What can be given if levothyroxine (T4) and vasopressin are no longer effective?

Refractory Vasopressor-Resistant Shock: Next-Line Agents

When norepinephrine (levophed) and vasopressin fail to maintain adequate blood pressure in septic shock, add angiotensin II, terlipressin, or epinephrine as salvage vasopressors, while simultaneously addressing reversible causes including adrenal insufficiency (hydrocortisone 200 mg/day) and hypothyroidism (thyroid hormone replacement). 1

Hemodynamic Phenotype-Directed Therapy

The choice of next agent depends critically on the underlying hemodynamic state, which should be assessed using cardiac output monitoring (pulmonary artery catheter, pulse contour analysis, or echocardiography) and ScvO2 monitoring. 1

High Cardiac Output, Low SVR (Warm Shock)

When norepinephrine and vasopressin at standard doses fail to restore MAP ≥65 mmHg:

• Add low-dose vasopressin (0.03 units/min), angiotensin II, or terlipressin as third-line vasoconstrictors to restore vascular tone 1
• Vasopressin doses >0.03-0.04 units/min should be reserved for salvage therapy only 1
• Critical caveat: These potent vasoconstrictors can reduce cardiac output, requiring continuous CO/ScvO2 monitoring 1
• If cardiac output drops with vasopressor escalation, add low-dose epinephrine or dobutamine to maintain tissue perfusion 1
• Terlipressin has longer duration of action than vasopressin or angiotensin, making toxicities more prolonged 1

Low Cardiac Output, Low Blood Pressure, Low SVR (Cold Shock)

This represents the most challenging hemodynamic profile:

• Add norepinephrine to epinephrine (if epinephrine is already being used) to increase diastolic blood pressure and SVR 1
• Once adequate blood pressure is achieved, add dobutamine, phosphodiesterase III inhibitors (enoximone preferred for minimal vasodilatory effects), or levosimendan to improve cardiac index and ScvO2 1
• Target hemodynamic goals: ScvO2 >70%, cardiac index 3.3-6.0 L/min/m², and normal perfusion pressure for age (MAP-CVP) 1

Low Cardiac Output, Normal Blood Pressure, High SVR

This phenotype requires afterload reduction rather than additional vasopressors:

• First-line vasodilators: Nitroprusside or nitroglycerin in patients with epinephrine-resistant shock and preserved blood pressure 1
• If cyanide toxicity (nitroprusside), methemoglobin toxicity (nitroglycerin), or continued low cardiac output develops, substitute milrinone or inamrinone 1
• Important caveat: Long elimination half-lives of phosphodiesterase inhibitors can lead to slowly reversible toxicities (hypotension, tachyarrhythmias), particularly with renal or hepatic dysfunction 1

Hormonal Replacement for Refractory Shock

Adrenal Insufficiency

Hydrocortisone 200 mg/day should be administered when adequate fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability: 1, 2

• Give as continuous infusion (preferred) or divided doses every 6 hours 1, 2
• Do not use ACTH stimulation test to identify patients requiring hydrocortisone 1, 2
• Taper hydrocortisone when vasopressors are no longer required to avoid secondary adrenal insufficiency 1, 2
• Duration typically 7-14 days, with gradual reduction rather than abrupt cessation 2

Thyroid Hormone Replacement

Thyroid replacement with triiodothyronine (T3) is warranted for documented thyroid insufficiency in refractory shock: 1

• This addresses the relative hypothyroidism that can occur in critical illness 1
• Critical safety consideration: In patients with suspected concurrent adrenal insufficiency, always start corticosteroids before thyroid hormone to prevent adrenal crisis 3

Addressing Reversible Causes of Refractory Shock

Before escalating to ECMO, systematically evaluate for occult morbidities: 1

• Mechanical causes: Pericardial effusion (pericardiocentesis), pneumothorax (thoracentesis), increased intra-abdominal pressure (peritoneal catheter/abdominal release) 1
• Endocrine: Hypoadrenalism (hydrocortisone), hypothyroidism (thyroid hormone) 1
• Hemorrhage: Ongoing blood loss (transfusion/hemostasis) 1
• Infection control: Necrotic tissue removal, source control with antibiotics achieving MIC <1, IV immunoglobulin for toxic shock 1
• Immunologic: Excessive immunosuppression (wean agents), immune compromise (white cell growth factors/transfusion for neutropenic sepsis) 1

ECMO as Ultimate Salvage Therapy

When potentially reversible causes are addressed and conventional therapies fail, ECMO becomes the final option: 1

• Expected survival with ECMO is approximately 50% 1
• Technical considerations: Flows >110 mL/kg/min should be avoided due to hemolysis risk 1
• Maintain free hemoglobin <10 μg/dL by using adequate catheter, circuit, and oxygenator sizes 1
• Normalize calcium concentration in red blood cell pump prime (typically 300 mg CaCl₂ per unit PRBC) 1
• Additional venous access may be required if ECMO flow <110 mL/kg/min with negative pressure <−25 mm Hg 1

Common Pitfalls to Avoid

• Failing to identify hemodynamic phenotype: Blindly adding vasopressors without knowing cardiac output can worsen outcomes in low-output states 1
• Ignoring endocrine causes: Relative adrenal insufficiency and hypothyroidism are frequently overlooked reversible causes 1, 2
• Starting thyroid hormone before steroids: This can precipitate adrenal crisis in patients with concurrent adrenal insufficiency 3
• Excessive vasopressin dosing: Doses >0.03-0.04 units/min should only be used as salvage therapy 1
• Missing mechanical complications: Pericardial effusion, pneumothorax, and increased intra-abdominal pressure are readily treatable if identified 1