Critical Care Mailbag: Fluid Resuscitation and Responsiveness

This approach makes absolute sense; however, in our shop (and I suspect in most others), we are held to the CMC standards of sepsis management, i.e. 30/ml/kg fluid bolus.

I chuckled at this conversation. 35 years ago we used to say that the hypotension in septic shock was due to pathologic vasodilation. That they were not necessarily fluid depleted but rather there was maldistribution of fluid (distributive shock). Therefore limit fluids an earlier use of vasopressors. Actually, giving large amounts of crystalloid to a patient who has systemic arterial dilation is not dissimilar from giving large amounts of crystalloid to a patient who is bleeding. In the latter does no good until you stop the bleeding. How much good will fluid do until you clamp down the vasculature? We never treated anaphylactic shock with massive amounts of fluid. We give early vasopressors. Two forms of inflammatory mediated distributive shock..curious...

This approach makes a lot of sense, but is there any evidence (even if low quality) that this approach is any better or associated with better outcomes than current CMC sepsis core measures? If so are you able to provide the resources/papers? Thank you.

Counterpoint, you'll have some septic patients develop a dynamic LVOT obstruction when you start pressors and those are a good example of patients who may benefit from additional fluid beyond the 30 cc/kg bolus.

Thanks so much Anand and Scott for this excellent segment. Loved the historical perspective, explanation of physiology and practical approach. Stepping back from the trees for the forest, I believe that whether you give 1 or 2 or 3L of crystalloid is likely less important than getting that patient in septic shock to the ICU fast. It is in the ICU where they probably have the capability to measure cardiac output properly if need be (rather than us doing multiple serial guesses based on MAP, IVC plumpness, global EF estimate, IF we have time at say a single coverage ED on an overnight shift with 20 people in the waiting room and other sick patients), 2 to 1 nursing, an intensivist who knows more than I do and probably has more experience with these patients etc. I think it should be emphasized that an early call to your intensivist to advocate getting your patient to the ICU ASAP is paramount. If anyone knows about any literature on this to back me up please share (and if no literature, then someone please study this). While we should know how to take care of these patients if/when there is a delay to getting to the ICU for sure, we should all be hyperaware of the location that these patients will likely receive the best care, and have frank discussions with the admin folks to make transfer from ED to ICU a priority. We're not all as smart and savvy as you two ;)

Hi Anton, there is plenty of literature supporting your feelings on this. In short, yes. Patient outcomes, in general, are better when time to ICU admission is decreased.

I was actually coming on to the message board to respond to Stephen. I have been in the midst of a review on fluid resuscitation in early sepsis for several months and have to say, some of the sentiments portrayed regarding early fluids seems odd to me. I have an overly long response to this but the short of it is that there seems to be this growing belief that early fluids are harmful. Not completely (seems that most agree that one liter or so is OK) but to the point where many are now repeating some of the same talking points with this underlying tone that giving a prespecified 30 mL/kg borders on craziness. Here is my response (I am sending this to the EMRAP mailbox and EMCRIT (Scott himself)):

The November 2021 EM:RAP had a segment by Scott Weingart and Anand (the Swami) Swaminathan on Fluid Resuscitation and Responsiveness discussing current strategies in early fluid resuscitation for sepsis. Mostly Scott talks about the need for judicious administration of fluids using various techniques that would predict a favorable response to fluid administration (or as he and others may prefer, evidence for fluid tolerance). This discussion was presented in the vein (pun intended) of a trending opinion insinuating that patients may be undergoing harm at the hands of providers administering large volumes of fluid in the resuscitation of septic patients. Therefore, there has been a push for an earlier initiation of vasopressors combined with a more restrictive fluids administration. At least one trial (CLOVERS) is looking at this question prospectively. In response, Stephen B. asks, “This approach makes a lot of sense, but is there any evidence (even if low quality) that this approach is any better or associated with better outcomes than current CMC sepsis core measures? If so are you able to provide the resources/papers?”

First, a noncomprehensive summary of literature specific to Stephen’s question would suggest that this is at least somewhat feasible. ANDROMEDA SHOCK trial compared peripheral perfusion markers (cap refill) compared to a more standard measurement (lactate clearance) and showed those undergoing responsiveness assessment had some improvement in 72-hour organ dysfunction scores while receiving ~400 mL less fluids in the first 8 hours. Further, the nonresponders receiving less fluids, did not have any measurable difference in outcome suggesting judicious fluids is at least safe. However, it has to be noted, both groups essentially received 30 mL/kg initially and there was minimal difference in fluid balance received between the two groups at 72 hours. Also, that 70% of the cohort was found to be fluid responsive initially.1
A similar story is noted with the FRESH trial using passive leg raise and had a lower fluid balance at 72 hours of 1.37 L. But again, both groups essentially received 30 mL/kg prior to enrollment. Also, this trial showed a high level of volume responders early on that drastically declines after 2 hours which may suggest that an early window for volume resuscitation may exist.2

The CLASSIC trial was ICU based and showed that limiting fluids based on this assessment is feasible but may be challenging as ~1/3 within this trial had protocol deviations.3

I don’t take issue with the idea that fluid responsiveness measurements are useful in the management of sepsis resuscitation. Exactly as Scott says, even just a gestalt of what the heart, IVC, and lungs look like can be critical in the management of a patient in shock, sepsis or otherwise. I also appreciate some of the more theoretical constructs that may argue against fluids, including glycocalyx degradation leading to third-spacing, short-lived, transient cardiac output benefits with boluses, and cardiac depression to may contribute to issues of congestive heart failure.

The issue I have is the voracity by which ACEP, other EM thought leaders, and Scott seem to dismiss the rather longstanding Surviving Sepsis guideline regarding fluids (30 mL/kg in 3 hours). The dissenting evidence presented in ACEP’s policy statement largely come from ICU-based, downstream studies observing that positive fluid balances between 24 hours and 8 days are associated with mortality risk.4–6 These same studies seem to get parroted out by some of the EM thought leaders as evidence for the harms we are doing patients with fluids. We even get subjected to eye-popping, bombastic claims by the same guy who said, “my intention was never to discover the cure for sepsis…it just kind of happened by mistake” in reference to HAT therapy, who calls this resuscitation the “great 30 mL/kg hoax” and “iatrogenic salt-water drowning.”7,8(p30) Unfortunately, outlandish statements seem to suck up most of our attention and too many seemed to have gotten behind this idea with not great basis.

A few African-based studies did show potential dangers with prespecified fluid volumes early in sepsis resuscitation but took place in resource-limited areas with patient cohorts comprised of high rates of malaria, anemia, tuberculosis, and HIV/AIDS.9,10 Many of these conditions are associated with low-oncotic pressure states likely predisposing patients to fluid-related complications and unlikely to represent cohorts from more developed nations. Further, there is increasing evidence that underlying anemia may alter the response to early fluids.11,12

So on to the low-quality evidence. I have been in the midst of systematic review on this topic and below is a list of 30 studies looking at early fluid resuscitation mostly 20-30 mL/kg three to 6 hours after sepsis onset. Twenty-one show survival benefit,13–32 ,33 ten with no mortality impact,34–43 and 1 showing harm.44 Again, these are all observational and considered “low-quality evidence” but better than no evidence. Certainly, many of these studies have points that could be heavily scrutinized but the signal seems to be pointing in one particular direction. Surely it would be hard to make the argument that initial 30 mL/kg could be considered harmful. It also seems to be safe to give these fluids to potentially volume-sensitive patients, including ESRD, CHF, liver disease, obesity, and those that subsequently develop acute lung injury (in some cases show survival benefit).16,19,23,24,27,35,44

I feel like it would be better to point out that many patients with sepsis-induced hypoperfusion may benefit from receiving 30 mL/kg of fluids. Or we can take the flipside as we did with fluid responsiveness and fluid tolerance…studies suggest that not reaching 30 mL/kg may kill your patient. Further, we in the emergency departments seem to do a poor job of giving this mandated amount of fluid. Yes, we have ways to help prove that your patient may benefit from these fluids so perhaps pick up an ultrasound and quell your anxieties around giving the fluids your patient may require.

I am very open to the idea that I may be wrong in my opinion that the 30 mL/kg guideline is reasonable and probably good one. I understand that observational evidence is on the lower rungs of supporting evidence. I also have a lot of respect for Scott Weingart’s opinions on most matters and have no doubt he would run circles around me on most topics. I feel like there is an information gap on this topic and I am merely attempting to fill that void. We can have our opinions on fluids but we need to stay balanced when presenting the underlying data behind it.

1. Hernández G, Ospina-Tascón 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(7):654-664. doi:10.1001/jama.2019.0071
2. Douglas IS, Alapat PM, Corl KA, et al. Fluid Response Evaluation in Sepsis Hypotension and Shock: a Randomized Clinical Trial. Chest. Published online 2020. doi:10.1016/j.chest.2020.04.025
3. Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42(11):1695-1705. doi:10.1007/s00134-016-4500-7
4. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43(5):625-632. doi:10.1007/s00134-016-4675-y
5. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251. doi:10.1186/s13054-015-0970-1
6. Sakr Y, Rubatto Birri PN, Kotfis K, et al. Higher Fluid Balance Increases the Risk of Death from Sepsis: Results from a Large International Audit∗. Critical Care Medicine. 2017;45(3):386-394. doi:10.1097/CCM.0000000000002189
7. Marik PE, Malbrain M. The SEP-1 quality mandate may be harmful: How to drown a patient with 30 mL per kg fluid! Anaesthesiol Intensive Ther. 2017;49(5):323-328. doi:10.5603/AIT.a2017.0056
8. 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
9. 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(13):1233-1240. doi:10.1001/jama.2017.10913
10. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495. doi:10.1056/NEJMoa1101549
11. Tan SMY, Zhang Y, Chen Y, See KC, Feng M. Association of fluid balance with mortality in sepsis is modified by admission hemoglobin levels: A large database study. PLoS One. 2021;16(6):e0252629. doi:10.1371/journal.pone.0252629
12. Ma P, Liu J, Shen F, et al. Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen. Crit Care. 2021;25(1):243. doi:10.1186/s13054-021-03682-7
13. Leisman D, Wie B, Doerfler M, et al. Association of Fluid Resuscitation Initiation Within 30 Minutes of Severe Sepsis and Septic Shock Recognition With Reduced Mortality and Length of Stay. Ann Emerg Med. 2016;68(3):298-311. doi:10.1016/j.annemergmed.2016.02.044
14. Leisman DE, Goldman C, Doerfler ME, et al. Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort. Crit Care Med. 2017;45(10):1596-1606. doi:10.1097/CCM.0000000000002574
15. Leisman DE, Doerfler ME, Schneider SM, Masick KD, D’Amore JA, D’Angelo JK. Predictors, Prevalence, and Outcomes of Early Crystalloid Responsiveness Among Initially Hypotensive Patients With Sepsis and Septic Shock. Crit Care Med. 2018;46(2):189-198. doi:10.1097/CCM.0000000000002834
16. Kuttab HI, Lykins JD, Hughes MD, et al. Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock. Crit Care Med. 2019;47(11):1582-1590. doi:10.1097/CCM.0000000000003960
17. Hu B, Chen JCY, Dong Y, et al. Effect of initial infusion rates of fluid resuscitation on outcomes in patients with septic shock: a historical cohort study. Crit Care. 2020;24(1):137. doi:10.1186/s13054-020-2819-5
18. Pruinelli L, Westra BL, Yadav P, et al. Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock. Crit Care Med. 2018;46(4):500-505. doi:10.1097/ccm.0000000000002949
19. Rajdev K, Leifer L, Sandhu G, et al. Fluid resuscitation in patients with end-stage renal disease on hemodialysis presenting with severe sepsis or septic shock: A case control study. J Crit Care. 2020;55:157-162. doi:10.1016/j.jcrc.2019.10.008
20. Jouffroy R, Saade A, Muret A, et al. Fluid resuscitation in pre-hospital management of septic shock. The American journal of emergency medicine. 2018;36(10):1754-1758.
21. Liu V, Morehouse JW, Soule J, Whippy A, Escobar GJ. Fluid volume, lactate values, and mortality in sepsis patients with intermediate lactate values. Ann Am Thorac Soc. 2013;10(5):466-473. doi:10.1513/AnnalsATS.201304-099OC
22. Lee SJ, Ramar K, Park JG, Gajic O, Li G, Kashyap R. Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study. Chest. 2014;146(4):908-915. doi:10.1378/chest.13-2702
23. Taenzer AH, Patel SJ, Allen TL, et al. Improvement in Mortality With Early Fluid Bolus in Sepsis Patients With a History of Congestive Heart Failure. Mayo Clin Proc Innov Qual Outcomes. 2020;4(5):537-541. doi:10.1016/j.mayocpiqo.2020.05.008
24. Liu VX, Morehouse JW, Marelich GP, et al. Multicenter Implementation of a Treatment Bundle for Patients with Sepsis and Intermediate Lactate Values. Am J Respir Crit Care Med. 2016;193(11):1264-1270. doi:10.1164/rccm.201507-1489OC
25. Waechter J, Kumar A, Lapinsky SE, et al. Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med. 2014;42(10):2158-2168. doi:10.1097/ccm.0000000000000520
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27. Murphy CV, Schramm GE, Doherty JA, et al. The importance of fluid management in acute lung injury secondary to septic shock. Chest. 2009;136(1):102-109. doi:10.1378/chest.08-2706
28. Levy MM, Rhodes A, Phillips GS, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43(1):3-12. doi:10.1097/CCM.0000000000000723
29. Noritomi DT, Ranzani OT, Monteiro MB, et al. Implementation of a multifaceted sepsis education program in an emerging country setting: clinical outcomes and cost-effectiveness in a long-term follow-up study. Intensive Care Med. 2014;40(2):182-191. doi:10.1007/s00134-013-3131-5
30. Scheer CS, Fuchs C, Kuhn SO, et al. Quality Improvement Initiative for Severe Sepsis and Septic Shock Reduces 90-Day Mortality: A 7.5-Year Observational Study. Crit Care Med. 2017;45(2):241-252. doi:10.1097/CCM.0000000000002069
31. Levy MM, Gesten FC, Phillips GS, et al. Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative. Am J Respir Crit Care Med. 2018;198(11):1406-1412. doi:10.1164/rccm.201712-2545OC
32. Wang HL, Shao J, Liu WL, et al. Initial fluid resuscitation (30 mL/kg) in patients with septic shock: More or less? Am J Emerg Med. 2021;50:309-315. doi:10.1016/j.ajem.2021.08.016
33. Won Ik Jeong, June-Sung Kim, Jaehyung Yu, Jinyoung Kang, Gina Yu, Yeonjoo Cho, Sungmin Jung, Won Young Kim, Seung Mok Ryoo. The prognostic value of 1-hour bundle completion in septic shock patients. Journal of the Korean Society of Emergency Medicine. 2019;30(6):537-544.
34. Truong TTN, Dunn AS, McCardle K, et al. Adherence to fluid resuscitation guidelines and outcomes in patients with septic shock: Reassessing the “one-size-fits-all” approach. Journal of Critical Care. 2019;51:94-98. doi:10.1016/j.jcrc.2019.02.006
35. Khan RA, Khan NA, Bauer SR, et al. Association Between Volume of Fluid Resuscitation and Intubation in High-Risk Patients With Sepsis, Heart Failure, End-Stage Renal Disease, and Cirrhosis. Chest. 2020;157(2):286-292. doi:10.1016/j.chest.2019.09.029
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40. Taylor SP, Karvetski CH, Templin MA, Heffner AC, Taylor BT. Initial fluid resuscitation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock. J Crit Care. 2018;43:7-12. doi:10.1016/j.jcrc.2017.08.025
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