The next few posts will review those studies which have studied various strategies for fluid resuscitation in patients with sepsis. The first paper is the recent study by Andrews and colleagues performed in Zambia.
OBJECTIVE: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.
DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 212 adults with sepsis (suspected infection plus 2:2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure <90 mm Hg or mean arterial pressure <65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.
INTERVENTIONS: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (2:65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.
MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.
RESULTS: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).
CONCLUSIONS AND RELEVANCE: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.
COMMENTARY:
This study clearly demonstrates that an aggressive approach to fluid administration, mirroring the recommendations of the Surviving Sepsis Campaign, increases the risk of death in patients with SEPTIC SHOCK. The protocol patients received a 2L bolus within 1 hour of enrollment, followed by an additional 2 liters over the subsequent 4 hours. This strategy is remarkably similar to those of the Surviving Sepsis Campaign, namely “1) We recommend that, in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg (2L in 70kg patient) of IV crystalloid fluid be given within the first 3 hour. 2) We further recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status.”
Septic shock is a consequence of profound vasodilatation. Fluids (in themselves) cannot reverse vasodilatory shock, and indeed in the setting of sepsis fluid boluses may cause further vasodilatation. Attempts at restoring blood pressure in septic shock with aggressive fluid administration reflects a complete lack of understanding of human physiology and is reckless behavior. Furthermore, the hemodynamic benefit of those who actually respond to fluids (only 50% of patients) is short lived, being about 30 minutes at best and 10 minutes at worst with a minimal increase in blood pressure and no evidence that it increases urine output. The net effect is the rapid transfer of fluid from the IV bag into the tissues.
The religious followers of the Surviving Sepsis Campaign Guidelines (2004, 2008, 20012 and 2016) will argue that the patients in the current study are not typical of sepsis patients around the world. This is not correct. The pathophysiology of sepsis is similar whether the patient is in Africa or in Europe… vasodilatory shock is vasodilatory shock and this condition is not a fluid responsive condition. Furthermore, they may argue that the Surviving Sepsis Guidelines are not recommended for patients in resource-poor settings. This is however again completely wrong. Dr JL Vincent has publically stated that “these guidelines are not for you (meaning me), these guidelines are not for me (JLV), No My Friends, they are for the non-expert clinician (in resource poor settings). Dr Machado (the co-author of the accompanying editorial) has vigorously endorsed the use of the Surviving Sepsis Campaign in resource limited settings. However, the evidence is clear: a protocol of aggressive fluid administration kills septic patients by “salt water drowning”.
Paul Marik
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Like FEAST, it appears that this study doesn’t shed light on whether the mortality difference was due to boluses or total fluid balance. Perhaps boluses are more to blame as at 72h there was no significant difference–the protocol group had a cumulative 5L infused compared to 4L in the usual care group (p = 0.33). I would love to know what the cumulative fluid balance was at discharge/death, and what the patients died of. In the supplementary appendix only 2 cases of iatrogenic pulm edema were listed.
Like FEAST I’m sure there will be alot of denial of generalizability. I recall from SMACC Gold Coast, whilst in audience,, Dr Myburg telling us the only fluid needed in sepsis was the mothers milk of Adrenalin
Agree 100%. Those who don’t like the results of this study will nit-pick about generalizability. They just cant face the truth.
Thanks for your input Dr. Marik. I am curious what your approach is to the usual call from the bedside nurse who reports that the patient’s urine output has fallen off. You give them a fluid bolus and their urine output does pick up then falls off, only to get additional requests for further fluids. For these patients, do you just ignore oliguria provided the other markers of perfusion remain adequate and vasopressor requirements are stable?
Kevin: This is a really good question. Firstly, ones approach to resuscitation must be individualized according to the major diagnosis (sepsis, DKA, GI bleed etc), the patients age (SBP goes up with aging, urine output goes down), baseline BP (Hx HTN, size of patient), comorbidities, etc. It is ridiculous to propose that the same intervention (30mls/kg) would be appropriate for all patients. Secondly, urine output is a poor marker of organ perfusion in sepsis; UO falls despite normal renal blood flow; likely due to ATN, microvascular dysfunction, etc. The FACCT study clearly demonstrated that UO is poorly responsive to fluid boluses. Secondly U/O is only one marker of organ perfusion; check MAP, skin temp (esp around knee), mentation, etc. Thirdly, when giving a fluid bolus, never give more than a 500cc bolus; then closely monitor the response. If it does not achieve the intended goal STOP. Fourthly, volume overload (high CVP) paradoxically leads to decreased urine output (due to renal congestion) and that giving fluid will worsen renal function ( a diuretic may help). And lastly ask yourself where you want the fluid to go- fluids are appropriate in patients with true dehydration and will resuscitate the intravascular as well… Read more »
Thanks for the post Dr. Marik. You mention that U/O is a poor marker of perfusion and mention the need to look at other markers of perfusion. I totally agree. If U/O is normal, it’s a good sign (adequate renal perfusion) but low UOP in septic shock is nonspecific as you mention.
However, the other markers that you mention such as mental status, skin temperature and MAP in my opinion are also poor and nonspecific markers of perfusion. Mental status may be altered from septic encephalopathy despite adequate cerebral perfusion. Skin temperature is not sensitive or specific in my experience for cardiac output/perfusion. And MAP may be elevated from endogenous or vasopressor induced vasoconstriction but doesn’t necessarily correlate with organ perfusion.
Cyrus: I agree. Assessing organ perfusion is a difficult problem.. requires close bed-side evaluation; We currently do not have very good “tools” to measure the adequacy of organ perfusion. . Good urine output is a reassuring sign but oliguria does not necessarily imply poor renal perfusion. .
Maybe at the end of the day, we all need to be clinicians when we tailor the treatment to the individual patient? Maybe the notion to give 3 liters of IV fluids should be replaced by the notion of reassessment your patients continuously?
Could not agree more. Each patient is different and treatment must be individualized.
all very interesting Paul, (and commentators). With Scotts most recent pod in mind, i’ll try to not waste your time. But the more i study “sepsis”, the less firm the ground beneath me becomes.
We just had our monthly ED dept meeting a few hours ago, and “sepsis compliance ” came up.
It was stated that we had ” (x) fall-outs” from jan to june; but the details were less clear; i.e.,” was reflex lactic done, did the patient get 30ml/kg NS per protocol.”….. but what is troubling is attempting to satisfy CMS, and institutional/ hospital-system-wide guidelines/requirements, and also providing the most knowledgable, correct, best patient care, and what is concerning is that it has become increasingly clear that all this is very unclear. and that some, like you, propose, no “shout”, that the two are not only not always aligned, but rather are in opposition.
what i find interesting is the vagueness, the varying, shifting, and sometimes opposing concepts in sepsis, including, it seems , basic definitions.
i still need to get Vit C, and thiamine in my armamentarium.
thank you, Paul.
tom.
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Dr. Marik, I really enjoy and appreciate your Status Quo Destabilizer role.
But what about those preload responsive patients? Some of them do need fluids. They do respond well.
I know, they are 50% at most. But they do respond well and escape from vasopressors and intoropics. And, many times, it is not short lived.
The question is: how much fuid? Maybe 30ml/kg is too much. One size does not fit all.
Maybe we should give them 500ml and routinely reassess them afterwards. No CVP measurement, please! I know very well the tale of the seven mares. We have more effective tools now, and depending on the patient´s context, one can pick up one tool over another to follow through.
As for the U/O, maybe it is not a goal in itself, it is only a marker of the illness severity. We should not intervene stubbornly if the kidney does not respond to fluids right off the bat. That situation could be a humbling reminder of the limits on our ability to control the physiologic response to disease. Primun non nocere.
Fluids are always necessary, let alone in sepsis!
The big issue is: When enough is enough?
Luciano: Thanks for your thoughtful comments, I agree. I have never said “don’t give fluids”. My position has been that fluids are like drugs and should be given with some thought and caution, as the desired effect may not be achieved. No two patients are the same, that’s why we we have doctors and nurses at the bedside; to evaluate patients’ and monitor their response to an intervention…. else we could have robots managing our patients. Some patients will respond to fluids (although this may be temporary) while many will not; furthermore the amount of fluid “required” is not fixed. It therefore seems absurd to have a single protocol which mandates giving 30ml/kg to all patients. The management of fluids should be similar to pressors; we don’t give a fixed dose of norepineprhine to patients in septic shock; rather we titrate the dose according to the effect (MAP).. and if escalating doses don’t increase the MAP we consider other therapeutic options.
Furthermore, there can no longer be any doubt that patients with a very large fluid balance have an increased risk of organ failure and death.
Dr Marik: Thank you so much for answering.
I was not grasping the whole point and now your explanation made it completely clear for me. I really thought you meant “don´t give fluids”.
I totally agree with your idea and your alert. The “30ml/kg to all septic patients” recommendation should be reevaluated.
Thank you, Dr Marik
Luciano
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