Refractory Septic Shock

Refractory septic shock is septic shock with persistent hypotension and hypoperfusion (mean arterial pressure under 65 mmHg, lactate over 2 mmol/L) despite adequate fluid and a noradrenaline dose of more than 0.25 microgram/kg/min, or an equivalent combination of vasopressors. It carries mortality over 50%.

Epidemiology. Septic shock affects about 1 in 5 patients with sepsis, with hospital mortality of 30 to 40%. Mortality rises steeply as vasopressor doses increase.

Causes of refractoriness. Uncontrolled source, inadequate antimicrobial coverage or resistant organisms, adrenal insufficiency, septic cardiomyopathy, severe acidosis, hypocalcaemia, hypovolaemia, tamponade, tension pneumothorax, drug effects and vasoplegia.

Pathophysiology. Inflammatory mediators and nitric oxide cause vasodilation and vascular hyporesponsiveness to catecholamines. Relative vasopressin deficiency, receptor downregulation, acidosis and adrenal dysfunction contribute. Capillary leak causes hypovolaemia, and cardiomyopathy reduces output in about 20 to 60% of patients.

Presentation is hypotension on high dose vasopressors, mottled skin, prolonged capillary refill, oliguria, confusion, rising lactate and multi-organ failure. Cardiac output may be low, normal or high.

Red flags.

• Noradrenaline over 0.25 microgram/kg/min, or lactate over 4 mmol/L.
• Poor source control, or necrotising infection.
• Falling cardiac output on echocardiography, or arrhythmia.

Repeat the search for source and cause: cultures (blood, urine, wound, respiratory), imaging (CT of the chest, abdomen and pelvis), echocardiography (right and left ventricular function, tamponade, vegetations), lactate, arterial gas, ionised calcium, cortisol, troponin, coagulation, procalcitonin and liver tests. Review the antimicrobial spectrum and dose against local resistance.

Differential diagnosis. Cardiogenic, hypovolaemic and obstructive shock, anaphylaxis, adrenal crisis, toxic shock syndrome, pancreatitis, drug toxicity (anti-hypertensives, sedatives) and endocrine causes.

Source control and antimicrobials. Drain, debride or remove infected devices within 6 to 12 hours. Give broad spectrum antimicrobials within 1 hour, dosed at the upper range with loading doses in shock, and adjust once cultures return.

Fluid. 30 mL/kg balanced crystalloid in the first 3 hours, then give further boluses (250 to 500 mL) only if the patient is fluid responsive. Consider albumin 4 to 5% when large crystalloid volumes are needed.

Vasopressors (mean arterial pressure target 65 mmHg).

• Noradrenaline 0.05 to 1 microgram/kg/min first line, through a central line (peripheral for a short time while central access is placed).
• Vasopressin 0.03 units/min (maximum 0.04 units/min) when noradrenaline exceeds 0.25 microgram/kg/min. Avoid higher doses because of digital and mesenteric ischaemia.
• Adrenaline 0.05 to 0.5 microgram/kg/min as a third agent, or when cardiac output is low. Expect lactate rise and tachyarrhythmia.
• Angiotensin II 20 nanogram/kg/min, titrated to a maximum of 80 nanogram/kg/min in the first 3 hours (maintenance up to 40 nanogram/kg/min), where available, with monitoring for thrombosis.
• Methylene blue 1 to 2 mg/kg IV over 20 to 60 minutes as a rescue for vasoplegia. Avoid in G6PD deficiency, and with serotonergic drugs because of serotonin syndrome.

Corticosteroid. Hydrocortisone 50 mg IV every 6 hours (or 200 mg daily by infusion) when vasopressor requirement is over 0.25 microgram/kg/min for 4 hours or more. Stop when vasopressors are off. Fludrocortisone 50 microgram daily may be added.

Inotrope. Dobutamine 2.5 to 20 microgram/kg/min for low cardiac output with adequate pressure, or add adrenaline. Levosimendan 0.05 to 0.2 microgram/kg/min is a specialist option. Venoarterial ECMO for refractory septic cardiomyopathy in selected centres.

Correct other contributors. Calcium (ionised calcium over 1.1 mmol/L), sodium bicarbonate 50 to 100 mmol IV for pH under 7.2 with acute kidney injury, correction of hypothermia, hypoglycaemia and tamponade.

Renal replacement therapy. For usual indications (refractory hyperkalaemia, acidosis, fluid overload, uraemia). Early initiation without these indications is not advised.

Monitoring. Arterial line, central venous access, lactate every 2 to 4 hours, cardiac output assessment (echocardiography or other), urine output, and capillary refill.

Referral and escalation. Intensive care, infection specialists and surgical teams. Discuss goals of care when organ failure is multiple and unresponsive.

Special groups. In pregnancy, tilt left and involve obstetrics. In renal and hepatic impairment, adjust antimicrobials after the first 24 hours. In children, adrenaline is first line for cold shock and noradrenaline for warm shock.