asfar P, Meziani F, Hamel JF, et al. “High versus low blood-pressure target in patients with septic shock.” N Engl J Med. 2014;370(17):1583-1593. DOI: 10.1056/NEJMoa1312173 ↩︎

  13. Lamontagne F, Richards-Belle A, Thomas K, et al. “Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial.” JAMA. 2020;323(10):938-949. DOI: 10.1001/jama.2020.0930 ↩︎

  14. Bai X, Yu W, Ji W, et al. “Early versus delayed administration of norepinephrine in patients with septic shock.” Crit Care. 2014;18(5):532. DOI: 10.1186/s13054-014-0532-y ↩︎

  15. Permpikul C, Tongyoo S, Viarasilpa T, et al. “Early use of norepinephrine in septic shock resuscitation (CENSER): a randomized trial.” Am J Respir Crit Care Med. 2019;199(9):1097-1105. DOI: 10.1164/rccm.201806-1034OC ↩︎

  16. De Backer D, Biston P, Devriendt J, et al. “Comparison of dopamine and norepinephrine in the treatment of shock.” N Engl J Med. 2010;362(9):779-789. DOI: 10.1056/NEJMoa0907118 ↩︎

  17. Russell JA, Walley KR, Singer J, et al. “Vasopressin versus norepinephrine infusion in patients with septic shock.” N Engl J Med. 2008;358(9):877-887. DOI: 10.1056/NEJMoa067373 ↩︎

  18. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. “Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial.” JAMA. 2016;316(5):509-518. DOI: 10.1001/jama.2016.10485 ↩︎

  19. Khanna A, English SW, Wang XS, et al. “Angiotensin II for the treatment of vasodilatory shock.” N Engl J Med. 2017;377(5):419-430. DOI: 10.1056/NEJMoa1704154 ↩︎

  20. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. “Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.” Am J Respir Crit Care Med. 2010;182(6):752-761. DOI: 10.1164/rccm.200912-1918OC ↩︎ ↩︎

  21. Jones AE, Shapiro NI, Trzeciak S, et al. “Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.” JAMA. 2010;303(8):739-746. DOI: 10.1001/jama.2010.158 ↩︎

  22. Perner A, Haase N, Guttormsen AB, et al. “Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis.” N Engl J Med. 2012;367(2):124-134. DOI: 10.1056/NEJMoa1204242 ↩︎

  23. Myburgh JA, Finfer S, Bellomo R, et al. “Hydroxyethyl starch or saline for fluid resuscitation in intensive care.” N Engl J Med. 2012;367(20):1901-1911. DOI: 10.1056/NEJMoa1209759 ↩︎

  24. Finfer S, Bellomo R, Boyce N, et al. “A comparison of albumin and saline for fluid resuscitation in the intensive care unit.” N Engl J Med. 2004;350(22):2247-2256. DOI: 10.1056/NEJMoa040232 ↩︎