ASA!

ASA is a common medication that is also commonly found in other medications (i.e. salicylic acid—topical keratolytic agent for wart removal and methyl salicylate in Oil of Wintergreen). ASA has multiple cellular effects, including:

•  Stimulation of the chemo-receptor trigger zone in the medulla, stimulating nausea and vomiting
•  Inhibition of COX, leading to a decrease in prostaglandin synthesis, prostacyclines and thromboxanesà leading to platelet dysfunction and gastric mucosal injury
• Interaction with cellular metabolism (i.e. oxidative phosphorylation, Krebs cycle)à leading to metabolic acidosis
•  Stimulation and activation of the Respiratory Center in the medulla, leading to hyperventilation (respiratory alkalosis)

Metabolism:  Normally, ASA is rapidly absorbed in the stomach with peak blood concentrations reached within 1 hour. Note that 90% is protein bound at therapeutic levels, and is thus, limited to the vascular space.  The drug is metabolized via several different routes in the liver, where it is partially glycinated to salicyluric acid (a less toxic form that is more rapidly excreted by the kidneys than salicylate). Absorption and elimination are drastically altered with overdose!

• Peak levels are frequently delayed (especially if ER, enteric coated)
•  As ASA concentrations riseà the normal protective mechanisms are overwhelmedà degree of protein binding falls and hepatic detoxification becomes overwhelmed and saturatedà thus, more drug reaches the tissues and elimination is dependent on the slow renal excretion
•  This increases the drug’s half life from 2-4 hours to up to 30h

Clinical Features of ASA OD

Early Symptoms: nausea/vomiting (N/V), tinnitus, vertigo, diarrhea; more severe intoxications involve AMS, hyper-pyrexia, non-cardiogenic pulmonary edema and coma

Early symptoms: typically present within 1-2 hours after a single acute ingestion

 Fatal intoxication: can occur after 10-30 g by adults

Toxicity: does NOT correlate completely with serum salicylate [ ], however; most patients have symptoms when serum levels are >2.9-3.6 mmol/L

Vital signs: hyperpnea (early), pyrexia (salicylates uncouple oxidative phosphorylation in the mitochondria—generation of heat), tachycardia (hypovolemia)

-Tinnitus: can even occur with therapeutic ranges; usually resolves. Can have transient HL

-Acid Base Abnormalities: variety

• Stimulation of Respiratory Center in Medullaà hyperventilationà Fall in PCO2, leads to Respiratory Alkalosis
• Anion gap Metabolic Acidosis (AGMA): due to accumulation of organic acids, including lactic acids and ketoacidosis
• Salicylic acid alone: has minor effects on serum pH
•  NET: most have either a primary respiratory alkalosis or, more commonly, a mixed primary respiratory alkalosis and primary metabolic acidosis

·       NOTE: salicylic acid is a weak acid that exists in charged and uncharged forms. It is the uncharged form that can easily cross cellular barriers (i.e. BBB, epithelium in renal tubule). Treatment is aimed toward decreasing the fraction of uncharged (protonated) molecules, which is accomplished by increasing the systemic pH (i.e. lowering the H+ concentration). This is aka “alkalinization” to help “trap” the salicylate anions within the renal tubule.

·       Altered Mental Status (AMS): direct toxicity in CNS, neuroglycopenia & cerebral edema

o   Risk of seizures

o   Note that salicylates lower CNS [glucose]; may have normal serum BG!

·       Pulmonary edema & ALI: more common in older adults, especially those with chronic ASA intoxication

·       Arrhythmia: sinus tachycardia; can have ventricular arrhythmias (fluid + lyte shifts and alteration of membrane permeability in the cardiac myocytes)

·       Hypovolemia: can be significant (N/V, osmotic diuresis, hyperthermia)

·       Thrombocytopenia: low platelets, capillary fragility, decreased platelet adhesion

·       Hepatic: liver injury can lead to decreased glycogen production and increased lactate production

    INVESTIGATIONS: Serum ASA (generally, most patients with signs of intoxication have a level of 2.9-3.6 mmol/L). FATAL intoxication can occur with 10-30 g in an adult!!

•      Measure serum level q2h until there is a decrease from peak
•      Levels >7.2 mmol/L: associated with increased M&M, and ABSOLUTE indication for HD                                                  
•      Renal Function: Cr, Urea, monitor urine output, K+
•      Electrolytes: hypokalemia if present, must be treated aggressively as it promotes absorption of K+ in the DT (via K+/H+ exchange pump), which promotes proton secretion, interfering with efforts at urinary alkalinization!
•      INR, PTT, CBC (plt)
•         Lactate, ABG, AG (generally elevated), albumin
•         Consider: CXR, CT head
•      Urine pH and K+ q1 hour
•         ABG and Salicylate level in serum, q1-2 hours

Diagnosis: suspect based on history, physical, acid-base findings and confirm with {salicylates}

Chronic Salicylate Poisoning: more common in the young and the elderly d/t excess therapeutic administration

·       Difficult to diagnosis; clinical findings in acute and chronic poisoning often overlap

·       Classic S&S from acute cases are often milder or even absent in the chronic setting

·       Treatment: does not differ, except a LOWER [ ] of salicylates is generally used for HD

o   HD is often needed; discuss with nephrology in any patient with elevated serum level and any of the following—CNS changes (i.e. delirium, lethargy, seizures), AKI, pulmonary edema, severe Acid-Base (i.e. pH<7.3 despite aggressive IVF) or electrolyte abnormalities with no alternative explanation

MANAGEMENT

• ABCs; Avoid intubation if needed; can be dangerous (the rapid RR is compensatory!!). Aggressive IVF, u/o, monitor
• GI decontamination if indicated:   1 g/kg up to 50 g of Activated Charcol (via OG or NG within 2h of ingestion)
• Supplemental Glucose
• ASA decreases cerebral glucose concentration despite a normal serum BG
•  Give supplemental glucose to patients with an AMS!
• There are no clinical studies in humans upon which to base treatment; aim to keep the patient’s BG in the high normal range (i.e. 8-12 mmol/L)
•  If unable to eat, use IV boluses of dextrose (50-100 mL of 50%) or add 50-100 g of dextrose to each liter of maintenance of IVF
• Alkalinization of serum & urine: with NaHCO3à AN ESSENTIAL component!

o   Bolus: 1-2 Meq Na HCO3/kg

o   Then, NaHCO3 infusion of 100 to 150 mEq in 1 L of D5W

o   Titrate the rate based on a urine pH of 7.5-8

o   Hypokalemia MUST be treated or prevented for alkalinization to be effective

o   Monitor K, q1-2 hours!

NOTE: Alkalemia from a respiratory alkalosis is NOT a contraindication to NaHCO3. ASA poisoned patients commonly present with an arterial pH between 7.50 and 7.55; these patients should be treated with sodium bicarbonate

NOTE #2: Blood gas analysis every two hours is indicated for monitoring to prevent severe alkalemia (arterial pH >7.60). A urine pH of 7.5 to 8 is desirable

Concurrent alkalinization of the urine is also beneficial by increasing salicylate excretion. 

IV fluids are needed to treat dehydration and maintain urine output. Initial fluid resuscitation is performed with isotonic saline, usually at a rate of 10 to 15 mL/kg per hour for the first two to three hours, and is then titrated to maintain a urine output between 1 to 2 mL/kg per hour

HEMODIALYSIS (HD): efficacy of salicylate removal can be enhanced with HD. Indications include

• AMS
•  Pulmonary or cerebral edema
• Renal insufficiency interfering with salicylate excretion
• Fluid overload preventing the administration of NaHCO3
•  Serum salicylate >7.2 mmol/L in acute overdose
• Clinical deterioration despite aggressive and appropriate supportive care
• Consult nephrology