The study which adopts a prospective observational method,was approved by the medical ethics review committee of The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University (Approval No.  S-22) , and informed consent was obtained from patients or their next of kin. Enrollment occurred between August 2019 to January 2021 in Department of Critical Care Medicine (ICU), Chengdu Third People's Hospital. Patients with septic shock were admitted to our department and they were placed with endotracheal intubation, invasive ventilator assisted ventilation, pulse indicator continuous cardiac discharge monitoring (PICCO) catheter and deep vein catheter due to their condition. Inclusion criteria were age ≥ 18 years, 24 h after ICU admission, heart rate greater than 95 bpm after appropriate hemodynamic therapy, need for norepinephrine (≥ 0.10 μg/kg/min) to maintain mean arterial pressure (MAP>65 mmHg), Global End-Diastolic Volume Index (GEDVI) > 700ml / m2, and Intrathoracic Blood Volume Index (ITBVI > 850ml/ m2).
Exclusion criteria were previous treatment with β blockers before or within 24h of ICU admission, severe valvular disease, congenital heart disease or cardiomyopathy, severe pulmonary bullae or spontaneous pneumothorax, need for inotropic agents or severe cardiac dysfunction (CI < 2.2L/min/m2 and GEDVI > 700ml / m2 and ITBVI > 850ml/ m2), adequate sedation and analgesia for less than 36 h, length of stay in the ICU less than 48 hours, surgery or re-operation within 48 hours after admission to ICU, and pregnancy.
Measurements of Hemodynamics
Enrolled patients within 24 hours of admission to the ICU, the primary treatments were taken as follows: 1) Hemodynamic therapy: hemodynamic therapy with shock resuscitation immediately after the patient was admitted to the ICU. Hemodynamic treatment objectives were: CI>3 L/min/m2 and GEDVI>700ml/m2, ITBVI>850ml/m2；MAP>65mmHg, central venous oxygen saturation （ScvO2）≥70%, and urine output >0.5 ml/kg/h. 2) Respiratory support therapy: Mechanical ventilation was performed in volume control mode (AVEA ,CareFusion, California, US) with a target tidal volume of 6 to 8 ml / kg or less. 3) Sedation and analgesia: Dexmedetomidine or midazolam was used for continuous intravenous infusion sedation, fentanyl or butorphanol was used for analgesia, 4) Others: Rational use of antibiotics to fight infection, insulin control of blood sugar, dynamic monitoring of blood lactic acid level, maintaining acid-base electrolyte balance, etc
24 hours after admission to ICU, patients whose heart rate was more than 95 beats / min after hemodynamic optimization and needed norepinephrine (≥0.10μg/kg/min) to maintain blood pressure began to receive intravenous esmolol (Esmolol Hydrochloride Injection, Qilu Pharmaceutical, Jinan, China) to control heart rate. The loading dose was 0.25 ~ 0.5mg/kg (intravenous injection, administration time at least 1min) and the maintenance dose was 0.05mg/kg/min, iv (intravenous pumping), which was dynamically adjusted by the doctor in charge according to the heart rate and the changes of the disease. 24 hours after the patient enters the ICU, the target heart rate was controlled at 80-94 bpm until he leaves the ICU .
Through continuous sedation at the bedside until the patient no spontaneous breathing and can hold his breath for 12s, steady-state CO, CVP and MAP were measured over the last 3 seconds of 12-second inspiratory hold maneuvers at plateau pressures of 5, 15, 25 and 35 cmH2O. The ventricular output (VO) curve and venous return (VR) curve were constructed for the 4 pairs of CO, MAP values and CO, CVP values obtained from the 4 plateau pressures. A linear regression line was fitted through these data points. When the flow velocity was zero, the cutoff values of the pressure axis were Pcc and Pmsf, respectively [16,17].
CVP, MAP, HR, GEDVI, ITBVI, extravascular lung water (EVLWI), cardiac stroke volume index (SI), CI, ScvO2, Pcc, Pmsf, VO curve slope, VR curve slope, blood lactate level (Lac), central venous-to-arterail carbon dioxide difference (Pcv-aCO2), dosage of norepinephrine and urine output per hour were observed and recorded before and 1 hour after esmolol treatment (that is, 24 and 25 hours after ICU admission). During the observation period, the patient was no longer treated with fluid resuscitation, and only the necessary drugs were given to maintain infusion. The systemic vascular resistance index (RIs) was defined as RIs=(MAP-CVP)/CI, arterial vascular resistance index (RIa)=(MAP-Pcc)/CI, venous vascular resistance index (RIv)=(Pmsf-CVP)/CI. When Pcc > Pmsf, there is a vascular waterfall.
Statistical analyses were performed using SPSS 22.0 (IBM, Armonk, NY, US). The measurement data are presented as mean±SD (x±s). The data before and after treatment with esmolol were compared by a paired-sample t test. The least square method was used to fit the linear regression of Pcc and Pmsf. Differences with a p value of less than 0.05 were considered statistically significant.