Dynamic testing based versus restrictive based fluid administration following early fluid resuscitation in septic shock patients, a pilot study

doi:10.21203/rs.3.rs-3425149/v1

Background

Efforts have been targeting early reversal of a hemodynamically unstable patient in septic shock. The classic rationale for fluid resuscitation in septic shock is to restore intravascular volume deficit with resultant augmentation of cardiac output. Latest surviving sepsis campaign guidelines recommended an initial fluid bolus with subsequent fluid administration, guided by dynamic testing.

AIM OF WORK

We aimed to test if restrictive fluid protocol was comparable to dynamic-based testing for fluid responsiveness protocol.

METHODS

This was a prospective cohort study, recruiting septic shock patients, conducted in Critical Care Department, Cairo University. All patients were initially resuscitated. Patients were randomized (1:1 ratio) to restrictive group (fluid administration with predetermined rate of 1 ml/kg/hour), and dynamic-based testing group (fluid administration according to dynamic measures, following passive leg raising method). Positive response was considered when cardiac output increased by 10%.

Results

Our study recruited 80 patients (39 males) with age of 57.3±18.8 years old. It was noted that clinical severity scores were higher in the restrictive group, with no significant difference in 3 hours lactate. Fluid strategy did not affect mortality. Logistic regression showed no significant difference regarding adjusted mortality, between those who showed acceptable fluid response according to dynamic testing and those who received a restrictive protocol (Hazard’s risk 0.913, P 0.903, CI 95% 0.212 – 3.935). Fluid strategy did not affect need for dialysis, nor mechanical ventilation, nor length of ICU stay.

CONCLUSION
Restrictive fluid strategy, following initial fluid resuscitation was comparable to dynamic testing-based strategy, in terms of mortality, need for ventilation, need for dialysis and ICU length of stay

Septic shock

fluid resuscitation

fluid responsiveness

Sepsis is a life-threatening problem with a vast magnitude worldwide. Efforts have been targeting early reversal of a hemodynamically unstable patient, spiraling down. Fluid administration in severe sepsis with proposed tissue hypoperfusion has been an ongoing debate and a matter of study over the last decades. ^1,2

The classic rationale for fluid resuscitation is to restore intravascular volume deficit with resultant augmentation of cardiac output. The latest surviving sepsis campaign guidelines SSC recommended an initial fluid bolus of 30 ml/kg. This was introduced as a part of a protocolized quantitative resuscitation (Early Goal Directed Therapy EGDT) by Rivers in 2001. ³ Rivers targeted clinical measurable variables that included mean arterial pressure MAP, central venous pressure CVP, and central oxygen venous saturation ScvO2. Other variables were recorded and acted upon, including hematocrit Hct, arterial oxygen saturation SaO2 and cardiac index CI. ³ However, this approach failed to demonstrate mortality reduction in several randomized controlled trials RCTs (ProCESS, ARISE and ProMISe trials). ^4-6Moreover, this approach was criticized, where a meta-analysis of 9 RCTs showed non-significant effect of EGDT versus routine care, on mortality.⁷

It was noted that EGDT increased resource demand in terms of ICU admissions and cardiovascular support measures without reducing mortality, organ supportive measures nor length of hospital stay. These studies targeted mainly ScvO2 which was adopted in SSC guidelines in 2012. This enthusiasm was cast away in 2016.

The latest surviving sepsis campaign guidelines recommended an initial fluid bolus with subsequent fluid administration, guided by dynamic testing. However, this approach was also not supported by RCTs findings (weak recommendation with low quality of evidence). ^8-9 Guidelines supported the notion of lactate -guided resuscitation and its modest benefit on mortality reduction. These recommendations needed retesting and further confirmation. ^8-9

AIM OF WORK

We aimed to test if restrictive fluid protocol was comparable to dynamic-based testing for fluid responsiveness protocol, following initial fluid resuscitation in septic shock patients. We hypothesized that both protocols were comparable, in terms of mortality. Secondary outcomes were length of ICU stay, mechanical ventilation and need of dialysis.

This was a prospective cohort study, recruiting 80 consecutive patients who were diagnosed with septic shock and managed according to surviving sepsis campaign guidelines. ⁸ This study was conducted in Critical Care Department (Cairo University) from March 2018 to December 2020. Informed consents were taken from participating patients and their kins. Local ethical board review in January 2018 was obtained.

Inclusion criteria included patients ≥ 18 years old, diagnosed with septic shock (sepsis with persisting hypotension despite adequate volume resuscitation and/or having a serum lactate level > 4 mmol/L (18 mg/dl) requiring vasopressors to maintain MAP ≥65 mm Hg). Sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. End organ damage is identified as an acute change in total Sequential [Sepsis-related] Organ Failure Assessment score (SOFA) or quick SOFA ≥ 2.

Exclusion criteria included patients under 18 years, refusal to consent, conditions that could affect lactate clearance e.g., hepatic, or renal impairment and alcoholic patients.

All patients were resuscitated following the Surviving Sepsis Campaign guidelines. ⁸Initial fluid resuscitation started with crystalloid (30 ml/kg) for patients with hypotension or lactate level >4mmol/L. Norepinephrine was used as the first-choice vasopressor to maintain a mean arterial pressure of ≥65 mm Hg and initiated within the first hour. Relevant cultures were obtained before the start of broad-spectrum antibiotics. Arterial lactate level measured on admission and remeasured after 3 hours following fluid resuscitation and vasopressor therapy. APACHE II and SOFA scores were calculated on admission.

Mean arterial pressure (MAP) was calculated as diastolic arterial blood pressure + 1/3 pulse pressure (SBP-DBP). Fluid bolus was defined as the amount of fluid in liters, given for initial resuscitation (30ml/Kg of crystalloids according to surviving sepsis campaign. ⁸ Fluid balance was defined as the amount of fluid in liters, given in the first 24 hours of admission.

All patients eligible to the study were randomized (1:1 ratio) to:

1. Restrictive group (40 patients): initial fluid resuscitation 30 ml/kg followed by norepinephrine and fluid administration with predetermined rate of 1 ml/kg/hour.

2. Dynamic-based testing group (40 patients): initial fluid resuscitation 30 ml/kg followed by norepinephrine and fluid administration according to dynamic measures i.e., change in cardiac output (measured by transthoracic echocardiography Aortic VTI * LVOT cross-sectional area), following passive leg raising method. A positive response was considered when cardiac output increased by 10%.

Patients randomized to group B underwent “passive leg raising” where it was estimated that passive leg raising method results in autotransfusion of about 500 ml of colloids. This was done while the patient was lying supine with head of bed elevated at 30⁰. Patient position was shifted in Trendelenburg position with head lying flat and legs raised to 45⁰. This was kept for 1 minute before judging for fluid responsiveness.

Fluid response was measured by transthoracic echocardiographic measurement of cardiac output. This was achieved through 4 chambers imaging of aorta and left ventricular outflow LVOT. Cardiac output = Aortic VTI * LVOT cross-sectional area. This was measured before passive leg raising and after the procedure. Cardiac output increase by at least 10%, was considered positive response to fluid administration and signified LV preload dependency.

Statistical methods

Data were statistically described in terms of range, mean ± standard deviation (± SD), number of cases & relative frequencies (percentages) when appropriate. Comparison of quantitative variables between the study groups was done using “t” test or Mann Whitney U test for independent samples when appropriate. For comparing categorical data, the Chi square test was performed. Logistic regression models were run to determine outcomes of restrictive approach versus dynamic-based testing approach. Unadjusted and adjusted regression models were reported. Kaplan Meier curves were plotted. A probability value (P value) less than 0.05 was considered statistically significant. Delta change was calculated as second reading minus first reading, divided by first reading. All statistical calculations were done using SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 22 for Microsoft Windows.

Our study recruited 80 patients in severe sepsis with hemodynamic instability. Our study comprised 39 males (48.8%) with an average age of 57.3±18.8 years old. No gender differences were noted between both groups. We randomly assigned recruited subjects into two equally sized treatment protocols. Comparing their baseline measurements and 24 hours later were recorded in table (1 and 2). Delta changes in vital signs and laboratory values in restrictive group versus dynamic-based testing group were represented in table (3). It was noted that clinical severity scores were higher in the restrictive group. However, rechecking lactate level within 3 hours of resuscitation showed no significant difference between both groups. They exhibited higher serum creatinine measurements. They also exhibited lower P/F ratios and lower partial pressure arterial oxygen (PaO2). The restrictive group showed significant improvement in P/F ratio (117.9±105.3 versus 146.4±121.7, P 0.028). On the contrary, dynamic-based testing group showed no significant changes in P/F ratio (222.6±117.9 versus 208.6±131.2, P

0.161). ICU stay, mechanical ventilation, fluids and outcomes were recorded in table (4). Fluid response was noted in 24 subjects in the dynamic group (40%).

Fluid strategy did not affect mortality. Unadjusted logistic regression showed there was no significant impact of fluid strategy on mortality, (Hazard’s risk 0.663, P 0.367, CI 95% 0.272 – 1.617). Logistic regression after adjusting for APACHE and lactate level, showed also that there was no significant difference regarding mortality, between those who were managed and guided through dynamic testing and those who received a restrictive protocol (Hazard’s risk 2.009, P 0.291, CI 95% 0.550 – 7.346).

Mortality was lower in fluid responders (6/24), in comparison to those who were kept on more restrictive protocol (25/40) and was illustrated in Kaplan Meier analysis in figure (1). Unadjusted logistic regression showed less favorable response for those who were managed restrictively versus those who were fluid responders, (Hazard’s risk -0.200, P 0.005, CI 95% 0.065 – 0.615). However, logistic regression after adjusting for APACHE and lactate level, showed that there was no significant difference regarding mortality, between those who showed acceptable fluid response according to dynamic testing and those who received a restrictive protocol (Hazard’s risk 0.913, P 0.903, CI 95% 0.212 – 3.935). This was confirmed through Cox regression as well. Fluid strategy did not affect the length of ICU stay as well.

Restrictive strategy received lower fluid amounts than dynamic testing-based protocol. Unadjusted logistic regression confirmed this finding, (Hazard’s risk 8.120, P <0.001, CI 95% 1113.3 – 1836.6). Logistic regression also confirmed this finding, after adjustment for baseline creatinine measurements. Also, vasopressors days were fewer in restrictive strategy.

However, dialysis and mechanical ventilation were higher in restrictive strategy. Logistic regression showed that the need for mechanical ventilation was irrespective of fluid strategy (Hazard’s risk 0.333, P 0.062, CI 95% 0.105 – 1.059). Unadjusted logistic regression showed that need for dialysis was higher in restrictively managed group, (Hazard’s risk 0.234, P 0.006, CI 95% 0.084 – 0.653). However, logistic regression also showed that the need for dialysis was irrespective of fluid strategy, after adjustment for baseline creatinine (Fluid strategy: Hazard’s risk 0.634, P 0.566, CI 95% 0.133 – 3.012. Creatinine: Hazard’s risk 3.214, P <0.001, CI 95% 1.862 – 5.547). incidence of acute kidney injury according to AKIN criteria was 42.5% in restrictive group versus 37.5% in dynamic-based testing with P 0.41. Forest plot of difference in between restrictive versus dynamic-based testing fluid protocol upon mortality (unadjusted and adjusted), need for dialysis (unadjusted and adjusted) and mortality was presented in figure (2).

Our study examined whether there would be a significant difference between dynamic testing-based fluid administration and restrictive fluid administration, following initial fluid resuscitation as guided by latest SCC surviving sepsis campaign guidelines. This study was inspired by recent findings from several studies which suggested that restrictive fluid administration is non-inferior to usual care. ^4-6

This notion ignited many questions regarding optimal fluid administration, following initial fluid resuscitation according to SCC. There have been controversial findings. Using surrogates for potentially restoring adequate tissue perfusion has been a matter of study over the last two decades. Mixed venous oxygen saturation has been targeted in SCC guidelines in 2012 as a target for resuscitation. This approach was paved by the findings of several authors. Rivers and Jansen examined using mixed venous oxygen saturation as a target for resuscitation and concluded that this approach resulted in improvements in mortality. ³On the contrary, ProCESS, ARISE and ProMISe trials could not prove beneficial outcomes of EGDT. ^4-6 These findings supported the notion that usual care is non-inferior to EGDT and might be less harmful in certain circumstances.

These contradictory findings encouraged adoption of lactate as an end-product of anaerobic metabolism. Lactate could indicate inadequate tissue perfusion, during resuscitation of hemodynamically unstable patients. Jones et al. examined lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy that recruited 300 patients. They concluded there was no significant difference in short term mortality among between both treatment protocols. ¹⁰ Normalization of lactate in 3 hours window was driven by several studies that demonstrated a significant reduction in mortality with lactate-guided resuscitation. ^11-17 Lactate clearance was proposed as a surrogate for effective resuscitation.However, this was a weak recommendation with low quality of evidence.

Our study recruited subjects in severe sepsis with evidence of tissue hypoperfusion. Recruited subjects were further divided after receiving initial fluid resuscitation (30ml/kg), into either dynamic testing-based fluid strategy versus restrictive fluid strategy.

It was noted that clinical severity scores were higher in restrictive protocol. Besides, supportive organ measures such as dialysis and mechanical ventilation, were more prevalent in the restrictive protocol. This could represent selection bias where ill patients with worse clinical conditions received lower fluid volumes substantially. Besides, this group showed higher baseline creatinine measurements which might explain the trend for lower volume administration. Logistic regression confirmed this trend, after adjustment for baseline creatinine measurements.

Logistic regression showed that the need for dialysis was irrespective of fluid strategy, after adjustment for baseline creatinine measurements. It has been noted that a restrictive fluid strategy did not worsen kidney functions. These findings were partly in line with previous studies that consistently showed benefits of restrictive fluid administration on lowering risk of acute kidney injury (AKI). ^17-20Vaaracompared a restrictive fluid management strategy to routine care and concluded that a restrictive fluid management regimen resulted in lower cumulative fluid balance with less adverse events. ²¹Another multicenter study reported that fluid overload was an independent risk factor for the incidence of AKI and increased the severity of AKI. A higher cumulative fluid balance was an important factor associated with 28-day mortality following AKI. ²²

In support of a conservative approach, the results of the pilot Conservative Versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial showed that AKI occurred less often in patients with septic shock who were randomly assigned to a restrictive fluid strategy. ²³

Our results showed that fluid strategy did not affect mortality nor length of ICU stay. We tried to adjust for known confounders (APACHE II and initial lactate measurement). It is well known that APACHE II shows an accuracy of predicting mortality in septic patients. ²⁴

Also, initial lactate measurements pose prognostic information, regarding septic shock. Fiho et al. stated that Initial blood lactate levels more than 2.5 mmol/L (hazard ratio [HR], 2.86; 95% CI, 1.53-5.33; P = 0.001) and Sepsis-related Organ Failure Assessment score at ICU admission (HR, 1.18; 95% CI, 1.09-1.27; P < 0.001) were associated with increased 28-day mortality. ²⁵

Several studies confirmed the association between positive fluid balance and morality. ^{18, 20, 26}Conservative approach was non-inferior to EGDT, in terms of mortality and adverse outcomes. Three large trials of early goal-directed therapy showed no beneficial effect of EGDT on mortality or organ function. ^4-6

Corl et al. examined liberal versus restrictive fluid resuscitation strategy and concluded that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared to usual care with no observable increase in mortality, organ failure, or adverse events. ²⁷

Shapiro et al. showed that restrictive fluid strategy and liberal strategy were comparable in terms of mortality. ²⁸A meta-analysis of 3 studies, conducted on pediatric populations that included 3288 subjects and investigated liberal versus conservative fluid therapy. Results showed that liberal fluid therapy might increase risk of in‐hospital mortality by 38% and risk of mortality at follow‐up (at four weeks) by 39%. ²⁹

Our findings showed that choice of fluid strategy did not affect the need for mechanical ventilation. Despite that our patients who were managed restrictively, showed lower P/F ratios. Restrictive group showed significant improvement in P/F ratio while changes in dynamic-based testing group were insignificant. Restrictive fluid management exerted beneficial effects on ARDS patients in the Fluid and Catheter Treatment Trial (FACTT). Those in the restrictive group had lower net fluid balances, similar 60-day mortality, and more days alive and free from mechanical ventilation. ³⁰

In a meta-analysis of 11 randomized trials (2051 patients, no significant difference in mortality was noted with conservative or deresuscitative strategies compared with a liberal strategy or usual care [pooled risk ratio (RR) 0.92, 95 % confidence interval (CI) 0.82–1.02, I 2 = 0 %]. A conservative or deresuscitative strategy resulted in increased ventilator-free days (mean difference 1.82 days, 95 % CI 0.53–3.10, I 2 = 9 %) and reduced length of ICU stay (mean difference −1.88 days, 95 % CI −0.12 to −3.64, I 2 = 75 %) compared with a liberal strategy or standard care. ³¹

We tried to further explore if this notion still stands for those who responded as dictated to fluid therapy versus those who were restrictively managed. It was noteworthy that there was no significant difference regarding mortality, between those who even showed acceptable fluid response and those who received a restrictive protocol (Hazard’s risk 0.913, P 0.903, CI 95% 0.212 – 3.935).

This study presented findings that need further confirmation. Is it possible that concurrent interest in dynamic testing would fade away as happened before for mixed venous oxygen saturation?

Restrictive fluid strategy, following initial fluid resuscitation was comparable to dynamic testing-based strategy, in terms of mortality, need for ventilation, need for dialysis and ICU length of stay.

Ethical Approval

This study was conducted in Critical Care Department (Cairo University). Local ethical board review approved the study protocol in January 2018.

Informed written consents were taken from participating patients and their kins after explanation of the study protocol and purpose.

Funding

This study was self-funded.

Availability of data and materials

Data and materials are available upon request.

Virág M, Leiner T, Rottler M, Ocskay K, Molnar Z. Individualized Hemodynamic Management in Sepsis. J Pers Med. 2021 Feb 23;11(2):157. doi: 10.3390/jpm11020157. PMID: 33672267; PMCID: PMC7926902.
Malbrain MLNG, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, Teboul JL, Rice TW, Mythen M, Monnet X. Principles of fluid management and stewardship in septic shock: it is time to consider the four D's and the four phases of fluid therapy. Ann Intensive Care. 2018 May 22;8(1):66. doi: 10.1186/s13613-018-0402-x. PMID: 29789983; PMCID: PMC5964054.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307. PMID: 11794169.
ARISE Investigators; ANZICS Clinical Trials Group; Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1. PMID: 25272316.
ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18. PMID: 24635773; PMCID: PMC4101700.
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17. PMID: 25776532.
Xu JY, Chen QH, Liu SQ, Pan C, Xu XP, Han JB, Xie JF, Huang YZ, Guo FM, Yang Y, Qiu HB. The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials. Anesth Analg. 2016 Aug;123(2):371-81. doi: 10.1213/ANE.0000000000001278. PMID: 27049857; PMCID: PMC4956677.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18. PMID: 28101605.
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Møller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y. Epub 2021 Oct 2. PMID: 34599691; PMCID: PMC8486643.
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158. PMID: 20179283; PMCID: PMC2918907.
Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. doi: 10.1164/rccm.200912-1918OC. Epub 2010 May 12. PMID: 20463176.
Lyu X, Xu Q, Cai G, Yan J, Yan M. [Efficacies of fluid resuscitation as guided by lactate clearance rate and central venous oxygen saturation in patients with septic shock]. Zhonghua Yi Xue Za Zhi. 2015 Feb 17;95(7):496-500. Chinese. PMID: 25916923.
Tian HH, Han SS, Lv CJ, Wang T, Li Z, Hao D, Shang QM, Wang XZ. [The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012 Jan;24(1):42-5. Chinese. PMID: 22248751.
Yu B, Tian HY, Hu ZJ, Zhao C, Liu LX, Zhang Y, Zhu GJ, Wang LT, Wu XH, Li J. [Comparison of the effect of fluid resuscitation as guided either by lactate clearance rate or by central venous oxygen saturation in patients with sepsis]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2013 Oct;25(10):578-83. Chinese. doi: 10.3760/cma.j.issn.2095-4352.2013.10.002. PMID: 24119693.
Gu WJ, Zhang Z, Bakker J. Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med. 2015 Oct;41(10):1862-3. doi: 10.1007/s00134-015-3955-2. Epub 2015 Jul 8. PMID: 26154408.
Simpson SQ, Gaines M, Hussein Y, Badgett RG. Early goal-directed therapy for severe sepsis and septic shock: A living systematic review. J Crit Care. 2016 Dec;36:43-48. doi: 10.1016/j.jcrc.2016.06.017. Epub 2016 Jun 29. PMID: 27546746.
Bellomo R, Ronco C, Mehta RL, Asfar P, Boisramé-Helms J, Darmon M, Diehl JL, Duranteau J, Hoste EAJ, Olivier JB, Legrand M, Lerolle N, Malbrain MLNG, Mårtensson J, Oudemans-van Straaten HM, Parienti JJ, Payen D, Perinel S, Peters E, Pickkers P, Rondeau E, Schetz M, Vinsonneau C, Wendon J, Zhang L, Laterre PF. Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference. Ann Intensive Care. 2017 Dec;7(1):49. doi: 10.1186/s13613-017-0260-y. Epub 2017 May 4. PMID: 28474317; PMCID: PMC5418176.
Salahuddin N, Sammani M, Hamdan A, Joseph M, Al-Nemary Y, Alquaiz R, Dahli R, Maghrabi K. Fluid overload is an independent risk factor for acute kidney injury in critically Ill patients: results of a cohort study. BMC Nephrol. 2017 Feb 1;18(1):45. doi: 10.1186/s12882-017-0460-6. PMID: 28143505; PMCID: PMC5286805.
Bellomo R, Ronco C, Mehta RL, Asfar P, Boisramé-Helms J, Darmon M, Diehl JL, Duranteau J, Hoste EAJ, Olivier JB, Legrand M, Lerolle N, Malbrain MLNG, Mårtensson J, Oudemans-van Straaten HM, Parienti JJ, Payen D, Perinel S, Peters E, Pickkers P, Rondeau E, Schetz M, Vinsonneau C, Wendon J, Zhang L, Laterre PF. Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference. Ann Intensive Care. 2017 Dec;7(1):49. doi: 10.1186/s13613-017-0260-y. Epub 2017 May 4. PMID: 28474317; PMCID: PMC5418176.
Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011 Feb;39(2):259-65. doi: 10.1097/CCM.0b013e3181feeb15. PMID: 20975548.
Vaara ST, Ostermann M, Bitker L, Schneider A, Poli E, Hoste E, Fierens J, Joannidis M, Zarbock A, van Haren F, Prowle J, Selander T, Bäcklund M, Pettilä V, Bellomo R; REVERSE-AKI study team. Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI): a pilot randomized controlled feasibility trial. Intensive Care Med. 2021 Jun;47(6):665-673. doi: 10.1007/s00134-021-06401-6. Epub 2021 May 7. PMID: 33961058; PMCID: PMC8195764.
Wang N, Jiang L, Zhu B, Wen Y, Xi XM; Beijing Acute Kidney Injury Trial (BAKIT) Workgroup. Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. Crit Care. 2015 Oct 23;19:371. doi: 10.1186/s13054-015-1085-4. PMID: 26494153; PMCID: PMC4619072.
Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettilä V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A; CLASSIC Trial Group; Scandinavian Critical Care Trials Group. 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 Nov;42(11):1695-1705. doi: 10.1007/s00134-016-4500-7. Epub 2016 Sep 30. PMID: 27686349.
Lan Gao, Qindong Shi, Hao Li, Qinyue Guo & Jinqi Yan. Prognostic value of baseline APACHE II score combined with uric acid concentration for short-term clinical outcomes in patients with sepsis, All Life, 2020, 13:1, 416-425, DOI: 10.1080/26895293.2020.1796828
Filho RR, Rocha LL, Corrêa TD, Pessoa CM, Colombo G, Assuncao MS. Blood Lactate Levels Cutoff and Mortality Prediction in Sepsis-Time for a Reappraisal? a Retrospective Cohort Study. Shock. 2016 Nov;46(5):480-485. doi: 10.1097/SHK.0000000000000667. PMID: 27380535; PMCID: PMC5058781.
Sadaka F, Juarez M, Naydenov S, O'Brien J. Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality. J Intensive Care Med. 2014 Jul-Aug;29(4):213-7. doi: 10.1177/0885066613478899. Epub 2013 Feb 27. PMID: 23753235.
Corl KA, Prodromou M, Merchant RC, Gareen I, Marks S, Banerjee D, Amass T, Abbasi A, Delcompare C, Palmisciano A, Aliotta J, Jay G, Levy MM. The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. Crit Care Med. 2019 Jul;47(7):951-959. doi: 10.1097/CCM.0000000000003779. PMID: 30985449; PMCID: PMC6579683.
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056/NEJMoa062200. Epub 2006 May 21. PMID: 16714767.
PRISM Investigators; Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, Canter RR, Coats TJ, Delaney A, Gimbel E, Grieve RD, Harrison DA, Higgins AM, Howe B, Huang DT, Kellum JA, Mouncey PR, Music E, Peake SL, Pike F, Reade MC, Sadique MZ, Singer M, Yealy DM. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380. Epub 2017 Mar 21. PMID: 28320242.
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056/NEJMoa062200. Epub 2006 May 21. PMID: 16714767.
Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B, Fan E. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170. doi: 10.1007/s00134-016-4573-3. Epub 2016 Oct 12. PMID: 27734109.

Table 1. Demographics, vital signs, laboratory values of all recruited subjects, restrictive group and dynamic-based testing group, on admission.

	All subjects	Restrictive	Dynamic	P
Age (years)	57.3±18.8	58.1±18.5	56.6±19.4	0.728
APACHE	20.6±6.7	22.4±6.9	18.8±6.0	0.015
SOFA	10.9±3.5	12.1±3.7	9.7±3.0	0.003
CRP	86.0±58.1	87.2±51.2	84.8±64.9	0.853
Lactate	4.5±1.5	5.0±1.8	4.1±1.0	0.008
Procalcitonin	2.7±1.9	2.4±1.2	2.9±2.4	0.296
Glasgow Coma Scale	13.2±2.0	12.8±2.1	13.5±1.9	0.106
MAP (mmHg)	63.8±2.3	63.1±2.6	64.6±1.7	0.002
HR (per minute)	106.7±5.6	105.8±4.6	107.7±6.4	0.136
RR (per minute)	22.1±4.0	22.6±3.2	21.6±4.7	0.269
Temperature	37.9±0.4	37.9±0.3	37.8±0.5	0.089
P/F ratio	164.1±122.8	117.9±105.3	222.6±117.9	<0.001
PO2(mmHg)	63.0±17.5	56.1±18.3	69.8±13.7	<0.001
PCO₂(mmHg)	39.3±14.3	39.8±16.0	38.8±12.7	0.757
HCO₃(mEq/L)	17.9±5.6	16.8±6.1	19.0±4.8	0.080
Hb (gm/dl)	9.6±2.3	9.3±2.4	10.0±2.3	0.199
PLT	204.1±123.5	191.1±132.4	217.1±114.1	0.349
TLC (10³/cc)	16.5±9.1	16.9±10.3	16.2±7.7	0.723
Creatinine (mg/dl)	3.4±2.2	4.2±2.3	2.6±1.9	0.001
Sodium (mEq/L)	143.3±14.0	141.1±13.3	145.6±14.5	0.149
Potassium (mEq/L)	4.1±1.1	4.1±1.3	4.1±1.0	0.846

Table 2. Vital signs and laboratory values of all recruited subjects, restrictive group and dynamic-based testing group, 24 hours later.

24 hours later	All subjects	Restrictive	Dynamic	P
Hb	9.4±2.1	9.4±2.1	9.3±2.3	0.759
PLT	199.8±118.3	184.0±127.3	202.8±110.6	0.482
TLC	17.8±10.0	18.4±11.8	17.1±8.3	0.563
Creatinine	3.2±2.2	3.9±2.0	2.6±2.2	0.005
GCS	11.1±2.9	10.2±3.6	11.1±3.1	0.224
PO2	66.8±15.7	60.9±19.7	68.5±17.1	0.068
FiO2	61.0±34.0	67.2±34.0	53.8±35.2	0.089
P/F ratio	177.5±130.0	146.4±121.7	208.6±131.2	0.036
MAP	68.5±3.5	68.2±3.3	68.3±4.2	0.882

Table 3. Delta change in vital signs and laboratory values in restrictive group versus dynamic-based testing group.

Group	Restrictive method	Dynamic Tests	P
Lactate delta change	56±68%	45±48%	0.402
Creatinine delta change	-1±33%	2±51%	0.727
P/F delta change	56±123%	1±69%	0.019
MAP delta change	8±4%	6±5%	0.068
SOFA change	-1.5±5.4	-0.3±3.5	0.253

Table 4. ICU stay, mechanical ventilation, fluids and outcomes in all recruited subjects and both groups.

	All subjects	Restrictive	Dynamic	P
Total fluid volume	3762.5±1096.5	3025.0±391.4	4500.0±1080.1	<0.001
Vasopressor days	5.7±4.7	4.5±2.6	6.9±5.9	0.023
ICU LOS	12.6±12.9	12.2±15.8	13.0±9.4	0.803
MV stay	8.1±6.8	6.7±6.0	9.9±7.4	0.065
Mech. Ventilation	63 (78.8%)	35 (87.5%)	28 (70.0%)	0.050
Dialysis	26 (32.5%)	19 (47.5%)	7 (17.5%)	0.004
Mortality	46 (57.5%)	25 (62.5%)	21 (52.5%)	0.249

No competing interests reported.

Dynamic testing based versus restrictive based fluid administration following early fluid resuscitation in septic shock patients, a pilot study

Status:

Version 1

Abstract

Figures

Background

METHODS

Results

Discussion

CONCLUSION

Declarations

References

Tables

Additional Declarations

Status:

Version 1