UMEM Educational Pearls - By Jordan Parker

Background:

Septic shock is a severe and common critical illness that is managed in the emergency department.  Our current foundation of treatment includes IV fluids, empiric antibiotic coverage, vasopressor therapy, source control and corticosteroids for refractory shock.  The levels of nitric oxide (NO) and hydrogen sulfide (H2S) are elevated in sepsis and associated with worse outcomes.  Hydroxocobalamin is an inhibitor of NO activity and production and a scavenger of H2S [1,2].  Most of the current data is limited to observational studies looking at hydroxocobalamin in cardiac surgery related vasodilatory shock with few case series and reports for use in septic shock.  The available data has shown an improvement in hemodynamics and reduction in vasopressor requirements in various vasodilatory shock states [2].  Chromaturia and self-limited red skin discoloration are common side effects but current data has not shown significant adverse events [3,4].  Patel et al, performed a phase 2 single-center trial to evaluate use of high dose IV hydroxocobalamin in patients with septic shock. 

Study:

• Single-center, double-blind RCT, 20 patients (10 hydroxocobalamin, 10 placebo)
• Included patients >/= 18 years of age within 48 hours of admission with a diagnosis of septic shock (based on Sepsis 3 criteria) who were receiving norepinephrine (NE) of 0.10 mcg/kg/min for at least 15 minutes or an equivalent dose of alternative vasopressor.
• Notable exclusion criteria were patients with a history of urinary calcium oxalate crystals, active hemolysis or bleeding, impending death.
• Intervention group received a single dose of 5 grams of IV hydroxocobalamin administered over 15 minutes
• Primary outcome – Feasibility Study (*Initial primary outcome was reduction in vasopressor dose but was changed during the COVID-19 pandemic to a feasibility study*)
• Secondary outcomes – Change in H2S levels and NE dose from randomization to 30 minutes and 3 hours after IV hydroxocobalamin.

Results

• Achieved feasibility with enrollment goal, receiving intervention, no contamination and good follow up.
• For secondary outcomes the study group showed a statistically significant relative decrease in vasopressor dose compared to placebo at 30 minutes (-36% vs 4%, p < 0.001) and 3 hours after infusion (-28% vs 10%, p = 0.019). 
• Non-statistically significant reduction in H2S levels in the intervention group compared to placebo.
• Tertiary outcomes of hospital mortality, ICU mortality, ICU and vasopressor free days did not show any significant difference between the groups. (The study was not designed with the power to look for a difference in these outcomes).  

Take home

There is a low risk of serious adverse events from high dose hydroxocobalamin use [3,4].  For now, it may be reasonable to consider in cases of septic shock refractory to standard care but there isn’t enough data to support its regular use yet.

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Diabetic ketoacidosis (DKA) is a serious condition that carries the risk of significant morbidity and mortality if not managed appropriately. Typically managed with an infusion of regular insulin, IV fluids, and electrolytes, there is evidence to support treatment of mild to moderate DKA with a subcutaneous (SQ) regimen using a combo of fast-acting and long-acting insulin instead, decreasing the need for ICU admission without increasing adverse events [1].  

What patients? 

• Isolated DKA without other ICU requirements 
• Mild-moderate severity as described below [2].

Adapted from Abbas et al. 

How to manage? 

• These patients still require aggressive fluid replacement, frequent POC & BMP monitoring, aggressive electrolyte repletion and treatment of any underlying precipitating cause for their DKA.   
• Insulin dosing should not be started until adequate electrolyte repletion has occurred. 
• There is no universally-accepted protocol and several exist [1-4].   A reasonable approach:

Initial dose 

• Insulin long-acting (glargine) 0.2 to 0.3 units/kg SQ or patient’s home dose 
• Insulin fast-acting (aspart/lispro) 0.3 units/kg SQ

Subsequent dosing: 

If serum glucose is > 250 mg/dL 

• Insulin short-acting 0.2 units/kg every 2 -4 hours

If serum glucose is < 250 mg/dL 

• Insulin short-acting 0.1 units/kg every 2 – 4 hours OR SSI every 4 hours

Bottom Line 

DKA management with a SQ insulin protocol is a reasonable approach for patients with mild to moderate DKA, is supported by the American Diabetes Association [5], and can be particularly helpful in this era of ED boarding and bed shortages.  Give a long-acting insulin dose every 24 hours (or restart the patient’s home long-acting regimen) and short-acting insulin every 2 to 4 hours.  Aggressive IV fluid resuscitation, electrolyte repletion, and treatment of underlying precipitating cause remain additional cornerstones of DKA management.

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