Hydrophobia (Fear of Fluids) in Septic Shock Does Not Pay!

As both an intensivist and emergency physician, I have the privilege of taking care of very sick patients, especially those with septic shock, from time zero in the ED to the time they transition from critical care. In my training some years ago, I was taught the initial management of shock includes a hemodynamic “rescue” with fluids, and lots of those. Once shock resolves, we can “back off” or de-escalate our resuscitation. However, we all have seen the ebb and flow of this approach in the last decades. With the publication of early goal-directed therapy, aggressive fluids that target hemodynamic end points became standard care at the turn of the century.1Rivers 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: 1368-1377Crossref PubMed Scopus (8115) Google Scholar Now, with ultrasound scanning, avoidance of central line-associated infection, and observational studies that show negative effects of fluids, resuscitation has amounted to a fluid bolus if the inferior vena cava is collapsible, and the initiation of vasopressor early via a 20-gauge peripheral venous catheter. With lactate as a well-accepted resuscitation end point, my colleagues (both attendings and residents) and I commonly have witnessed many patients who were admitted to our service experiencing a “bimodal” hyperlactatemia. They have elevated lactate on presentation, which improves after some fluids. With fluid restriction (because it is believed to be harmful), lactate increases again as vasopressor is initiated for ICU admission. Resumed fluid resuscitation is then required to titrate off the vasopressor(s) and resolve the lactic acidosis. Whether the second lactate peak is catecholamine-induced or from tissue hypoxia, is this good resuscitation? One may ask. Two multicenter randomized trials that were published in New England Journal of Medicine last year may help us realize that hydrophobia does not pay. The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) study enrolled patients with sepsis-induced hypotension in the ED to test the hypothesis that the restriction of fluids with early vasopressor results in a lower mortality rate.2Shapiro NI Douglas IS et al.National Heart, Lung, Blood Institute Prevention, Early Treatment of Acute Lung Injury Clinical Trials NetworkEarly restrictive or liberal fluid management for sepsis-induced hypotension.N Engl J Med. 2023; 388: 499-510Crossref PubMed Scopus (55) Google Scholar The study aimed to include 2,320 patients, but was terminated for futility at the second interim analysis with 1,563 patients enrolled. All patients received a median of 2.1 L of fluid prior to enrollment. Seven hundred eighty-two patients were assigned to the restrict fluid group, in which vasopressor was prioritized, with fluids a rescue measure for refractory hypotension or significant lactic acidosis. The other 781 patients were assigned to the liberal fluid group, in which 500-mL fluid boluses were prioritized and rescue vasopressor was administered only for hypotension refractory to fluids, significant lactic acidosis, or fluid overload. The results showed no difference in 90-day mortality rates: 14.0% in the restrictive fluid group vs 14.9% in the liberal fluid group. There were also no differences in various secondary outcomes and patient subgroups. However, vasopressor administration was significantly greater with longer duration in the restrictive fluid group: 59.0% and 9.6 ± 10.0 h, respectively, compared with 37.2% and 5.4 ± 8.6 h in the liberal fluid group. Importantly, 67.3% of patients in the restrictive fluid group were admitted to the ICU, compared with 59.2% in the liberal fluid group, which is a statistically significant 8.1% increased ICU admissions. Is this higher resource use acceptable for the fear of fluids when a mortality benefit is not realized? Once the patient is admitted to the ICU, the second study from the Conservative vs Liberal Approach to Fluid Therapy of Septic Shock in the Intensive Care (CLASSIC) trial group published 7 months earlier evaluated the effects of the restriction of fluids in patients who already were receiving vasopressor after at least 1 L of fluids.3Meyhoff T.S. Hjortrup P.B. Wetterslev J. et al.Restriction of intravenous fluid in ICU patients with septic shock.N Engl J Med. 2022; 386: 2459-2470Crossref PubMed Scopus (106) Google Scholar Similar to the CLOVERS trial, in the restrictive fluid group, 250 to 500 mL crystalloid can be given if the following occurrences are present: lactate ≥ 4 mM, hypotension refractory to vasopressor, lower extremity mottling, or oliguria. Fluids were given as long as hemodynamic status was improving in the standard fluid group. One thousand five hundred forty-five patients were enrolled and analyzed: 764 patients in the restrictive fluid group and 781 in the standard fluid group. There was no difference in 90-day mortality rates: 42.3% in the restrictive fluid group vs 42.1% in the standard fluid group. Subgroup analyses also showed no differences in mortality rates. There were no differences in adverse events, days alive without life support, and days alive outside the hospital at 90 days. Although it was obvious that the restrictive fluid group received less fluid administration, the study did not analyze the difference in number, dosing, and duration of vasopressors. Based on results of the CLOVERS and CLASSIC trials, we can conclude that restrictive fluid resuscitation in the ED and then ICU does not result in any beneficial outcome other than increased use of ICU resources. A cost-effectiveness analysis can be considered, but it may be quite apparent that the increased use of vasopressor and its implicit ICU care is more costly than several liters of crystalloid, potentially avoiding ICU admissions. Do we need more studies to convince me that hydrophobia is not beneficial? Another less notable study performed by Yeo et al4Yeo H.J. Lee Y.S. Kim T.H. et al.Vasopressor initiation within 1 hour of fluid loading is associated with increased mortality in septic shock patients: analysis of National Registry data.Crit Care Med. 2022; 50: e351-e360Crossref PubMed Scopus (17) Google Scholar examined a national multicenter registry of the Korean Sepsis Alliance to determine differences in the outcome of patients with septic shock according to whether vasopressor was initiated within 1 h of the first fluid bolus. Of 2,126 patients, propensity score matching was performed in 415 patients that resulted in 149 patients having vasopressor ≤ 1 h matched to 149 patients having vasopressor > 1 h. The early vasopressor group had significantly fewer fluids in the first 6 h compared with the late vasopressor group: 1.8 ± 0.9 L vs 2.1 ± 0.8 L. At day 3, the early vasopressor group had significantly higher Sequential Organ Failure Assessment scores of 9.2 ± 4.8 vs 7.7 ± 3.8 and higher lactate of 2.8 (range, 1.5-6.8) vs 1.7 (range, 1.2-2.9) mM. Importantly, the early vasopressor group had significantly higher 28-day mortality rate: 47.7% vs. 33.6%. Although the quality of evidence in this nonrandomized study was definitely less than the CLOVERS trial, one must wonder if the CLOVERS trial had completed its expected enrollment of 2,320 patients, would the mortality rate be higher in the restrictive fluid group with early vasopressor use. In summary, the phases of shock resuscitation include (1) salvage or rescue, (2) optimization, (3) stabilization, and (4) de-escalation.5Vincent J.L. De Backer D. Circulatory shock.N Engl J Med. 2013; 369: 1726-1734Crossref PubMed Scopus (866) Google Scholar However, restricting fluids in favor of early vasopressor with the resulting bimodal hyperlactatemia and the hope of avoiding the adverse effects of hypervolemia suggests that the fluids paradigm should be (1) de-escalation, (2) catch-up, and then (3) rescue therapy. This seems irrational at best! None declared. Other contributions: The author thanks the Sepsis Steering Committee of CHEST for their review of this commentary prior to submission.