Fluids or vasopressors: Is sepsis management that simple?

In recent months, we have seen the results of the much awaited Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial showing that a restrictive fluid and early vasopressor strategy initiated on arrival of patients with sepsis and hypotension in the ED did not result in decreased mortality compared with a liberal fluid approach (PETAL Network. www.nejm.org/doi/10.1056/NEJMoa2202707). The March 2023 issue of CHEST Physician provided a synopsis of the trial highlighting several limitations (Splete H. CHEST Physician. 2023;18[3]:1). Last year in 2022, the Conservative versus Liberal Approach to Fluid Therapy in Septic Shock (CLASSIC) trial also showed no difference in mortality with restrictive fluid compared with standard fluid in patients with septic shock in the ICU already receiving vasopressor therapy (Meyhoff TS, et al. N Engl J Med. 2022;386[26]:2459). Did CLOVERS and CLASSIC resolve the ongoing debate about the timing and quantity of fluid resuscitation in sepsis? Did their results suggest a “you can do what you want” approach? Is the management of sepsis and septic shock limited to fluids vs vasopressors? Hopefully, the ongoing studies ARISE FLUIDS (NCT04569942), EVIS (NCT05179499), FRESHLY (NCT05453565), 1BED (NCT05273034), and REDUCE (NCT04931485) will further address these questions.

In the meantime, I continue to admit and care for patients with sepsis in the ICU. One example was a 72-year-old woman with a history of stroke, coronary artery disease, diabetes, and chronic kidney disease presenting with 3 days of progressive cough and dyspnea. In the ED, temperature was 38.2° C, heart rate 120 beats per min, respiratory rate 28/min, blood pressure 82/48 mm Hg, and weight 92 kg. She had audible crackles in the left lower lung. Her laboratory and imaging results supported a diagnosis of sepsis due to severe community-acquired pneumonia, including the following values: white blood cell 18.2 million/mm3; lactate 3.8 mmol/L; and creatinine 4.3 mg/dL.

While in the ED, the patient received 1 liter of crystalloid fluids and appropriate broad spectrum antibiotics. Repeat lactate value was 2.8 mmol/L. Patient’s blood pressure then decreased to 85/42 mm Hg. Norepinephrine was started peripherally and titrated to 6 mcg/min to achieve blood pressure 104/56 mm Hg. No further fluid administration was given, and the patient was admitted to the medical ICU. On admission, a repeat lactate had increased to 3.4 mmol/L with blood pressure of 80/45 mm Hg. Instead of further escalating vasopressor administration, she received 2 L of fluid and continued at 150 mL/h. Shortly after, norepinephrine was titrated off. Fluid resuscitation was then deescalated. We transfered the patient to the general ward within 12 hours of ICU admission.

Could we have avoided ICU admission and critical care resource utilization if the patient had received more optimal fluid resuscitation in the ED?

While our fear of fluids (or hydrophobia) may be unwarranted, the management of this patient was a common example of fluid restriction in sepsis (Jaehne AK, et al. Crit Care Med. 2016;44[12]:2263). By clinical criteria, she was in septic shock (requiring vasopressor) and appropriately required ICU admission. But, I would posit that the patient had severe sepsis based on pre-Sepsis 3 criteria. Optimal initial fluid resuscitation would have prevented her from requiring vasopressor and progressing to septic shock with ICU admission. Unfortunately, the patient’s care reflected the objective of CLOVERS and its results. Other than the lack of decreased mortality, decreased ventilator use, decreased renal replacement therapy, and decreased hospital length of stay, restricting fluids resulted in an increase of 8.1% (95% confidence interval 3.3 to 12.8) ICU utilization. Furthermore, the data and safety monitoring committee halted the trial for futility at two-thirds of enrollment. One must wonder if CLOVERS had completed its intended enrollment of 2,320 patients, negative outcomes would have occurred.

Should an astute clinician interpret the results of the CLOVERS and CLASSIC trials as “Fluids, it doesn’t matter, so I can do what I want?” Absolutely not! The literature is abundant with studies showing that increasing dose and/or number of vasopressors is associated with higher mortality in septic shock. One example is a recent multicenter prospective cohort study examining the association of vasopressor dosing during the first 24 hours and 30-day mortality in septic shock over 33 hospitals (Roberts RJ, et al. Crit Care Med. 2020;48[10]:1445).

Six hundred and sixteen patients were enrolled with 31% 30-day mortality. In 24 hours after shock diagnosis, patients received a median of 3.4 (1.9-5.3) L of fluids and 8.5 mcg/min norepinephrine equivalent. During the first 6 hours, increasing vasopressor dosing was associated with increased odds of mortality. Every 10 mcg/min increase in norepinephrine over the 24-hour period was associated with a 33% increased odds of mortality. Patients who received no fluids but 35 mcg/min norepinephrine in 6 hours had the highest mortality of 50%. As fluid volume increased, the association between vasopressor dosing and mortality decreased, such that at least 2 L of fluid during the first 6 hours was required for this association to become nonsignificant. Based on these results and a number of past studies, we should be cautious in believing that a resuscitation strategy favoring vasopressors would result in a better outcome.

Shock resuscitation is complex, and there is no one-size-fits-all approach. With the present climate, the success of resuscitation has been simplified to assessing fluid responsiveness. Trainees learn to identify the inferior vena cava and lung B-lines by ultrasound. With more advanced technology, stroke volume variation is considered. And, let us not forget the passive leg raise. Rarely can our fellows and residents recite the components of oxygen delivery as targets of shock resuscitation: preload, afterload, contractility, hemoglobin, and oxygen saturation. Another patient example comes to mind when fluid responsiveness alone is inadequate.

Our patient was a 46-year-old man now day 4 in the ICU with Klebsiella bacteremia and acute cholecystitis undergoing medical management. His comorbidities included diabetes, obesity, hypertension, and cardiomyopathy with ejection fraction 35%. He was supported sson mechanical ventilation, norepinephrine 20 mcg/min, and receiving appropriate antibiotics. For hemodynamic monitoring, a central venous and arterial catheter have been placed. The patient had a heart rate 92 beats per min, mean arterial pressure (MAP) 57 mm Hg, central venous pressure (CVP) 26 mm Hg, stroke volume variation (SVV) 9%, cardiac output (CO) 2.5 L/min, and central venous oxygen saturation (ScvO₂) 42%.

Based on these parameters, we initiated dobutamine at 2.5 mcg/kg/min, which was then titrated to 20 mcg/kg/min over 2 hours to achieve ScvO₂ 72%. Interestingly, CVP had decreased to 18 mm Hg, SVV increased to 16%, with CO 4.5 L/min. MAP also increased to 68 mm Hg. We then administered 1-L fluid bolus with the elevated SVV. Given the patient’s underlying cardiomyopathy, CVP < 20 mm Hg appeared to indicate a state of fluid responsiveness. After our fluid administration, heart rate 98 beats per min, MAP 70 mm Hg, CVP increased to 21 mm Hg, SVV 12%, CO 4.7 L/min, and ScvO₂ 74%. In acknowledging a mixed hypovolemic, cardiogenic, and septic shock, we had optimized his hemodynamic state. Importantly, during this exercise of hemodynamic manipulation, we were able to decrease norepinephrine to 8 mcg/min, maintaining dobutamine at 20 mcg/kg/min.