Fluid Resuscitation in Severe Sepsis and Septic Shock: Beneficial or Harmful?

7/1/18 8:00 AM

Fluid resuscitation, the administration of intravenous fluids to correct sepsis-induced tissue hypoperfusion, has been used for the past 40 years as part of the treatment of sepsis. The basis for this treatment lies in findings made in the late 1960s. During this time, it was found that vasodilatory shock was a critical component of septic shock, and that increased circulation within the vascular system is associated with septic shock survival. It was also found that sepsis is associated with increased lactate levels and oliguria, both of which were thought to be caused by tissue hypoperfusion. Thus physicians sought to use treatments such as fluid resuscitation to increase cardiac output and circulation.

Interestingly, research indicates that fluid resuscitation may not be effective, leading some to assert that it should no longer be used for sepsis treatment. Those not fully convinced assert that fluid resuscitation may still be useful if administered at the correct time. This has started an ongoing debate in the medical community, the arguments of which we will cover here.

Those against the use of fluid resuscitation argue that current sepsis treatment is based on an incorrect understanding of sepsis pathology, a reliance on inaccurate models, and disorganized research.

Previously, it was believed that increased lactate levels were caused by tissue hypoxia and tissue hypoperfusion. However, it has since been shown that tissue hypoxia is absent in sepsis cases and that there are actually elevated levels of oxygen in skeletal muscle. New findings also suggest that production of lactate may be caused by increased sodium–potassium pump (Na+/K+-ATPase) activity in muscles and that inhibition of Na+/K+-ATPase with Ouabain leads to decreased lactate production. The authors concluded that instead of focusing on hypoxia, physicians should focus on metabolism of lactate production.

In the past it was also believed that oliguria is indicative of renal tissue hypoperfusion and that fluid resuscitation is a necessary treatment. However, when more accurate, hyperdynamic models of sepsis, were used for study, it was found that renal blood flow actually increases. Further, fluid resuscitation in practice, has not led to changes in oliguria or renal functioning.

Delivery-dependent oxygen consumption has also been a predominant theory in the treatment of sepsis. This theory states that if more oxygen is delivered to patients, then there will be greater oxygen consumption and a reduction in tissue hypoperfusion and hypoxia. In contrast, findings suggest that greater oxygen consumption may not reverse hypoxia.

Moreover, sepsis research models are imprecise as they don’t closely match sepsis progression in humans. In humans, sepsis follows a hyperdynamic model whereby cardiac output increases and systemic vascular resistance (SVR) decreases. In animal models, such as murine models, sepsis follows a hypodynamic model, where cardiac output decreases and SVR increases. Studies of hypodynamic models have shown fluid resuscitation to be an effective treatment, but these findings have not been replicated in hyperdynamic models.

Prior to 2001, evidence for use of fluid resuscitation wasn’t based on randomized controlled trials (RCT). In 2001 RCTs on Early Goal-directed therapy (EGDT) were conducted and demonstrated the efficacy of fluid resuscitation. While fluid resuscitation was an important component of the EGDT, it wasn’t the only intervention and thus it can’t be concluded that fluid resuscitation alone can improve sepsis outcomes. Further, in these trials the administration of fluids wasn’t carefully monitored; fluid use was not distributed equally between groups and the timing of fluid resuscitation was not consistent among groups. However, more recent EGDT studies have distributed fluid use equally among groups and have improved the timing of administration. Results of these studies indicate that EGDT didn’t improve mortality rates for septic shock patients, but increased the number of ICU admissions.

It is important to note that research on fluid resuscitation is contradicting. Those in support of fluid resuscitation may cite retrospective patient studies, where early fluid resuscitation was found to be associated with better patient outcomes. They may also cite the FENICE study which tried to ascertain how physicians administer fluids and the triggers that necessitate fluid resuscitation. The study is highly critical of current fluid administration practices stating, “prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs [fluid challenges] is not always taken into account.” In this sense, “...fluid therapy should be regarded like other drug therapy with specific indications and tailored recommendations for timing, type and dose of fluid.” In fact, studies have shown that with more timely administration of fluids, sepsis outcomes can improve. Earlier this year, a study was published that found that earlier administration of fluids led to increased mortality benefits. It was also found that the recommended 3 hour bundle from SCCM wasn’t sufficient and that fluid administration must occur within a shorter window.

Another study, published in 2017 by the SCCM, tracked the administration of fluids, paying special attention to timing. This observational cohort study was conducted over a 1.5 year timeframe and included 11,181 patients from nine hospitals. Patients were separated into three groups based upon timing of first fluid administration after sepsis identification: 30 minutes or less, 31-120 minutes, and greater than 120 minutes. During this study hospitals followed the sepsis resuscitation bundle and focused on fluid initiation, the time at which fluids are first administered. In-hospital mortality was the primary outcome. Mechanical ventilation, ICU admission, hospital LOS, ICU days, and lactate clearance were the secondary outcomes. The results indicated that earlier resuscitation is associated with better outcomes, “Compared with more than 120 minutes, fluid initiation in less than 30 minutes and 31-120 minutes was associated with significantly lower hospital mortality, mechanical ventilation, ICU admission, LOS, and ICU days after controlling for confounders.” The study suggests that the correlation between mortality and time of administration could be indicative of a time threshold for administration, whereby “volume expansion has rapidly diminishing marginal benefit beyond a critical window…” This could also mean that there is no dose-response effect for treatment of sepsis treatment and that sepsis pathology follows an endovascular integrity model.

While the latter may be true, the study didn’t account for conservative versus liberal fluid administration. Thus it can’t definitively be claimed that the dose-response theory doesn’t hold as there is a chance that it could still play a role in fluid administration. Further, the study didn’t compare the administration of fluids to no fluid administration and thus we still don’t know whether fluid resuscitation is beneficial. However, it is clear that earlier fluid administration is associated with better survival than later fluid administration.

The issue of fluid resuscitation is complex as studies conducted on this topic seem to arrive at different conclusions. Some studies show that the biological basis of sepsis pathology is faulty and thus current practices of fluid resuscitation are not warranted. Some studies even show increased mortality rates with fluid administration, while other studies prove that early administration of fluids leads to better outcomes.

It is without doubt that more research needs to be done in this area. New studies should focus of the difference between administering fluids and not administering fluids, while simultaneously focusing on the timing and the difference between conservative and liberal fluid administration strategies. However, until definite conclusions are made and there is a general consensus in the medical community, sepsis treatments should be based on a per case basis where individual variability is taken into account.

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