Sepsis is a life-threatening condition caused by an infection in the body that spreads to the blood stream. Our body's immune system responds by sending inflammatory markers and white blood cells to identify and kill this foreign invader. Unfortunately, this response happens systemically leading to vasodilation throughout the body; our blood vessels become more permeable causing fluid to leak into the interstitial space. This cascade of events is SIRS (systemic inflammatory response syndrome). Sepsis can lead to septic shock, which is a type of distributive shock. Rapid identification and early treatment of this life-threatening condition correlates to better outcomes.
Sepsis patients need fluid replacement and antibiotics. The standard fluid replacement strategy for septic patients is 30 ml/kg over the first three hours; for a 50 kg (110 lbs) patient that would be 1500 ml of fluid.
(Photo from: https://www.mememaker.net/meme/well-let-me-tell-you-something-brother)
Don't get me wrong these patients do need volume replacement but at what point is enough....enough!? There are some practitioners that will give more than 30 ml/kg to these patients before adding in a vasopressor. I hear a lot of "lets start with 2 liters and go from there." Some providers forgetting that this 30ml/kg bolus needs to be calculated using ideal body weight not actual weight (think of our obese patients).
What is my point here? 1: we're waiting way too long to add on vasopressors. 2: we're over resuscitating these patients with excess fluid. 3: we're missing the obvious signs of patients not being fluid responsive. 4: we're prolonging hypotension which negatively impacts kidney function. ENTER THE TOPIC OF DISCUSSION: EARLY PRESSORS IN SEPSIS. Side note: norepinephrine (levophed) is the preferred first line vasopressor for sepsis.
There are multiple arguments presented for starting early pressors in sepsis. I am going to focus on the following:
- Improve kidney function
- Prevent fluid overload
- Improvement in patient outcome
(MrZaphod on Imgur, 2022)
Improved Kidney Function
Our kidneys act as a filter, getting rid of waste/toxins in our body that we eventually excrete as urine. Adequate blood flow thru our kidneys is needed to ensure this process functions normally. Hypotension results in decreased end organ (ex: kidneys) perfusion; the longer this goes on the greater the risk of acute kidney injury (AKI) and possibly irreversible kidney damage. There are no quality studies that specifically tracked impacts on kidney function for patients that received early vassopressors versus delayed vasopressors. One study by Ospina-Tascon et al. (2020) concluded that starting early vasopressors resulted in no significant increase in acute renal failure and/or renal replacement therapy requirements. The study defined "very early start of vasopressor (VE-VPs)" as starting pressors within or less than an hour post-sepsis bolus (Ospina-Tascon, et al., 2020).
Maybe one day we'll get a study that tracks kidney function both acutely and chronically for these two groups. We talk about how time is brain (for strokes) and it is no different for our kidneys. If we want to prevent kidney damage due to septic shock then improving perfusion to the kidneys as soon as possible IS important. Studies have shown that starting vasopressors early shortens the time to initial target MAP of 65 mmHg.
Short of it: prolonged periods of hypotension = AKI/kidney insufficiency/Kidney failure; aggressive management of septic shock with early pressors = improved kidney function/reduction in kidney damage.
Preventing Fluid Overload
Septic shock does require us to resuscitate these patient's with an initial fluid bolus, no doubt. They are losing large amounts of volume due to third spacing from leaky blood vessels throughout the body. Most common practice is to not start vasopressors until our 30 ml/kg fluid bolus is complete, if the patient is still hypotensive (not fluid responsive) then start vasopressors. How long does it take to get this initial 30 ml/kg? Depends but some studies show around 2-3 hours, from the time the patient arrives at emergency room.
Based on my personal experience of septic shock patients, I would argue that if we trend these patient's vitals we would be able to identify which were not going to respond to fluids much sooner. Using MAP we can see what I will call the roller coaster affect of MAP rising and falling or even at a stand still (no change). This is not fluid responsive. Lets say the patient does achieve a MAP of at least 65 mmHg during their first 500-1000 mL of fluid administration; you go to change out to the next fluid bag and the MAP falls below 65 mmHg, is this fluid responsive? NO! They need vasopressors, do not wait to finish the 30 ml/kg bolus.
Where is all this excess fluid going? Into the interstitial space and eventually to their lungs causing pulmonary edema. Starting pressors early decreases the amount of fluid resuscitation needed. The CENSER study, a double blind randomized control trial, showed a significant difference in the occurrence of pulmonary edema in patients that received early low dose norephinephrine compared to standard treatment (Permpikul, Chairat et al, 2019). The study stated: "the early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P = 0.004)" (Permipiku, Chairat et al, 2019). How early did the CENSER study start norepinephrine? "Median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001)" (Pemipiku, Chairat et al, 2019).
Improved Outcomes
Studies/trials have been focused heavily on this one potential benefit. Does early vasopressors improve overall outcome? The CENSER study concluded that there was no significant difference in 28 day mortality: "The 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P = 0.15) (Pemipiku, Chairat et al, 2019)."
What about if we start vasopressors VERY early? An RCT was performed looking at in hospital survival, with two treatment arms: very early administration of norepinephrine VS late administration of norepinephrine. "NEP infusion started after 25 (20-30) and 120 (120-180) min in the early and late groups (p = 0.000)" (Elbouhy MA, Soliman M et al, 2019). The RCT concluded: "the early group had survival rate of 71.9% compared to 45.5% in the late group (p = 0.007)" (Elbouhy MA, Soliman M et al, 2019). This was a small study with only 101 patients.
Improved outcomes is a heavy focus and will remain to be in future studies. I think this needs to be expanded to include monitoring sepsis survivors long term after their event to see if there are other metrics that can be obtained besides overall survival and mortality benefit. Are survivors coming back to the hospital with new medical conditions/problems? Are they at higher risk of serious medical events? Any changes in their activities of daily living (ADLs)? Does early vasopressor administration improve outcomes long term?
Final Thoughts/Future Research
Before we wrap up let's take a look at the 2021 surviving sepsis campaign guidelines, first hour bundle of care:
(Surviving Sepsis Campaign Guidelines 2021 Website)
We are supported by a well respected evidence based guideline to NOT wait until the completion of the initial fluid bolus to start vasopressors (norepinephrine). This is listed as a strong recommendation.
The amount of studies out there is pretty exhaustive, we reviewed some of the most discussed trials. My final 0.02 cents:
- Early vasopressor administration in sepsis = earlier shock control
- Results in less fluid administration = less fluid overload
- Limits severity of AKI or possibly preventing chronic kidney damage
- Potential mortality benefit (more trials needed)
- Unknown long term benefits on ADLs, repeat visits to hospital, etc....
Two trials to look out for in the future: CLOVERS and EVIS.
Both trials are comparing early vasopressors in sepsis VS liberal fluid administration. CLOVERS study was stopped early due to: "Findings from a randomized, non-blinded, phase 3 clinical trial supported by the National Institutes of Health found no significant difference in 90-day mortality rates, nor safety concerns, after providing patients with one of two common treatment strategies for sepsis. The findings were published in the New England Journal of Medicine (No differences found between liberal or restrictive fluid treatment strategies for septic-inducted hypotension) and were simultaneously presented at the 2023 Critical Care Congress" (CLOVERS: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis | PETAL Network, n.d.).
Click here for overview of EVIS trial
References:
CLOVERS: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis | PETAL Network. (n.d.). Copyright PETAL Network. All Rights Reserved. https://petalnet.org/studies/public/clovers
Elbouhy MA, Soliman M, Gaber A, Taema KM, Abdel-Aziz A. Early Use of Norepinephrine Improves Survival in Septic Shock: Earlier than Early. Arch Med Res. 2019 Aug;50(6):325-332. doi: 10.1016/j.arcmed.2019.10.003. Epub 2019 Oct 31. PMID: 31677537.
Evans, Laura1; Rhodes, Andrew2; Alhazzani, Waleed3; et al. Executive Summary: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock 2021. Critical Care Medicine 49(11):p 1974-1982, November 2021. | DOI: 10.1097/CCM.0000000000005357
Ospina-Tascón, G.A., Hernandez, G., Alvarez, I. et al. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care 24, 52 (2020). https://doi.org/10.1186/s13054-020-2756-3
Permpikul, Chairat et al. “Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial.” American journal of respiratory and critical care medicine vol. 199,9 (2019): 1097-1105. doi:10.1164/rccm.201806-1034OC
Add comment
Comments