CONTENTS
Approach to shock
Refractory shock
Shock is a state of systemic hypoperfusion, with inadequate blood supply to the tissues. Unfortunately, this may occur in different ways. The most simple physiology of shock is cardiogenic shock, with low cardiac output to the entire body. However, septic shock can occur with an elevated cardiac output due to microvascular dysfunction at the tissue level (blood shunts through some vessels, while ignoring others). Because shock has varying physiologies, it defies any simple operational definition at the clinical level. Shock is a bit like obscenity – after a while, you know it when you see it.
Shock is extraordinarily important because it is generally a final common pathway before death. Most serious diseases are capable of causing shock. Left untreated, shock will progress to multi-organ failure and death. However, shock is often reversible, thereby avoiding death.
The importance of promptly diagnosing shock and discerning its cause cannot be overstated. Unfortunately, shock may present in a variety of ways, so diagnosis isn't always so simple. For example, shock is typically associated with hypotension and reduced cardiac output, but it can also occur with normal blood pressure and an increased cardiac output.
Different types of shock present differently. For example, the stereotypical patient with early sepsis and distributive shock will appear quite different from the patient with cardiogenic shock (table below). Unfortunately, reality isn't quite this simple. Advanced cardiogenic shock often causes bacterial translocation from the intestines, leading to systemic inflammation and vasodilation. Alternatively, advanced septic shock frequently causes a septic cardiomyopathy. Thus, advanced cardiogenic shock and advanced septic shock may be very difficult to sort out.
There is no single diagnostic test for shock. Patients with various forms of shock will present differently. Nonetheless, there is a constellation of findings which often occurs in the context of shock. As patients accrue many of these features, the possibility of shock should be seriously considered.
hemodynamics (trends > absolute values)
- Hypotension (e.g., MAP below ~65 mm, or significant drop from baseline).
- Elevated shock index:
- Shock index = HR / SBP.
- Shock index above ~0.8 suggests significant instability.
- Bradycardia: cardiac output is directly proportional to heart rate. Severe bradycardia (e.g. heart rate below ~45) should always raise concern for shock. Even if the blood pressure is maintained by compensatory systemic vasoconstriction, cardiac output and perfusion may still be poor (more on bradycardia here).
oliguria (or dark urine)
- Urine output below ~0.5 cc/kg/hour is worrisome for renal malperfusion.
- Dark urine also suggests renal hypoperfusion (e.g., immediately after Foley catheter insertion, before the urine output is known).
- (More on the approach to oliguria: 📖).
skin perfusion
- Cool hands and knees are an early sign of vasoconstriction with reduced cardiac output. Normal people may have cool hands, but if all extremities are cool that's more specific for hypoperfusion.
- Mottling is less sensitive, but more specific for hypoperfusion and elevated mortality (figure below). Mottling suggests active endogenous vasoconstriction, implying that the patient would benefit from an increase in cardiac output (e.g. an inotrope) – not additional exogenous vasoconstrictors.
- Capillary refill time: The ideal technique may be to compress the fingertip using a slide with enough pressure to cause blanching for ten seconds. Any clear surface can also be used, such as a plastic urine specimen container.(27908340) Normal capillary refill time is <3-4 seconds, whereas >5 seconds suggests impaired perfusion.
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2017/06/mottling.png?resize=400%2C289&ssl=1)
delirium
- New-onset delirium can be a sign of shock (especially septic shock). However, this is neither very sensitive nor specific.
- Most new-onset delirium isn't due to shock.
- ⚠️ Patients with acute-on-chronic cardiogenic shock can maintain normal mentation despite profoundly low cardiac output.
hyperlactatemia (or jumping anion gap)
- Lactate >4 mM suggests shock, but this has a broad differential diagnosis. Lactate usually doesn't reflect oxygen deficiency, but rather endogenous epinephrine in response to physiologic stress.🌊 This explains why lactate can be normal in shocked patients who have inadequate sympathetic nervous function.
- High lactate level is worrisome. This should be interpreted to represent shock or some other impending disaster until proven otherwise.
- Normal lactate isn't necessarily reassuring (it can occur in shock).
- (Further discussion of the evaluation of hyperlactatemia: 📖)
- 💡 A sudden jump in the patient's anion gap suggests hyperlactatemia if there is no obvious alternative explanation (e.g., absence of starvation or diabetes that could cause ketoacidosis). In a hospitalized patient, a jumping anion gap represents shock until proven otherwise.
- (Further discussion of the evaluation of anion gap elevation: 📖)
arrhythmic shock
- Tachyarrhythmia (usually >>150 b/m).
- Bradyarrhythmia (usually <45 b/m).
hypovolemic shock
- Hemorrhage:
- External bleeding (penetrating trauma, postpartum).
- GI bleed.
- Retroperitoneal bleed.
- Intraperitoneal bleed.
- Hemothorax.
- Hypovolemia:
- Vomiting and/or diarrhea.
- Over-diuresis.
- Post-ATN or postobstructive polyuria.
LV failure (“cardiogenic” shock)
- LV systolic failure:
- Myocardial infarction.
- Myocarditis.
- Overdose (e.g., beta-blocker).
- Acute aortic or mitral valve regurgitation:
- Endocarditis.
- Papillary muscle rupture.
- Aortic dissection.
- Prosthetic valve thrombosis.
- Dynamic LV outflow tract obstruction (LVOTO).
RV failure
- Pulmonary embolism.
- Decompensated chronic pulmonary hypertension.
- Right ventricular myocardial infarction.
obstructive
- Tamponade.
- Tension pneumothorax.
- Elevated intrathoracic pressure:
- Abdominal compartment syndrome.
- AutoPEEP.
vasodilatory shock (“distributive” shock)
- Severe systemic inflammation:
- Septic shock.
- Pancreatitis.
- Post-cardiac arrest SIRS.
- Post-MI SIRS.
- Anaphylaxis.
- Endocrine:
- Adrenal crisis.
- Thyroid storm.
- Neurogenic shock:
- Trauma.
- Spinal anesthesia.
- Liver failure.
- Excess vasodilatory drugs.
history and data review
- ? Cardiac history (Especially any prior information about cardiac structure/function such as EKG, echo, or even chest CT showing chamber size).
- ? Adrenal disease (Noting: Patients chronically on oral steroid may be assumed to be insufficient).
- ? History of venous thromboembolic disease.
- ? Immunosuppression, ? Invasive devices (e.g. hemodialysis catheters).
- ? Recent procedures or trauma.
- ? Current medications & changes in medication list.
examination
labs
- Electrolytes (including Ca/Mg/Phos).
- Complete blood count with differential.
- Coagulation studies.
- CRP (C-reactive protein).
- Lactate.
- If septic shock is suspected:
- Blood cultures x2.
- Urinalysis with reflex culture.
- Sputum culture if clinically indicated.
- Procalcitonin (if initiating antibiotics).
- Endocrine evaluation:
- Random cortisol level (if adrenal insufficiency is possible).
- TSH (if thyroid storm suspected).
- Troponin (if ECG/history suggest acute MI).
radiologic studies
- EKG is occasionally helpful (e.g., may reveal occlusive MI, or RV strain).
- CXR (e.g., may reveal pneumonia, or cardiogenic edema implying LV failure).
- CT may be considered depending on the clinical scenario:
- CTA to evaluate for pulmonary embolism.
- CT abdomen/pelvis to evaluate for septic focus.
differential & categorization
Findings on ultrasonography and physical examination may be integrated as shown below. This tends to work best in previously-healthy patients with a single mechanism of shock. Patients with multiple chronic problems or multifactorial shock may defy categorization.
Stabilization must start immediately, often before the cause of shock is known. The following are common interventions to consider.
volume resuscitation
- Fluid administration should be tailed to the individual patient's hemodynamic assessment.
- Fluid is often provided in boluses (e.g., 500 ml) with attention to patient response. The total amount of fluid administered should generally be limited to <1-2 liters in the absence of a history suggesting substantial total-body volume depletion (e.g., severe gastroenteritis with a colostomy).
- Fluid administration can be diagnostic and therapeutic in confusing situations where hypovolemia is suspected:
- If fluid resuscitation alone resolves shock, this supports a diagnosis of hypovolemia.
- If fluid resuscitation fails, this suggests an alternative diagnosis. This is especially true if fluid resuscitation results in adequate filling pressures (e.g., full IVC) without resolving the shock.
vasopressor administration
- Vasopressor administration should be started immediately if the blood pressure is inadequate (e.g., MAP<60 mm).
- Vasopressors may be administered via peripheral vein.
- Norepinephrine may be given peripherally with careful monitoring of the IV site for limited periods of time.
- Phenylephrine or epinephrine have a lower risk of extravasation and may be safer to use in situations with less rigorous monitoring.🌊
antibiotics
- If sepsis is possible, cultures should be performed and empiric antibiotics should be started without delay.
- In patients with possible sepsis, you don't necessarily need to go extremely broad with the antibiotics. A single broad-spectrum agent may be reasonable (e.g., piperacillin-tazobactam).
steroids
- Indicated for patients whom you suspect have adrenal crisis, for example:
- Patients with known adrenal insufficiency.
- Patients taking chronic steroids who recently missed doses.
- When in doubt about adrenal insufficiency, a reasonable approach is to give 6 mg dexamethasone and check a cortisol level simultaneously. Dexamethasone doesn't interfere with the cortisol level, allowing you to perform an ACTH-stim test later on if indicated. (More on adrenal crisis 📖)
Patients with refractory shock usually have a pre-identified etiology of their shock. Nonetheless, some degree of clinical re-evaluation is often useful:
diagnostic tests to consider for patients failing to respond to therapy
- Cardiac imaging:
- Laboratory evaluation may include:
- ABG/VBG and electrolytes (to evaluate pH status).
- Glucose level.
- Ionized calcium level.
- Cortisol level.
- TSH +/- free T4 levels.
- Lactate level.
- Complete blood count (to evaluate for hemorrhage).
- Infectious evaluation (e.g., CRP, procalcitonin, blood cultures).
treatment options include
Multimodal therapy is often required. Below are over a dozen potential treatments to consider:
define & optimize MAP targets
- Central arterial line insertion (femoral or axillary):
- Radial arterial lines may underestimate blood pressure. 🌊
- Reducing MAP target:
- If very high doses of norepinephrine are required to achieve a MAP >65 mm (e.g. >1 ug/kg/min), this may be causing more harm than good. Reducing the MAP target to >55 or >60 could potentially represent a more beneficial balance of vasopressor benefit vs harm.
review medications & stop drugs that cause hypotension
- Hemodynamically stable analgosedation:
- Propofol or dexmedetomidine are excellent sedatives, but they can reduce the blood pressure.
- More hemodynamically stable agents may be preferable (e.g., ketamine infusion, PRN benzodiazepines).
- Discontinue any alpha-blockers being utilized for BPH (benign prostatic hypertrophy).
optimize preload
- PEEP reduction: for ventilated patients, reduction of the mean airway pressure may increase preload.
- autoPEEP? Evaluate for this and manage aggressively.
- Volume administration: patients have usually been fluid resuscitated by this point, but preload and fluid status should be re-evaluated (e.g., with POCUS).
metabolic optimization
- Temperature management:
- Hypothermia causes cardiac dysfunction.
- Hyperthermia causes increased metabolic demands and reduced systemic vascular resistance.
- Intravenous calcium:
- Consider this for patients with ionized calcium <0.8 – 0.9 mM.
- Further discussion of calcium infusions for refractory shock: 📖
- pH optimization:
- Bicarbonate: management of acidosis may improve vasopressor responsiveness.
- Ventilator management: consider increasing tidal volume and respiratory rate (but avoid autoPEEP).
- Dialysis: may be required.
- IV thiamine (to empirically treat for beriberi; may improve lactate clearance).
- Steroid (may enhance vascular responsiveness to vasopressors; especially for patients with sepsis/SIRS). (38202178)
- High dose insulin infusion (primarily for beta-blocker or calcium channel blocker poisoning with reduced systolic function). 📖
vasopressor optimization
- Titration of conventional pressors:
- High-dose norepinephrine (there is no maximal dose 🌊).
- Vasopressin:
- 0.06 U/min is safe (with monitoring for digital ischemia & hypoperfusion).
- 0.1 U/min has been used in post-cardiac surgery vasoplegia. (18305265)
- Epinephrine challenge (empirical evaluation of the response to 4 mcg/min of epinephrine; if a favorable response occurs then titrate to effect).
- Methylene blue: discussed below: ⚡️
- Hydroxocobalamin: discussed below: ⚡️
- Angiotensin II (if your hospital has this).
heart rate optimization
- For paced patients:
- Temporary transvenous pacemaker: titrate heart rate to 100-120 b/m to determine if this improves perfusion.
- Permanent pacing: consult electrophysiology to increase heart rate.
- ⚠️ Caution: if increasing the rate of the electrical pacemaker reduces the number of native beats that are conducting through the patient's native conduction system, this may not be beneficial.
- For relative/absolute bradycardia, may consider:
- Positive chronotropic agents (e.g., isoproterenol).
- Therapies for refractory bradycardia (e.g., atropine). 📖
- For atrial fibrillation: What is the optimal heart rate? 📖
antibiotics
- Antibiotics should be considered if septic shock is possible.
right ventricular optimization
- Inhaled epoprostenol for patients with right ventricular dysfunction.
- More on managing RV failure: 📖
contraindications & cautions with MB
- ⚠️ Risk of serotonin syndrome (e.g., recent use of selective serotonin reuptake inhibitors, high-dose fentanyl). (28655448)
- ⚠️ G6PD deficiency (glucose-6-phosphate dehydrogenase deficiency) – either personal or family history.
- Methylene blue can act as an oxidizing agent at high doses (e.g., >7 mg/kg). This may cause methemoglobinemia. In patients with G6PD deficiency, this could also cause hemolytic anemia.
- ⚠️ Hemodynamics:
- Severe pulmonary hypertension (MB will increase the pulmonary vascular resistance).
- Cardiogenic shock (increased afterload may promote pulmonary edema).
- Hypovolemic shock (excessive afterload could reduce cardiac output).
- Mesenteric vasoconstriction may occur. (38365828)
- ⚠️ Continuous renal replacement therapy:
- Methylene blue can cause some hemodialysis machines to malfunction.
- ⚠️ Poor IV access: Extravasation of methylene blue may cause tissue necrosis.
- ⚠️ Pregnancy: Nitric oxide is expressed in the placenta. Methylene blue could place the fetus at risk of hypoxia, due to placental vasoconstriction. (32705530)
- ⚠️ Medication interactions: Methylene blue may inhibit CYP enzyme metabolism, leading to accumulation of some medications (e.g. digoxin, warfarin, fentanyl).
indications for MB
- Refractory vasoplegic shock of any etiology.
- Especially following cardiothoracic surgery.
- Possibly also: septic shock, anaphylaxis.
- Metformin poisoning.📖
dose of MB
- Usual dose is 1-2 mg/kg (e.g., 100 mg). This may be infused over a variable time frame (from 5 minutes to six hours, depending on patient acuity). The largest RCT investigating methylene blue in septic shock utilized 100 mg doses diluted in 500 ml saline that were infused over 6 hours every day, for a total of three days. (36915146)
- ⚠️ If administered rapidly, methylene blue will temporarily cause spuriously low pulse oximetry results.
- ⚠️ Methylene blue can cause tissue necrosis if it extravasates. Ideally MB should be infused via a central line. Dilution in larger volumes of carrier solution might also reduce this risk (e.g., 100 mg diluted in 500 ml saline).
- Infusion for refractory shock states:
- Studies have described infusions ranging from 0.25 – 1 mg/kg/hour. (29329694)
- Infusions can be continued for up to 48-72 hours, with weaning off based on hemodynamics.
- Infusion increases the risk of drug accumulation, so this should probably be limited to truly refractory shock. The half-life of methylene blue may range from ~5-24 hours, casting some doubt on whether an ongoing infusion is pharmacokinetically required. An alternative strategy is to repeat doses of 1-2 mg/kg q4-6 hours as needed. (29329694)
- ⚠️ Doses >7 mg/kg may cause numerous side effects (nausea, vomiting, confusion, dyspnea, tremulousness, diaphoresis, methemoglobinemia, hemolytic anemia).
- Hepatic and/or renal dysfunction: patients may metabolize methylene blue slowly, so exercise caution with repeated doses or continuous infusions.
pharmacology of MB
- Half-life may range from ~5-6 hours. (38365828)
- Methylene blue is mostly metabolized by the liver (CYP 1A2, 2C19, and 2D6), but ~40% is excreted unchanged in the urine.
role of MB in therapy for septic shock
- MB was historically utilized as a salvage therapy for patients refractory to all other treatments. However, a recent meta-analysis of RCTs found a mortality benefit from methylene blue (when combining patients with septic shock and patients with post-surgical vasoplegia). (37880041) A single-center RCT found that early MB administration accelerated shock resolution, with subsequent reduction in ICU length of stay. (36915146) These studies suggest that earlier introduction of MB into therapy could be reasonable. However, MB has yet to demonstrate efficacy in a large, multicenter randomized controlled trial.
- MB seems to be a fairly safe therapy if appropriate caution is utilized surrounding drug-drug interactions, contraindications (listed above), and cumulative dose (ideally maintained below ~5 mg/kg and spread out over time). Extravasation with skin necrosis does remain a concern, even at lower doses. Consequently, it might be reasonable to consider MB for patients who are failing to respond well to vasopressors and have central vascular access.
mechanisms of action
- (1) Methylene blue causes vasoconstriction by inhibiting nitric oxide synthase:
- This is a potentially dangerous way to increase blood pressure, because it could potentially impair microvascular perfusion.
- Historically, a nitric oxide synthesis inhibitor was shown to increase mortality in septic shock.(14707556)
- (2) Methylene blue inhibits guanylate cyclase, thereby blocking the conversion of guanosine triphosphate to cGMP (an intracellular signaling molecule which increases vasodilation).
- (3) Methylene blue may be able to accept electrons from NADH and transfer them to cytochrome C in the mitochondria, thereby bypassing parts of the electron transport chain. This could restore mitochondrial function in some situations where parts of the electron transport chain are dysfunctional; for example metformin toxicity.(28840449)
contraindications & cautions with hydroxocobalamin
- ⚠️ Continuous renal replacement therapy:
- Hydroxocobalamin can cause some hemodialysis machines to malfunction.
- ⚠️ Laboratory artifacts may occur: including measurement of: (37225547, 38030578)
- Alkaline phosphatase.
- Bilirubin.
- Creatinine.
- Glucose.
- Hemoglobin.
- Potential complications:
indications for hydroxocobalamin
- [1] Refractory vasodilatory shock, potentially including:
- Postoperative vasoplegia.
- Drug-induced vasoplegia.
- Refractory septic shock (supported by a pilot trial showing reduced vasopressor requirements, and animal studies showing improved survival). (36174744)
- [2] Cyanide toxicity.
- Hydroxocobalamin may be preferred over methylene blue in patients with contraindications to methylene blue, including: (37225547)
- G6PD deficiency.
- Risk for serotonin syndrome.
- Severe pulmonary hypertension.
- (Additional contraindications to methylene blue are listed in the section above.)
dose of hydroxocobalamin
- The usual dose is 5 grams IV over 10-15 minutes (this is the dose in Cyanokit). (37225547) However, some reports describe the use of 10 grams. (38202178)
- Most studies describe the use of a single dose of hydroxocobalamin. (38030578)
pharmacokinetics
- Half-life may be ~26-31 hours. (37225547)
pharmacodynamics & mechanism of action
- Hydroxocobalamin inhibits nitric oxide directly and also inhibits nitric oxide synthase. It might also function by elimination of the endogenous vasodilator hydrogen sulfide (H2S). (37225547)
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- Patients who have suffered cardiac arrest or MI will often develop a post-arrest or post-MI distributive shock due to cytokine release and systemic inflammation. This may lead to a confusing multifactorial picture, where distributive shock may obscure the primary problem.
- There is no sign, symptom, or lab which is entirely sensitive for shock. Therefore, no single investigation can exclude shock (e.g. “the patient is mentating well so she cannot be in shock” or “the lactate is normal so that excludes shock” are both incorrect statements).
- Patients in distributive shock may have a normal blood pressure, particularly if they have chronic hypertension.
- Diagnostic algorithms for shock (like any diagnostic algorithms) work best among patients with a single disease process who were previously normal. Unfortunately, many patients have multifactorial shock on an abnormal baseline (e.g. chronically reduced ejection fraction) – so simple algorithms will fail these patients.
- The most common cause of shock of unclear etiology is septic shock. However, other causes should be carefully excluded prior to reaching an empiric diagnosis of septic shock (e.g. echocardiography to evaluate for massive pulmonary embolism or pericardial tamponade).
- Don't forget to evaluate archival data (e.g. old EKGs and CT scans). These may help sort out chronic pathology versus acute pathology.
References
- 28984705 Gidwani H, Gómez H. The crashing patient: hemodynamic collapse. Curr Opin Crit Care. 2017 Dec;23(6):533-540. doi: 10.1097/MCC.0000000000000451 [PubMed]
- 29329694 Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB. Management of Refractory Vasodilatory Shock. Chest. 2018 Aug;154(2):416-426. doi: 10.1016/j.chest.2017.12.021 [PubMed]
- 31348056 Chow JH, Abuelkasem E, Sankova S, Henderson RA, Mazzeffi MA, Tanaka KA. Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock. Anesth Analg. 2020 Jan;130(1):15-30. doi: 10.1213/ANE.0000000000004343 [PubMed]
- 32145658 Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care. 2020 Jun;57:148-156. doi: 10.1016/j.jcrc.2020.02.011 [PubMed]
- 32705530 Puntillo F, Giglio M, Pasqualucci A, Brienza N, Paladini A, Varrassi G. Vasopressor-Sparing Action of Methylene Blue in Severe Sepsis and Shock: A Narrative Review. Adv Ther. 2020 Sep;37(9):3692-3706. doi: 10.1007/s12325-020-01422-x [PubMed]
- 36174744 Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J, Markiewicz A, Spiegelhoff K, Hipp LA, Canales B, Szabo A, Heyland DK, Stoppe C, Zielonka J, Freed JK. High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The Intravenous Hydroxocobalamin in Septic Shock Trial). Chest. 2023 Feb;163(2):303-312. doi: 10.1016/j.chest.2022.09.021 [PubMed]
- 36915146 Ibarra-Estrada M, Kattan E, Aguilera-González P, Sandoval-Plascencia L, Rico-Jauregui U, Gómez-Partida CA, Ortiz-Macías IX, López-Pulgarín JA, Chávez-Peña Q, Mijangos-Méndez JC, Aguirre-Avalos G, Hernández G. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023 Mar 13;27(1):110. doi: 10.1186/s13054-023-04397-7 [PubMed]
- 37225547 Kumar N, Rahman GR, Falkson S, Lu SY, Dalia A. Hydroxocobalamin in Refractory Vasodilatory Shock: More Questions than Answers. J Cardiothorac Vasc Anesth. 2023 Sep;37(9):1773-1775. doi: 10.1053/j.jvca.2023.05.001 [PubMed]
- 37880041 Pruna A, Bonaccorso A, Belletti A, Turi S, Di Prima AL, D'amico F, Zangrillo A, Kotani Y, Landoni G. Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials. J Cardiothorac Vasc Anesth. 2023 Oct 1:S1053-0770(23)00802-9. doi: 10.1053/j.jvca.2023.09.037 [PubMed]
- 38030578 Wedemire C, Samavat H, Newkirk M, Parker A. Treatment of refractory shock with vitamin B12 : A narrative review. Nutr Clin Pract. 2024 Apr;39(2):356-365. doi: 10.1002/ncp.11095 [PubMed]
- 38202178 Bacchi B, Cabrucci F, Chiarello B, Dokollari A, Bonacchi M. Severe Refractory Vasoplegic Shock Syndrome after OPCABG Successfully Treated with Hydroxycobalamin: A Case Report and Review of the Literature. J Clin Med. 2023 Dec 28;13(1):169. doi: 10.3390/jcm13010169 [PubMed]
- 38365828 Arias-Ortiz J, Vincent JL. Administration of methylene blue in septic shock: pros and cons. Crit Care. 2024 Feb 16;28(1):46. doi: 10.1186/s13054-024-04839-w [PubMed]