The Surviving Sepsis Campaign (SSC) recommends a minimum of 30 mL/kg crystalloid for hypotension or high lactate levels. The evidence for this practice, however, is of low quality. The origin of the 30 mL/kg fluid bolus recommendation stems from an attempt to quickly restore circulation and perfusion in the early stages of sepsis and septic shock, and it is largely based on expert opinion and retrospective observational studies, rather than randomized controlled trials. Recent studies suggest a more restrictive fluid approach may not result in harm, challenging the SSC's recommendation. In this blog post, we will dive further and examine the practice of fluid resuscitation in sepsis and septic shock treatment, unpacking the origins, evidence, and implications of the controversial 30 mL/kg guideline.
What is the origin of the 30 mL per kg recommendation?
The recommendation for septic patients with hypotension or high blood lactate concentration to receive at least 30 mL/kg of intravenous crystalloid within 3 hours was introduced in the fourth edition of the Surviving Sepsis Campaign (SSC) guidelines in 2016. The latest revision of the SSC guidelines combines previous 3- and 6-hour bundles into a single "1-hour bundle" requiring immediate resuscitation for all patients. The 30 mL/kg volume recommendation, despite lacking controlled data for support, is cited by the SSC as "usual practice" in early resuscitation stages, as observed in the PROCESS, ARISE, and PROMISE trials.
Observational evidence from the International Multicentre Prevalence Study on Sepsis (IMPreSS) indicates that compliance with all SSC recommendations correlates with a 40% reduction in hospital mortality. However, the effect of fluid resuscitation wasn't analyzed as an independent element . A large-scale study that isolated the 30 mL/kg fluid bolus as a separate element found no significant effect on patient outcomes based on time to completion or volume of the bolus .
A severity-adjusted observational study suggested that in real-world scenarios, clinicians usually administer less fluid to patients with severe sepsis and septic shock than recommended by the SSC guidelines. In this same study, patients who received more than 5 L of fluid during the first hospital day had a significantly increased risk of death, indicating the potential dangers of excessive fluid administration .
In addition, the SSC does not specify which weight the clinician should use (actual body weight, predicted body weight, or ideal body weight). The weight metric affects the amount of fluid prescribed. Furthermore, the fixed resuscitation volume of 30 mL/kg for all patients with septic shock contradicts the individualized and personalized approach recommended for medical treatments.
Sepsis Pathophysiology and the Potential Risks of Fluid Resuscitation
Overall, there is currently no solid evidence supporting fluid resuscitation as an effective and safe treatment for sepsis. Fluid resuscitation's effectiveness in treating sepsis has been questioned due to the complexities in sepsis pathophysiology, potential harm to organ function, and the absence of solid clinical evidence.
Fluid resuscitation for severe sepsis and septic shock was assumed effective based on an incomplete understanding of sepsis pathophysiology, specifically an overemphasis on organ hypoperfusion. It's now more understood that the dysfunction of vital organs in sepsis (e.g., the brain, heart, kidneys, and liver) is mainly due to bioenergetic failure rather than organ hypoperfusion or microcirculatory dysfunction. Fluid resuscitation can probably benefit a subset of septic patients who are truly hypovolemic (dehydrated), but the benefit is really questionable in septic patients who do not have hypovolemia.
Sepsis affects the heart's response to fluid resuscitation, potentially worsening cardiac function. In patients with sepsis the Frank-Starling (or cardiac function curve) is shifted downwards and to the right. This shift, combined with changes in ventricular compliance, means that large volume fluid resuscitation can result in substantial increases in filling pressures. These increased pressures can lead to pulmonary edema due to high left atrial pressure and also to elevated hepatic and renal venous pressures due to high right atrial pressure, both of which can ultimately contribute to organ dysfunction .
Furthermore, only around 50% of septic shock patients show a significant increase in stroke volume in response to fluid resuscitation and these responders often quickly become non-responsive to fluid challenges [Figure 1]. Hence, the septic heart exhibits a restricted reaction to fluid loading, and the aggressive administration of fluids will yield minimal benefits in terms of hemodynamics. Moreover, it can induce significant detrimental effects downstream .
Two critical studies highlight the potential risks associated with an aggressive fluid resuscitation strategy. The noteworthy 'Fluid Expansion as Supportive Therapy (FEAST)' trial, which involved 3,141 children with severe sepsis, assigned participants to receive fluid resuscitation through 40 mL/kg of 0.9% saline, 4% albumin, or a no-volume resuscitation protocol. This study was halted prematurely because of a 40% increase in mortality rates within the fluid groups. Strikingly, none of the patient subgroups seemed to benefit from the high-volume fluid resuscitation method. It was an unforeseen revelation that the rise in mortality rates in the fluid recipients wasn't due to complications from fluid overload, but instead was tied to a delayed onset of cardiovascular collapse resulting in untreatable shock .
Following the FEAST trial, a randomized controlled trial in Zambia involved 209 adult patients with septic shock. This trial compared a 6-hour sepsis protocol against standard care, with the protocol requiring a 2-liter fluid bolus within the first hour of admission, followed by an extra 2 liters over the ensuing 4 hours. This approach mirrors the Surviving Sepsis Campaign (SSC) guideline closely. Interestingly, despite receiving a markedly larger volume of fluid, the protocol group showed an increased need for vasopressor agents. Furthermore, the standard care group demonstrated significantly improved 28-day survival rates when compared to the protocol group (58% vs. 36%, P=0.02) .
So Restrictive Fluid Strategy May Improve Outcome, Is this True?
Based on the aforementioned physiological factors, observational data, and small trials, there is a strong rationale and growing interest for an alternative approach that uses lower volumes of fluid and earlier initiation of vasopressor agents (a restrictive fluid strategy) in patients with septic shock. Two well-designed randomized control trials were published over the past one year.
The first one (The CLASSIC Trial) in an international, randomized trial that examined patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid and compared the outcomes between a group receiving restricted intravenous fluid therapy (770 patients and one receiving standard intravenous fluid therapy (784 patients). The study included patients whose onset of shock had occurred within 12 hours before screening and the primary outcome was death from any cause within 90 days after randomization .
The restrictive-fluid group received a median of 1798 ml of intravenous fluid in the ICU, while the standard-fluid group received a median of 3811 ml. At 90 days, the mortality rates were similar in both groups: 42.3% in the restrictive-fluid group and 42.1% in the standard-fluid group (P=0.96). The frequency of serious adverse events in the ICU was also similar in both groups: 29.4% in the restrictive-fluid group and 30.8% in the standard-fluid group.
The study concluded that restricting intravenous fluid in adult patients with septic shock in the ICU did not result in fewer deaths at 90 days than standard intravenous fluid therapy.
The CLOVERS trial hypothesized that a restrictive fluid strategy used during the first 24 hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy .
The study was conducted across 60 U.S. centers, comparing a restrictive fluid strategy in 782 patients (prioritizing vasopressors and lower intravenous fluid volumes) with a liberal fluid strategy in 781 patients (prioritizing higher volumes of intravenous fluids before vasopressor use) in septic patients over a 24-hour period. Patients were randomized within 4 hours of meeting the criteria for sepsis-induced hypotension resistant to initial treatment with 1 to 3 liters of intravenous fluid.
As expected, the restrictive fluid group received less intravenous fluid but had earlier and more frequent use of vasopressors, and for a longer duration, than the liberal fluid group. Mortality rates before discharge home by day 90 were similar in both groups, 14.0% in the restrictive fluid group and 14.9% in the liberal fluid group, with a difference of -0.9 percentage points (P=0.61). The number of reported serious adverse events was similar in the two groups.
The study concluded that the restrictive fluid strategy did not result in significantly lower or higher mortality rates by day 90 than the liberal fluid strategy in patients with sepsis-induced hypotension who already received an initial fluid bolus. This initial bolus was between 1-3 liters which mean that those patients received the initial fluid bolus of about 30 mL/kg prior to initiating the restrictive strategy.
But What About the 30 ml per kg Bolus, has it been investigated?
The absence of a consistent correlation between fluid administration and patient outcomes, combined with potential detrimental effects of aggressive fluid loading, suggests that a universal 30 mL/kg fluid bolus may not be ideal for all septic patients. However, as will be discussed below, both the CLASSIC and the CLOVERS trials do not provide a definitive resolution to this matter. There is, therefore, an urgent need for individualized fluid strategies that consider patient-specific characteristics (e.g., age, body weight, comorbidities, type and severity of infection, etc.) and real-time monitoring data.
In the CLASSIC trial, the initial fluid volume given before randomization was at least 1 liter. In the restrictive group, patients received an additional average of 1.2 liters of intravenous fluid within the first 24 hours of their stay in the ICU. Although this amount is equivalent to 30 mL/kg (based on body weight), it was administered gradually over a 24-hour period. The cumulative fluid balance, which considers the total volume of fluid administered minus the total fluid output (including urine output, fluid removed by renal replacement therapy, and other fluid losses like bleeding, ascites, diarrhea, or drain losses) over a 5-day period, was 2,297 mL in the restrictive group compared to 3,187 mL in the standard group. This indicates a difference of only -890 mL between the two groups.
In the CLOVERS trial, the initial fluid volume given before randomization ranged from 1 to 3 liters, which corresponds to approximately 14-42 mL/kg in an average 70 kg person. Additionally, patients in the restrictive group received a median of 1267 mL of fluid by the end of the first day. This means that patients in the restrictive group also received approximately 30 mL/kg within the early stages of the first day.
Based on these findings, it would be difficult to conclude that administering less than 20-30 mL/kg of fluid is appropriate for patients with septic shock.
So, let's repeat the question and see if we get different answers:
While fluid resuscitation remains a critical component in the initial management of septic shock, the "one size fits all" approach based on the 30 mL/kg fluid bolus seems to be under scrutiny. This is due to the lack of high-quality evidence supporting its efficacy or harm. The pathophysiology of sepsis and the associated cardiovascular dysfunction highlight the need for careful, individualized assessment of the risk and benefit in fluid administration. Perhaps the pendulum is swinging away from universal fluid bolus mandates towards a more personalized fluid resuscitation strategy, adjusted to individual patient's needs and responses.
My personal approach is to give the initial fluid bolus based on evidence of hypoperfusion associated with objective measures of fluid responsiveness or to patients with hypovolemia, and any further fluid is based on restrictive fluid strategy and objective measures of responsiveness.
Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D, Divatia J, Du B, Evans L, Ferrer R, Girardis M, Koulenti D, Machado F, Simpson SQ, Tan CC, Wittebole X, Levy M. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med. 2015 Sep;41(9):1620-8. [PubMed]
Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.N Engl J Med 2017;376:2235-44. 10.1056/NEJMoa1703058 [PubMed]
Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database.Intensive Care Med 2017;43:625-32. 10.1007/s00134-016-4675-y [PubMed]
Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest. 1988 May;93(5):903-10. doi: 10.1378/chest.93.5.903. PMID: 3359845. [PubMed]
Hernández G, Ospina-Tascon GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial.JAMA 2019;321:654-64. 10.1001/jama.2019.0071 [PubMed]
Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-95. 10.1056/NEJMoa1101549 [PubMed]
4. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA 2017;318:1233-40. 10.1001/jama.2017.10913 [PubMed]
Meyhoff TS, et al.; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17. PMID: 35709019. [PubMed]
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. doi: 10.1056/NEJMoa2212663. Epub 2023 Jan 21. PMID: 36688507. [PubMed]