Current and emerging therapeutic options for refractory septic shock: A systematic review

Table 2 Study description

Ref.	Type of study	Type of patients	Primary outcomes	Number of patients	Mean age	Mortality
Lyu et al[15], 2022	RCT, single-center, double-blind	Adult patients with septic shock	Mortality at 90 days	Intervention Group: 213 patients received a combination of hydrocortisone, vitamin C, and thiamine. Control Group: 213 patients received 0.9% saline	64	90-day Mortality: 40.4% in the intervention group vs 39.0% in the placebo group. 28-day Mortality: 37.1% in the intervention group vs 36.2% in the placebo group
Ibarra-Estrada et al[16], 2023	RCT, double-blind	Adults Diagnosed with septic shock due to suspected or confirmed infection, requiring NE to maintain a MAP ≥ 65 mmHg and serum lactate > 2 mmol/L after adequate fluid resuscitation	28-day mortality	Methylene blue group: 45 patients received methylene blue as an adjunctive therapy. Placebo group: 46	46-47	28-mortality: MB 33% and P 46%
Hajjar et al[17], 2019	RCT, double-blind	Adults (≥ 18 years) with cancer admitted to the ICU, showing documented or strong clinical suspicion of infection and meeting at least two criteria of the systemic inflammatory response syndrome	28-day all-cause mortality	Vasopressin group: 125 patients NE group: 125 patients	NR	28-day mortality: Vasopressin group: 56.8%. NE group: 52.8%. 90-day mortality: Vasopressin group: 72.0%. NE group: 75.2%
Moskowitz et al[18], 2020	RCT, multicenter, double-blind	Adult patients with septic shock with infusion vasopressors	Change in SOFA score	Intervention: 100 patients received a combination of vitamin C, hydrocortisone, and thiamine. Control: 100 patients received a placebo	68	30-day mortality: Intervention group: 34.7%, placebo group: 29.3%
Fujii et al[19], 2020	RCT, multicenter, open label	Adults with documented infection, increase of at least 2 points in the SOFA score. Lactate levels greater than 2 mmol/L. Vasopressor dependency for at least 2 hours prior to enrollment	Time alive and free from vasopressors	Intervention Group: 109 patients received intravenous vitamin C, hydrocortisone, and thiamine. Control group: 107 patients received intravenous hydrocortisone alone	61.7	Intervention group: 28.6% mortality. Control group: 24.5% mortality
Sevransky et al[20], 2021	RCT, double-blind, adaptive	Adults with sepsis requiring mechanical ventilation or high-flow oxygen support due to respiratory failure. Continuous vasopressor support to maintain adequate blood pressure	days free of vasopressors and mechanical ventilation in the first 30 days	Treatment group: 1000 patients received combination therapy with vitamin C, thiamine, and corticosteroids. Control group: 1000 patients received matching placebos for each active agent	65	Interrupted before ending
Wang et al[21], 2022	Pilot RCT	Adults (≥ 18 years) with septic shock. NE dose ≥ 15 µg/minute	Renal perfusion: Assessed through changes in urine output and renal function parameters	22 patients: TP group: 10 patients. Usual care group: 12 patients	62.5	27.3% for the TP group and 41.7% for the usual care group
Cherukuri et al[22], 2019	RCT, double-blind	Adult patients with sepsis or septic shock	Length of ICU stay: Days on ventilator: Days on intravenous blood pressure support: 28-day mortality rate	Intervention: 32 patients received 100000 IU of vitamin A intramuscularly daily for 7 days. Control: 32 patients received a blinded placebo	51	28-Day Mortality Rates. Vitamin A group: 34%. Placebo group: 28%
Douglas et al[23], 2020	RCT, multicenter	Adults who presented with signs of sepsis and hypotension (MAP ≤ 65 mmHg) after receiving between 1 L and 3 L of fluids	Positive fluid balance at 72 hours or at ICU discharge, whichever occurred first	83 patients in the intervention group and 41 patients in the usual care group	62	Intervention group: 20.5%. Control group: 24.4%
Morelli et al[24], 2008	RCT	Adult patients with septic shock	The mortality rate is 28 days after treatment initiation. The outcome aimed to assess the effectiveness of combined dobutamine and TP treatment in improving survival rates in patients with septic shock	60	65	TG (dobutamine and TP): What is the primary and secondary outcome. 40% mortality. CG (standard treatment): 60% mortality
Albanèse et al[25], 2005	RCT, open-label study	Diagnosed with hyperdynamic septic shock after fluid resuscitation-Exhibited hemodynamic instability (MAP ≤ 60 mmHg). Had two or more organ dysfunctions	MAP achieved in patients with hyperdynamic septic shock after treatment with either NE or TP	20 patients, NE group: 10 patients, TP group: 10 patients	65	30% among the patients with hyperdynamic septic shock
Hyvernat et al[26], 2016	RCT, double-blind study	Persistent hypoperfusion despite adequate fluid resuscitation and NE administration. Defined as severe sepsis with arterial hypotension (SBP < 90 mmHg or MAP < 70 mmHg) despite adequate fluid resuscitation	Mortality in 28-day	59 in the 200 mg group and 63 in the 300 mg group	64.8	200 mg group: 52.5%. 300 mg group: 44.4%
Annane et al[27], 2002	RCT double-blind, parallel group	Adults (> 18 years). Required NE to maintain MAP. Urinary output less than 0.5 mL/kg/hour for at least 1 hour. Arterial lactate levels higher than 2 mmol/L	28-day survival	Corticosteroid group: Number of Patients: 151. Treatment: Received hydrocortisone (50 mg IV every 6 hours) and fludrocortisone (50 µg orally once daily) for 7 days. Placebo group: Number of patients: 149. Treatment: Received matching placebos for 7 days	63	Corticosteroid group: 43.0% (65 out of 151 patients). Placebo group: 49.7% (74 out of 149 patients)
Morelli et al[35], 2009	Pilot RCT	Patients diagnosed with septic shock. MAP below 65 mmHg despite adequate volume resuscitation	The primary outcome was the total NE dose required to maintain a MAP of 65-75 mmHg over the 48-hour treatment period	TP group: 15 patients. Vasopressin group: 15 patients. NE gsroup: 15 patients	65	Zero during 48 hours
Lv et al[36], 2017	RCT, double-blind	Adults (≥ 18 years). Onset of septic shock within 6 hours	28-day all-cause mortality	Hydrocortisone group: 58 patients. Placebo group: 60 patients	Hydrocortisone group: 65.4 years. Placebo group: 66.1 years	28-day mortality: Hydrocortisone group: 23.1%. Placebo group: 32.2%. In-Hospital mortality: Hydrocortisone group: 31.0%. Placebo group: 40.0%
Russell et al[32], 2008	RCT, multicenter, double-blind	Adults diagnosed with septic shock requiring vasopressor support, NE	28-day all-cause mortality	Vasopressin group: 396 patients. NE group: 382 patients	64	28-day mortality: Vasopressin group: 35.4%. NE group: 39.3%. 90-day mortality: Vasopressin group: 43.9%. NE group: 49.6%
Russell et al[31], 2009	Post hoc, multicenter, blinded RCT substudy	(≥ 16 years). Diagnosed with septic shock, ongoing hypotension requiring at least 5 µg/minute of NE infusion for a minimum of 6 hours	28-day mortality	Corticosteroid treatment group: Vasopressin + corticosteroids: 296 patients. NE + corticosteroids: 293 patients. Corticosteroid treatment group: Vasopressin: 93 patients. NE: 97 patients	60	28-day mortality overall: Corticosteroids + vasopressin: 35.9% corticosteroids + NE: 44.7%. No corticosteroids + vasopressin: 66.7%. No corticosteroids + NE: 62.9%
Yildiz et al[37], 2011	RCT, double-blind	Adults (≥ 18 years). Confirmed sepsis, characterized by infection and systemic inflammatory response syndrome. Patients were often classified based on severity scores, such as APACHE II or SOFA, indicating varying degrees of organ dysfunction	28-day mortality	Steroid group: 100 patients. Placebo group: 100 patients	60	Steroid group: 16 (59.3) and placebo group: 15 (53.6)
Keh et al[30], 2003	RCT, double-blind crossover	Proven or strongly suspected infection. Presence of three or more of the following conditions: Mechanical ventilation. Heart rate > 90 beats per minute. Temperature > 38 °C or < 36 °C. White blood cell count > 12000 cells/µL or < 4000 cells/µL, or > 10% immature cells. Sepsis-induced hypotension: SBP < 90 mmHg or a reduction of > 40 mmHg from baseline	Change in MAP and systemic vascular resistance after treatment with low-dose hydrocortisone compared to placebo	Hydrocortisone group: 20. Placebo group: 20	Hydrocortisone group: 54. Placebo group: 50	Hydrocortisone group: 30%. Placebo group: 30%
Keh et al[38], 2016	RCT, double-blind	Adults (≥ 18 years). Evidence of infection Systemic response to infection (at least 2 systemic inflammatory response syndrome criteria). Organ dysfunction present for no longer than 48 hours. Not in septic shock at the time of randomization	Development of septic Shock: Within 14 days of treatment	Hydrocortisone group: 190. Placebo group: 190	65	28-day mortality: Hydrocortisone group: 21.1%. Placebo group: 23.7%. 90-day mortality: Hydrocortisone group: 28.4%. Placebo group: 30.5%. 180-day mortality: Hydrocortisone group: 34.2%. Placebo group: 36.8%
Annane et al[34], 2018	RCT, multicenter, double-blind	Adults (≥ 18 years). Diagnosed with septic shock requiring vasopressor therapy	90-day all-cause mortality	Hydrocortisone plus fludrocortisone: 614. Placebo: 626	63	28-day mortality: Hydrocortisone plus Fludrocortisone: 20%. Placebo: 25%. 90-day all-cause mortality: Hydrocortisone plus fludrocortisone group: 30%. Placebo group: 36%
Venkatesh et al[33], 2019	RCT, multicenter, double-blind	Adults undergoing mechanical ventilation. Documented or strongly suspected infection. Treated with vasopressors or inotropic agents at least 4 hours prior to randomization	90-day all-cause mortality	Hydrocortisone: 1988. Placebo: 1902	63	28-day mortality: Hydrocortisone group: 197. Placebo group: 199. 90-day all-cause mortality: Hydrocortisone group: 511; placebo group: 526
Liu et al[28], 2018	RCT, multicenter, double-blind	Adults with hypotension despite adequate fluid resuscitation, and at least two diagnostic criteria for systemic inflammatory response syndrome	28-day mortality	TP group: 312 patients. NE group: 305 patients	61	28-day mortality: TP group: 40%; NE group: 38%
Xiao et al[29], 2016	RCT	Adults with SBP < 90 mmHg and MAP < 65 mmHg are required to use vasoactive agents	7-day mortality	NE group: 17, NE + TP group: 15	63.2	7-day mortality: NE group 76.5% and NE + TP 33.3%

APACHE II: Acute Physiology and Chronic Health Evaluation II; ICU: Intensive care unit; MAP: Mean arterial pressure; NE: Norepinephrine; RCT: Randomized clinical trial; SOFA: Sequential Organ Failure Assessment; SBP: Systolic blood pressure; TP: Terlipressin.