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

Table 3 Secondary endpoints of the studies

Ref.	Secondary outcomes	Adverse events
Lyu et al[15], 2022	28day mortality; ICU mortality; Hospital mortality; reversal of shock; time to shock reversal; 12 hours delta SOFA score; ICU free days; vasopressor free days; ventilator support free days; length of stay in ICU; length of stay in hospital	Hyperglycemia; hypernatremia; fluid overload
Ibarra-Estrada et al[16], 2023	Hemodynamic parameters; organ dysfunction; length of stay; adverse events	Hypotension; serotonin syndrome; there was a risk of serotonin syndrome, particularly in patients taking selective serotonin reuptake inhibitors. Allergic Reactions to methylene blue. Other minor events; nausea, vomiting, and local infusion site reactions
Hajjar et al[17], 2019	90 days all cause mortality; days free from advanced support; adverse effects	Arrhythmia
Moskowitz et al[18], 2020	Kidney failure; 30 day mortality; ventilator free days; shock free; ICU free days	Hyperglycemia; hypernatremia; new hospital acquired infections
Fujii et al[19], 2020	90 days mortality; duration of ICU stay; duration of hospital stay; The total length of time patients remained hospitalized. Organ dysfunction scores; adverse events	Intervention, 10 (10.2%) vs usual care, 7 (15.6%). Not related
Sevransky et al[20], 2021	Mortality at 30 days, ICU mortality, mortality at 180 days, length of ICU stay, length of hospital stay, and longterm emotional and cognitive outcomes at 180 days
Wang et al[21], 2022	Mortality rate at 28 days. Hemodynamic parameters; Including MAP and NE requirements. Adverse events related to TP use. Changes in serum creatinine levels and other renal function indicators	Cardiovascular events; increased heart rate or arrhythmias. Renal events; worsening renal function or acute kidney injury. Gastrointestinal events; ischemic colitis or other gastrointestinal complications. New infections or worsening of existing infections. Injection Site Reactions; Localized reactions at the site of TP administration
Cherukuri et al[22], 2019	Serum vitamin A levels; cortisol response; incidence of adverse effects	Nausea; injection site reactions
Douglas et al[23], 2020	RRT; mechanical ventilation; discharge rates; mortality rates	Arrhythmias; NE extravasation
Morelli et al[24], 2008	NE requirements; systemic and regional hemodynamic; organ function; SvO2	TP; cardiac ischemia; decreased cardiac output; gastrointestinal ischemia; skin reactions as pallor due to vasoconstriction. Dobutamine; tachyarrhythmias; increased myocardial oxygen demand; hypotension
Albanèse et al[25], 2005	Cardiac index; oxygen delivery index; oxygen consumption index; renal function; blood lactate levels	NE; tissue ischemia due to excessive vasoconstriction; arrhythmias or increased heart rate; increased oxygen demand of tissues; decreased mesenteric blood flow; TP; decreased cardiac index and potential for reduced oxygen delivery; bradycardia; fluid overload is used with caution in patients with renal impairment
Hyvernat et al[26], 2016	Vasopressor requirements, infectious and digestive complications, hemodynamic responses, days free from mechanical ventilation, vasopressors, and renal replacement therapy, adverse events	Haemorrhagic events; superinfections
Annane et al[27], 2002	Mortality rates; overall mortality rates at various time points (e.g., 7 days, 14 days). Time to vasopressor withdrawal; adverse events; clinical improvement	Infections; increased incidence of new infections in both groups. Gastrointestinal issues; stress ulcers or gastrointestinal bleeding. Hyperglycemia; observed in the corticosteroid group. Electrolyte Imbalances; Including hyponatremia and hyperkalemia. Neurological Events; Such as delirium or altered mental status
Morelli et al[35], 2009	Hemodynamic parameters; organ function; adverse events; mortality	Tachyarrhythmias; 1 in the vasopressin group. 4 in the NE group. Changes in bilirubin levels; higher total and direct bilirubin concentrations in the vasopressin and NE groups; platelet count; a decrease in platelet count was observed only in the TP group over time. Renal function; RRT was noted in the NE group
Lv et al[36], 2017	In hospital mortality; reversal of shock; duration of ICU stay; duration of hospital stay	Hyperglycemia; hydrocortisone group; 90.9%; placebo group; 81.5%
Russell et al[32], 2008	90 days mortality; organ dysfunction; adverse events; vasopressor requirements	Cardiac events (e.g., arrhythmias); Ischemic events (e.g., limb ischemia); other complications related to the use of vasopressors
Russell et al[31], 2009	Duration of vasopressor support; sock reversal; organ dysfunction; length of ICU stay; adverse events	Arrhythmias; limb ischemia; gastrointestinal ischemia
Venkatesh et al[33], 2018	28 days all cause mortality; Evaluated to assess shorter term effects. Duration of vasopressor use; measured to determine the impact on hemodynamic support. Duration of mechanical ventilation; assessed to evaluate respiratory support needs. Organ dysfunction; quality of life	Hyperglycemia; gastrointestinal bleeding; secondary infections
Yildiz et al[37], 2011	Adverse events; hormonal levels; incidence of adrenal insufficiency (AI) and Relative Adrenal Insufficiency (RAI); Assessment of adrenal function in patients; APACHE II and SOFA scores; clinical characteristics	No serious adverse events were reported in either the steroid or placebo groups
Keh et al[30], 2003	Inflammatory markers; NE requirements; immune function; mortality rates	Infections; increased incidence of secondary infections in both groups, but no significant difference between hydrocortisone and placebo. Gastrointestinal bleeding, though it was not significantly higher in the hydrocortisone group. Hyperglycemia; the hydrocortisone group required insulin management for some patients
Keh et al[38], 2016	Time until septic shock; mortality 28 days, 90 days, 180 days; secondary infections; weaning failure; muscle weakness; hyperglycemia	Hyperglycemia; secondary infections; muscle weakness; weaning failure
Annane et al[34], 2018	Mortality rates; days alive and free of vasopressors; organ failure; mechanical ventilation	Gastrointestinal bleeding; superinfection; hyperglycemia; neurologic sequelae
Liu et al[28], 2018	change in sofa score; days alive and free of vasopressors; incidence of serious adverse events	Digital ischemia; severe diarrhea; arrhythmias; intestinal ischemia
Xiao et al[29], 2016	hemodynamic parameters; complications; success rate for 6 hours resuscitation goals	Cardiac arrhythmias; skin necrosis at infusion sites; other organ dysfunctions

APACHE II: Acute Physiology and Chronic Health Evaluation II; ICU: Intensive care unit; NE: Norepinephrine; SOFA: Sequential Organ Failure Assessment; TP: Terlipressin; SvO₂: Oxygen venous saturation.