The recommendation for a fluid bolus in a septic patient is 30 mL/kg. Is there any evidence that supports rounding down to the nearest 500 mL or 1000 mL?

Comment by InpharmD Researcher

Studies comparing restrictive versus standard fluid administration in adult septic patients have generally reported similar outcomes in mortality and serious adverse events, suggesting that a lower fluid dose may be an acceptable strategy in critical care. However, direct comparisons specifically between the 30 mL/kg dose recommended by the Surviving Sepsis Campaign (SSC) and rounding down to 500 mL or 1,000 mL are more limited. The 30 mL/kg fluid bolus recommendation has also been criticized due to its lack of evidence for use and potential for harm.

Background

The recommendation for a 30 mL/kg crystalloid fluid bolus in a septic patient was established by the Surviving Sepsis Campaign (SSC), with the current guidelines published in 2018 still recommending the bolus regimen (strong recommendation, low quality of evidence). Since its publication, reviews and commentaries from real world settings note the minimal supporting clinical data and reliance on expert opinion for this recommendation. These reviews suggest that the 30 mL/kg fluid challenge can needlessly expose patients to large volumes of fluid, and could actually be harmful by overloading organ function and paradoxically worsening shock. Other guidelines like American College of Emergency Physicians (ACEP) recommend individualizing fluid resuscitation needs for each patient. [1], [2], [3]

A 2020 review discussing the lack of supporting evidence for fluid resuscitation in septic shock recommends a flat initial bolus of 500 mL of balanced crystalloid solutions, followed by monitoring of patient’s response and contemplation of further bolus doses. This recommendation is based on the initial findings from a 1832 publication that pioneered the concept of fluid resuscitation that administered a fluid “ounce after ounce” while closely observing the patient. In other words, the recommendation lacks clinical evidence, but the authors consider it a safer approach to resuscitation of critically ill patients. [2], [3], [4]

A 2014 article reviews the evidence around fluid administration in patients with septic shock by comparing goal-directed fluid therapy (GDT) approaches to usual care or historical controls. The GDT approaches aimed to achieve specific fluid administration targets within a defined time period, often targeting a central venous pressure (CVP) of 8-12 mmHg. The four randomized controlled trials that were assessed comparing GDT to usual care did not find a significant reduction in mortality with GDT. However, these trials were inconsistent and heterogeneous. When the largest trial (ProCESS) was removed, the remaining three trials showed a significant reduction in mortality with GDT. Notably, the ProCESS trial found that patients receiving usual care received significantly less IV fluid at 6 hours and had numerically lower mortality compared to the GDT group. [5]

Eighteen observational studies were also analyzed. While bundled GDT was associated with a significant increase in survival overall, the difference in IV fluid volumes administered between treatment groups showed significant heterogeneity across studies. Most studies reported greater IV fluid volumes in the GDT groups, but the differences were inconsistent. There are also several limitations noted across the randomized and observational studies. In particular, multiple interventions were compared between groups, not just fluid administration, making it difficult to attribute outcomes to any single component. The inconsistent results regarding IV fluid volumes administered further complicate determining the optimal fluid resuscitation approach. These findings suggest there are potential risks of excessive IV fluid administration in septic shock patients. However, the evidence does not firmly provide quantitative fluid administration targets and there was no direct evidence for rounding down fluid boluses to the nearest 500 mL or 100 mL amount. [5]

In a 2021 retrospective chart review, medical records of emergency general surgery (EGS) patients who were undergoing surgery for abdominal sepsis within 24 h of admission were analyzed for incidence of mortality. A total of 301 patients (55% male, mean age 55 years) were included over 8 years, of which 257 (85%) patients survived to discharge. Though fluid restrictions were not assessed within the study, investigators observed an increasing mortality rate per increment with increasing preoperative resuscitation fluid per kg (<10 to <70 mL/kg; 8.8% vs 31.6%; p= 0.004). Lower mortality rates were observed in patients who received <30 mL/kg (11.3%) versus patients who received >30 mL/kg (21%; p= 0.02). However, once analysis was corrected for age and physiologic factors, there were no significant differences in mortality between groups. [6]

References:

[1] Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;44(6):925-928. doi:10.1007/s00134-018-5085-0
[2] Marik PE, Byrne L, van Haren F. Fluid resuscitation in sepsis: the great 30 mL per kg hoax. J Thorac Dis. 2020;12(Suppl 1):S37-S47. doi:10.21037/jtd.2019.12.84
[3] Spiegel R, Hockstein M, Waters J, Goyal M. The Survival of the Surviving Sepsis Campaign. Med Clin North Am. 2022;106(6):1109-1117. doi:10.1016/j.mcna.2022.08.006
[4] MacGillivray N. Dr Latta of Leith: pioneer in the treatment of cholera by intravenous saline infusion. J R Coll Physicians Edinb. 2006;36(1):80-85.
[5] Chen C, Kollef MH. Conservative fluid therapy in septic shock: an example of targeted therapeutic minimization. Crit Care. 2014;18(4):481. Published 2014 Aug 29. doi:10.1186/s13054-014-0481-5
[6] Moran B, Major E, Kufera JA, Tisherman SA, Diaz J. Pre-operative fluid resuscitation in the emergency general surgery septic patient: does it really matter?. BMC Emerg Med. 2021;21(1):86. Published 2021 Jul 22. doi:10.1186/s12873-021-00479-3

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

The recommendation for a fluid bolus in a septic patient is 30 mL/kg. Is there any evidence that supports rounding down to the nearest 500 mL or 1000 mL?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Restriction of Intravenous Fluid in ICU Patients with Septic Shock

Design

International, randomized trial

N= 1,554

Objective

To evaluate the effects of restriction of intravenous (IV) fluids on mortality and other important outcomes in adult patients with septic shock in the intensive care unit (ICU)

Study Groups

Restrictive fluid (n= 755)

Standard fluid (n= 776)

Inclusion Criteria

Age 18 years or older, treated in the intensive care unit for septic shock (suspected or confirmed infection, plasma lactate level of 2 mmol/L or higher), receiving at least 1 liter of intravenous fluids in the 24 hours prior to screening, receiving ongoing curculatory support

Exclusion Criteria

Septic shock > 12 hours, life-threatening bleeding, acute burn injury involving >10% of body-surface area, pregnancy

Methods

Patients with septic shock were screened in the ICU for inclusion. Patients were randomly assigned 1:1 to restrictive IV fluid therapy or standard IV fluid therapy. Treatment assignments were not blinded, but outcomes assessment was blinded.

For restrictive group, IV fluids were only allowed under 4 conditions related to severe hypoperfusion or fluid replacement/deficiencies if enteral route is not available.

Standard group had no upper limit on IV fluids and could be given as long as hemodynamic improvement, to replace losses/deficiencies, or for maintenance if ICU protocol recommended.

The assigned IV fluid intervention was given until ICU discharge, up to 90 days. Concomitant interventions like antibiotics and renal replacement left to clinician discretion.

Duration

90 days or until discharge

Outcome Measures

Primary: Death within 90 days after randomization

Secondary: Intravenous fluid data, patients with one or more serious adverse events in the ICU (cerebral, cardiac, intestinal, or limb ischemic events)

Baseline Characteristics

 

Restrictive fluid (n= 755)

Standard fluid (n= 776)    

Age, years

71 70    

Male

59.9% 58.2%    

Coexisting condition

Hematologic or metastatic cancer

Ischemic heart disease or heart failure

Chronic hypertension

Long-term dialysis

 

17.0%

15.4%

45.8%

1.2%

 

18.0%

19.5%

46.4%

1.5%

   

Median time from ICU admission to randomization, hours

3

3

   

Median predicted 90-day mortality

40%

40%

   

Source of ICU admission

Emergency department or prehospital

Hospital ward

Operation room or recovery room

Another ICU

 

39.3%

34.2%

22.9%

3.6%

 

38.5%

38.7%

19.7%

3.1%

   

Focus of infection

Gastrointestinal

Pulmonary

Urinary tract

Skin or soft tissue

Other

 

36.8%

27.7%

15.8%

8.2%

11.3%

 

38.3%

26.5%

17.1%

8.2%

9.8%

   

Median volume of intravenous fluid 24 hours before randomization, mL

3200 3000    

Results

Endpoint

Restrictive fluid (n= 755) Standard fluid (n= 776) Difference (restrictive minus standard)  

Intravenous fluid volume, median mL (interquartile range [IQR])

After 1 day

After 5 days

After 90 days

 

500 (0 to 1400)

1450 (445 to 3200)

1798 (500 to 4366)

 

1313 (500 to 2500)

3077 (1535 to 5300)

3811 (1861 to 6762)

 

-813

-1627

-2013

 

Total fluid volume, median mL (IQR)

After 1 day

After 5 days

After 90 days

 

1,843 (964 to 3150)

8,864 (4865 to 13,488)

10,433 (5024 to 25,567)

 

2,708 (1403 to 4267)

10,800 (6178 to 15,459)

12,747 (6453 to 28,110)

 

-865

-1936

-2314

 

Cumulative fluid balance

After 1 day

After 5 days

After 90 days

 

725 (0 to 1837)

1,676 (−137 to 4117)

1,645 (−461 to 4423)

 

1,342 (308 to 2759)

2,420 (759 to 4996)

2,368 (368 to 5517)

 

-617

-744

-723

 
  Restrictive fluid (n= 755) Standard fluid (n= 776)

Adjusted relative risk (confidence interval [CI])

p-Value

Death by day 90

323/764 (42.3%) 329/781 (42.1) 1.00 (95% CI; 0.89 to 1.13) 0.96

Serious adverse events

Cerebral ischemia

Myocardial ischemia

Intestinal ischemia

Limb ischemia

Severe acute kidney injury

221/751 (29.4%)

17/755 (2.3%)

16/755 (2.1%)

41/755 (5.4%)

18/755 (2.4%)

173/750 (23.1%)

238/772 (30.8%)

18/776 (2.3%)

6/776 (0.8%)

44/776 (5.7%)

18/776 (2.3%)

189/772 (24.5%)

0.95 (99% CI; 0.77 to 1.15)

 

 

 

 

 

0.46

 

 

 

 

 

Adverse Events

See above

Study Author Conclusions

Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy.

InpharmD Researcher Critique

Patients and staff were not blinded and aware of group assignments, some important data was not collected, some patients received fluid before enrollment or had protocol violations, more fluid may be given in standard care in other settings, the study had limited power, and the goal of detecting a 7 percentage point difference in mortality may be considered large.



References:

Meyhoff TS, Hjortrup PB, Wetterslev J, et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022;386(26):2459-2470. doi:10.1056/NEJMoa2202707

 

Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial

Design

International, stratified, parallel-group, open-label, randomized clinical trial

N= 1,554

Objective

To evaluate the effects of restriction of intravenous fluids on mortality and other important outcomes in adult patients with septic shock in the ICU.

Study Groups

Restrictive-fluid (n= 75)

Standard-fluid (n= 76)

Inclusion Criteria

Patients aged 18 years or above, in ICU, with sepsis criteria within the previous 24 hours, severe circulatory impairment, received at least 30 mL/kg IBW of fluid in the last 6 hours, and ongoing norepinephrine infusion.

Exclusion Criteria

Received RRT or imminent RRT, plasma K+ >6 mmol/L, plasma creatinine >350 µmol/L, FiO2 >0.8 and PEEP >10 cmH2O, life-threatening bleeding, acute burn injury, not considered for full life-support, consent not obtained.

Methods

Fluid boluses in the fluid restriction group were permitted only if severe hypoperfusion occurred. In the standard care group, fluid boluses were permitted as long as circulation improved. Both groups maintained MAP of at least 65 mmHg using norepinephrine.

Duration

90 days post-randomisation

Outcome Measures

Primary: Volumes of resuscitation fluid at day 5 and during ICU stay

Secondary: Total fluid input, fluid balance, protocol violations, serious adverse reactions.

Exploratory: Death within 90 days, time to death, days alive without mechanical ventilation or RRT, ischemic events, maximum change in plasma creatinine, worsening of AKI.

Baseline Characteristics

 

Restrictive-fluid (n= 75)

Standard-fluid (n= 76)    

Age, years

69 73    

Male

69% 62%    

Weight, kg

80 72    

Hypertension

47% 38%    

Source of ICU admittance

Emergency department

General ward

Operating room or recovery room

Other ICU

 

24%

37%

36%

3%

 

22%

36%

38%

4%

   

Source of sepsis

Lungs

Abdomen

Urinary tract

Soft tissue

Other

 

31%

51%

11%

17%

9%

 

47%

43%

13%

7%

9%

   

Days from hospital admission to randomization

1

1

   

Sequential Organ Failure Assessment (SOFA) score

10

10

   

Simplified Acute Physiology Score (SAPS) II

52

56

   

Fluids given prior to randomization, mL

4200

4790

   

Results

Endpoint

Restrictive-fluid (n= 75)

Standard-fluid (n= 76)

Fluid restriction vs standard (95% confidence interval [CI])

p-Value

Volumes of resuscitation fluid, mL (interquartile range [IQR])

First 5 days after randomization

During ICU stay after randomization

 

500 (0 to 2500)

500 (0 to 3250)

 

2000 (1000 to 4100)

2200 (1000 to 4750)

 

-1241 (-2043 to -439)

-1407 (-2358 to -456)

 

< 0.001

< 0.001

Total fluid input, mL

First 5 days after randomization

During ICU stay after randomization

 

12,411 (5518 to 17.035)

18,291 (5518 to 34,045)

 

13,687 (7163 to 17,082)

16,970 (7163 to 29,889)

 

-820 (-2968 to 1329)

-2036 (-10,920 to 6848)

 

0.45

0.65

Cumulated fluid balance, mL

First 5 days after randomization

During ICU stay after randomization

 

1752 (-1153 to 3758)

1923 (-1964 to 5415)

 

2680 (407 to 5114)

2014 (-168 to 4678)

 

-1148 (-2531 to 235)

-475 (-2254 to 1304)

 

0.06

0.60

Serious adverse reaction events per day during the ICU stay

0.14 (0 to 0.50) 0.15 (0 to 0.52) N/A 0.85

Adverse Events

No statistically significant difference in serious adverse reactions between the groups.

Study Author Conclusions

A protocol restricting resuscitation fluid successfully reduced fluid volumes compared with standard care in ICU patients with septic shock. Patient-centred outcomes suggested benefit with fluid restriction, but the trial was not powered to show differences in these exploratory outcomes.

InpharmD Researcher Critique

The study was well-designed with concealed allocation and blinded statistical analysis, enhancing its validity. However, it was relatively small and not powered to detect differences in exploratory outcomes. There were baseline imbalances and protocol violations, which may have impacted results. The study's findings are promising but require confirmation in larger trials.



References:

Fluid restriction group (250–500 mL isotonic crystalloid such as saline or Ringer’s solutions fluid boluses) in case of severe hypoperfusion vs standard of care

 

Non-invasive assessment of fluid responsiveness to guide fluid therapy in patients with sepsis in the emergency department: a prospective cohort study
Design

Prospective cohort study

N= 30

Objective

To quantify the effect of a fluid challenge on non-invasively measured Cardiac Index (CI) in patients with sepsis without shock

Study Groups

All study subjects (N = 30)

Inclusion Criteria

Patients presenting to the ED with sepsis, evidence of infection, and organ dysfunction as per sepsis-3 guidelines

Exclusion Criteria

Patients <16 years, increased abdominal pressure, concurrent acute events, metastatic cancer in palliative setting, septic shock, or inability to measure cardiac output (CO) non-invasively

Methods

CO was measured non-invasively using the ClearSight system. After consent, a finger cuff was applied at least 5 minutes post-transfer to minimize adrenergic stimulation. Once calibrated, three baseline readings for CO, CI, stroke volume (SV), and systemic vascular resistance (SVR) were taken at 1-minute intervals. A passive leg raise (PLR) test was then performed to simulate a fluid bolus by elevating the legs to induce an autotransfusion. Measurements were repeated at 30, 60, 90, and 120 seconds. Patients then received 500 mL of 0.9% NaCl over 15 minutes, with final readings taken after the fluid challenge. A 15% increase in CI after PLR identified fluid responders.

Duration

May 2018 to March 2019

Outcome Measures

Primary: Percentage of subjects with >15% increase in CI after PLR

Secondary: Relation between changes in CI after PLR and fluid bolus, differences in characteristics between responders and non-responders

Baseline Characteristics Characteristic

Value

Male 18 (60%)
Age, years 75 (68–83)
Length, cm 173 (167–180)
Weight, kg 77 (70–86)
Heart rate, bpm 110 (100–115)
Systolic blood pressure, mmHg 130 (117–153)
Mean arterial pressure, mm Hg 90 (78–108)
Oxygen saturation, % 94 (93–95)
Respiratory rate, per min 25 (22–30)
Temperature, °C 39.2 (38.5–39.6)
Results Parameter Responders Non-responders p-Value
Baseline CI, L/min/m2 3.3 (1.9–3.8) 3.3 (2.7–4.0) 0.40
Baseline SV, mL 63 (44–69) 61 (49–80) 0.73
Baseline SVR, dyn.s/cm5 800 (750–1354) 816 (719–1095) 0.88

SV stroke volume; CI, Cardiac Index; SVR, systemic vascular resistance.

Seven out of 30 patients (23%) showed a >15% increase in CI after PLR and a 500 mL fluid bolus; fluid responders had a higher eGFR (64 vs 37, p= 0.009) but similar characteristics to non-responders.

The change in CI after PLR was strongly positively correlated with the change in CI after a 500 mL NaCl 0.9% fluid bolus (r= 0.88, p< 0.001)

Adverse Events

No adverse events reported.

Study Author Conclusions

In patients with sepsis without shock, three out of four patients do not demonstrate a clinically relevant increase in CI after a fluid challenge. Non-invasive CO monitoring with a PLR test can identify patients who might benefit from fluid resuscitation.

Critique

Limitations of the study include potential sampling bias, lack of control arm, and exclusion of patients unable to obtain a reliable signal with the ClearSight system.

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References:

Koopmans NK, Stolmeijer R, Sijtsma BC, et al. Non-invasive assessment of fluid responsiveness to guide fluid therapy in patients with sepsis in the emergency department: a prospective cohort study. Emerg Med J. 2021;38(6):416-422. doi:10.1136/emermed-2020-209771