Resuscitation in Sepsis: How Much is Too Much?

Authors: Adrianna Levesque, MD (Senior EM Resident at SAUSHEC, US Army) and Brit Long (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)

**THIS IS THE SECOND IN A 2-PART SERIES**

For a quick review of which fluid to choose, please see Part I here:

Fluid Choice in Sepsis: Does it matter?

There are many choices in the type of fluid used to resuscitate a septic patient, and your choice of fluid does matter. In treating septic patients, how do we determine if we have provided an adequate amount of fluids? What treatments are appropriate and at what point is testing too invasive?

In 2002, a new standard of care was established when the Surviving Sepsis Campaign (SSC) highlighted the importance of recognizing sepsis and initiating treatment early. Once we find that a patient meets Systemic Inflammatory Response Syndrome (SIRS) criteria with a source of infection, rapid and appropriate treatment including resuscitation is a must. Early fluid resuscitation is necessary for septic patients, but there is large variance on the aggressiveness of fluid resuscitation. There is disagreement amongst the experts on the total amount of fluids that should be administered and the end points for resuscitation. We must ask ourselves, at what point does our aggressive resuscitation actually start to harm our patients?

Rivers et al. changed the entire perspective of treating septic patients and driving the Surviving Sepsis Campaign (SSC) with “Early Goal-Directed Therapy” (EGDT). The mainstay of EGDT is aggressive and early initiation of antibiotics, while optimizing the amount of oxygenation to tissue with IV fluids, transfusion of blood, and treatment with vasoactive medications during the first 6 “golden” hours. This single-center trial of 263 patients required close monitoring of the patients’ vital signs, central venous pressure, central venous oxygen saturation, urine output, and serum lactates. The results were staggering and indicated that patients receiving EGDT had higher central venous oxygenation, lower lactate concentrations, lower base deficits, higher pHs, and significantly lower in-hospital mortality (30.5% compared to the standard treatment group 46.5%, p=0.009).¹

However, there are several arguments regarding the invasiveness of the Rivers trial… Is there really a need to obtain central venous access on all of our septic patients? Are blood transfusions necessary to maintain a certain hemoglobin level to provide patients with the adequate amount of oxygenation to their tissues to prevent hypoperfusion and/or improve outcomes in septic shock?

First, it would seem that blood transfusions seem to be one of the more invasive treatments in EGDT. Is it really necessary to have a hemoglobin greater than 10g/dL or more? The TRISS Trial Group focused specifically on the risks and benefits associated with transfusion of red blood cells (pRBCs) in patients with septic shock. This multicenter study with a total of 998 patients randomized to lower (≤7g/dL) and higher (≤9g/dL) threshold transfusion groups had similar 90-day mortality, rates of life support, and rates of ischemic events. The results of this trial indicated that a Hgb level of 7g/dL should be the transfusion threshold for patients with sepsis and/or septic shock.²

In the past 18 months, three new trials have been published in the New England Journal of Medicine regarding goal directed treatment in early septic shock. The ProCESS Investigators conducted a multicenter prospective randomized trial in the United States with 1341 patients placed into one of three treatment groups: traditional EGDT; protocol-based standard therapy not requiring a central venous catheter placement, inotropes or blood transfusions; or the standard therapy group. This study showed that the monitoring of central hemodynamics and oxygen saturation monitoring did not result in better patient outcomes than standard patient care. Further, this study showed no significant benefit in protocol-based resuscitation as compared to the clinical judgment of the treating provider.³

The ARISE Investigators conducted a multicenter prospective randomized trial in Australia and New Zealand with 1600 patients randomized to EGDT versus usual care. The results indicated that patients receiving EGDT received a larger mean volume of fluid resuscitation in the first 6 hours, were more likely to receive red blood cell transfusions, and were more likely to be treated with dobutamine. Despite these differences in treatments, there was no significant difference for in-hospital mortality, duration of ventilator support, duration of renal replacement therapy, length of hospital stay, or 90-day mortality.⁴

The ProMISe Trial Investigators also conducted a multicenter prospective trial randomizing patients to EGDT versus standard care. This study was conducted in England with a total of 1260 patients enrolled. The results of this study indicated patients in the EGDT treatment arm received more intravenous fluids, vasoactive drugs, and red blood cell transfusions. These patients as a group received more days of cardiovascular support and spent more time in the ICU. Also, there were no differences in the rates of serious adverse events or 90-day mortality.⁵

All three of these trials failed to show the benefit of strict EGDT. In fact, the results of the ProMISe Trial indicate that treatment with EGDT may have been more harmful to patients than those who received standard care given their results.⁵ It seems as though implementing protocolized measurement of central hemodynamics and requiring treatments with inotropes and transfusions is actually more harmful to our patients, as these interventions do not improve patients’ outcomes.⁶ Rather than an algorithmic approach to treatment of patients in early septic shock, these studies confirmed the most important aspects in management of sepsis are simply early recognition, early treatment with antibiotics, and adequate volume resuscitation.

The SSC 3 hour bundle remains the same:

1. Obtain a lactate level
2. Obtain blood cultures prior to giving antibiotics
3. Administer broad-spectrum antibiotics
4. Administer 30cc/kg fluid bolus for serum lactate ≥ 4mmol/L or hypotension

However, given the findings of the ProCESS, ARISE, and PROMISE trials, the 6-hour SSC bundle recommendations have changed. Vasopressors should still be started for patients with a mean arterial pressure (MAP) less than 65 mmHg. The measurement of clinical response is no longer limited to obtaining a central venous pressure >8mm Hg and a central venous oxygenation (ScVO2) of >70%. The recommendations now allow for the ability of clinical exam and cardiovascular ultrasound rather than requiring the need for a central line in all patients with septic shock.⁷

WHAT GOALS SHOULD WE BE FOCUSING ON TO END OUR FLUID RESUSCITATION IN SEPTIC PATIENTS?

Jones et al. studied lactate clearance as a goal for end of resuscitation. The results of this study demonstrated that patients with early septic shock treated to normalization of their central venous and mean arterial pressure did not benefit from additional management to normalize lactate.⁸ A review of literature also indicates that an elevated serum lactate is associated with a stress response and is not associated with tissue hypoperfusion. While a persistently elevated serum lactate during resuscitation is associated with poor prognosis, a decrease in serum lactate does not guarantee a patient’s survival or improvement.⁹ The current evidence suggests that the use of lactate clearance is questionable as an end resuscitation goal.  Elevated lactate in septic shock may not be due to anaerobic metabolism with poor perfusion and low oxygen delivery to tissues, but rather stimulation of beta-2 adrenergic receptors from endogenous epinephrine. However, lactate elevation is associated with worse prognosis. At the same time, lactate does work for identifying occult shock. If lactate is used as a marker for endogenous catecholamine release, rather than poor perfusion, lactate will be elevated in patients maintaining blood pressure due to catecholamine surge. These patients are often on the cusp of rapid decompensation, requiring further care and resuscitation.¹⁰

Based on all of the studies previously cited, it appears that there is not a clear end point to resuscitation in sepsis. There are numerous parameters that can be assessed, including but not limited to heart rate, MAP, ScVO2, hemoglobin, central venous pressure, urine output, and serum lactate. No study has indicated that one particular parameter is more useful than another to specifically guide the physician’s continued resuscitation in early sepsis after administration of antibiotics and an initial fluid bolus. The most recent studies demonstrate that ScVO2 monitoring and aggressive treatment of anemia does not change patient outcomes.^3-5 Specific care should be taken to treat a MAP less than 65 mmHg with vasopressors.⁷ We should not focus our treatment to target a specific parameter. Rather, we should focus our continued treatment of the septic patient based on a combination of repeat physical examination, monitoring of vital signs, and hemodynamics. The whole clinical picture must be taken into account.

IN REGARDS TO GIVING IV FLUIDS FOR RESUSCITATION, HOW MUCH IS TOO MUCH, AND IS THERE SUCH A THING AS “TOO MUCH?”

This is often a vital question to consider in the ED management of these patients. Smith and Perner conducted a study of 164 patients in septic shock and concluded that patients with shock for greater than 72 hours had reduced mortality with higher fluid volumes.¹¹ This recommendation for higher fluid volumes in resuscitation of a septic patient should be taken into context given that these patients met criteria for shock for at least 72 hours (evidence of end organ failure and vasopressor requirement to maintain systolic BP > 90). The majority of studies published actually indicate that treatment with higher fluid volumes is harmful.¹² Of note, the patients who were in the higher volume treatment arm of the Smith and Perner study received a median of 7.5 liters at 72 hours.¹¹ This is a relatively lower amount of fluid volume as compared to the median fluid resuscitation fluids of 20.5 liters at 72 hours in the VASST study and a mean of 16 liters in the study conducted by Jones et al.^8,12-13

Alsous et al. evaluated the effect of negative fluid balance in 36 patients with septic shock admitted to the ICU. The researchers found that for patients with septic shock, a negative fluid balance on any of the first three days after admission was associated with better survival when compared to patients with a positive fluid balance.¹⁴ The implication being that patients aggressively hydrated to the point of volume overload did worse than patients who were relatively hypovolemic. The SOAP study, a multicenter, observational study conducted in Europe with a total of 3,147 patients found that similar to an increase in the patients’ age, a positive fluid balance was one of the strongest prognostic factors of mortality. This study demonstrated that while a positive fluid balance is likely a marker of the severity of sepsis, it is also an independent predictor of poor outcome.¹⁵

Boyd et al. conducted a retrospective study of the 778 patients in septic shock enrolled in the VASST study and found that a greater positive fluid balance at 12 hours and 72 hours was associated with an increased risk of mortality, and optimal survival occurred with a positive fluid balance of approximately 3 liters at 12 hours.¹³  The included patients met criteria for septic shock and were receiving at least 5 mcg/min of norepinephrine. This study suggests a cautious fluid resuscitation strategy should be followed.

In the first six hours of resuscitation, fluids should be used urgently and liberally, but at the same time adequate reassessment of the septic patient should occur to monitor for fluid overload and potential harm. A patient’s fluid status should be readdressed prior to administration of subsequent fluid boluses, as we have many studies indicating that we may be causing harm if we are too aggressive, specifically in ICU period of the patient’s care.^13-16

HOW DO WE DETERMINE AN ACCURATE FLUID ASSESSMENT OF THE SEPTIC PATIENT?

The goal of fluid resuscitation in the patient with severe sepsis and early septic shock is to help facilitate the patient’s cardiac output, therefore increasing the total amount of tissue perfusion. There are several aspects that should be considered when assessing a patient’s fluid status and/or fluid responsiveness, prior to treating with boluses. If excessively treated with fluids, patients can suffer from acute lung injury, heart failure, abdominal compartment syndrome, cerebral edema, and higher risk of mortality.¹⁶ Physical exam findings including jugular venous pressure, edema, and urine output often don’t correlate with a patient’s ability to respond to a fluid bolus when in septic shock. There are several dynamic indices including the IVC distensibility index, pulse pressure variation, and stroke volume variation; however, these indices require a mechanically ventilated patient and calculation before every fluid bolus. There are several commercial devices available for hemodynamic monitoring, but many of these are also labor intensive and impractical for use in a busy emergency department.¹⁷ It seems as though the use of CVP, IVC measurement, and the passive leg raise are the most feasible tools available to assess a patient’s fluid status in the Emergency Department.

HOW MUCH DOES CVP ACTUALLY REFLECT FLUID STATUS?

Marik et al. conducted a systematic review of 24 studies to determine the relationship between CVP and blood volume, as well as to determine the utility of CVP measurement as a measurement for fluid status. The review suggested that there is poor correlation between the CVP and measured blood volume, and the change in CVP and change in stroke volume do not correlate. These findings indicate that CVP should not be used to make clinical decisions with regards to fluid management.¹⁸ However, Boyd et al. found that CVP does correlate with fluid balance in the first 12 hours of resuscitation in 778 patients studied in septic shock, but the utility of CVP falls drastically after 12 hours of resuscitation.¹³ Based on the literature, it is difficult to determine whether CVP can adequately assess a patient’s fluid status, but it seems possible that Marik’s review and finding that CVP measurements are unreliable may be more specific to ICU patients that have already received initial resuscitation.

Respiratory variation in IVC measurements can be quickly and easily determined in the Emergency Department using bedside ultrasound.  Muller et al. studied 40 spontaneously breathing patients in shock and found that a change of greater than 40% in IVC diameter was associated with fluid responsiveness while a change in IVC less than 40% does not exclude fluid responsiveness.¹⁹ Lanspa et al. conducted a prospective observational pilot study on spontaneously breathing patients admitted to the ICU for septic shock after initial resuscitation was completed and found that IVC index is a good predictor of fluid responsiveness with 9 fluid nonresponders having a median 11% change in IVC measurement with respiration and 5 fluid responders having a median 52% change in IVC measurement.²⁰ While measuring the respiratory variations in IVC seems simplistic, it should not be used as an Emergency Medicine physician’s sole basis for determining a patient’s fluid responsiveness.^19,21 Further studies must be conducted to validate the IVC change in measurement as an accurate assessment of fluid responsiveness during initial resuscitation of patients in septic shock, as the majority of these studies consist of specific, small patient cohorts already admitted to the ICU.

CONCLUSIONS

Where does this leave the emergency physician? At the end of the day providing fluid is vital to adequately resuscitating the patient with sepsis. However, treatment with excessive IV fluids has been shown to be harmful. A combination of clinical end points such as mental status, improved vital signs, urine output, distal perfusion (capillary refill), and ultrasound measurement of IVC should all be used to monitor a septic patient after initial fluid bolus and antibiotic administration. Further studies must be completed to establish if any dynamic parameter can be easily and feasibly utilized in the Emergency Department to determine fluid responsiveness and end points for resuscitation.

REFERENCES/FURTHER READING

1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377
2. Holst L, Haase N, Wetterslev J et al. Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. New England Journal of Medicine. 2014;371(15):1381-1391.
3. A Randomized Trial of Protocol-Based Care for Early Septic Shock. New England Journal of Medicine. 2014;370(18):1683-1693.
4. Goal-Directed Resuscitation for Patients with Early Septic Shock. New England Journal of Medicine. 2014;371(16):1496-1506.
5. Mouncey P, Osborn T, Power G et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. New England Journal of Medicine. 2015;372(14):1301-1311.
6. Marik P. The demise of early goal-directed therapy for severe sepsis and septic shock. Acta Anaesthesiol Scand. 2015;59(5):561-567.
7. Surviving Sepsis Campaign. Updated Bundles in Response to New Evidence. 2015. Available at: http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.pdf.
8. Jones A, Shapiro N, 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):739-46.
9. Marik P, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care. 2013;1(1).
10. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Critical Care. 2014;18(5):503.
11. Smith S, Perner A. Higher vs. lower fluid volume for septic shock: clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Critical Care. 2012;16(3):R76.
12. Prowle J. Fluid resuscitation in septic shock: too much, too little or just right? Critical Care. 2012;16(3):436.
13. Boyd J, Forbes J, Nakada T, Walley K, Russell J. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Critical Care Medicine. 2011;39(2):259-265.
14. Alsous F, Khamiees M, DeGirolamo A, et al. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest 2000; 117:1749–1754.
15. Vincent JL, Sakr Y, Sprung CL, et al: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34:344–353.
16. Durairaj L. Fluid Therapy in Resuscitated Sepsis. Chest. 2008;133(1):252.
17. Scott M, Mallemat H. Assessing Volume Status. Emergency Medicine Clinics of North America. 2014;32(4):811-822.
18. Marik P. Does Central Venous Pressure Predict Fluid Responsiveness? Chest. 2008;134(1):172.
19. Muller L, Bobbia X, Toumi M et al. Respiratory variations of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use. Critical Care. 2012;16(5):R188.
20. Lanspa M, Grissom C, Hirshberg E, Jones J, Brown S. Applying Dynamic Parameters to Predict Hemodynamic Response to Volume Expansion in Spontaneously Breathing Patients With Septic Shock. Shock. 2013;39(2):155-160.
21. Bodson L, Vieillard-Baron A. Respiratory variation in inferior vena cava diameter: surrogate of central venous pressure or parameter of fluid responsiveness? Let the physiology reply. Critical Care. 2012;16(6):181.