Acetaminophen Overdose

Today we discussed our approach to Acetaminophen overdose or poisoning. I wanted to elaborate a bit more on the clinical progression of symptoms:

Initial: mild, non-specific

Stage I (0.5-24h): nausea, vomiting, diaphoresis, pallor, lethargy, malaise, asymptomatic;

o   Labs are often normal +/- enzyme elevation, CNS usually normal

Stage II (24-72h):

o   Hepatotoxicity: transaminase elevation, RUQ pain, elevation INR, Bilirubin

o   Nephrotoxicity: may see evidence of oliguria, elevated Urea, Cr

Stage III (72-96h)

o   Liver function abnormalities: peak; enzymes elevated, INR elevated, Bilirubin elevated, hypoglycemia, lactic acidosis

o   Worsening symptoms: jaundice, confusion, bleeding diasthesis, hepatic encephalopathy

o   AKI: primarily due to acute tubular necrosis and vascular endothelial damage & ischemia, with elevated Cr, urea, hematuria, proteinuria, granular/epithelial casts. Occurs in ~10% of severe poisonings

o   Death most commonly occurs in this stage *(from multi-organ failure)

Stage IV (4 days to 2 weeks): recovery may be slow, particularly in ill patients

o   Histological recovery lags behind clinical recovery, and may take up to 3 months 

Resources:
Rowden A, et al. Updates on acetaminophen toxicity. Med Clin N America 2005; 89: 1145-59

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

The interesting world of Heme! Evans Syndrome

Evans Syndrome

We recently mentioned Evans Syndrome (ES) in Morning Report.

This condition was initially described by Evans and colleagues in 1951, when describing a cohort of patients whose clinical presentation and course was characterized by autoimmune hemolytic anemia and immune thrombocytopenia; interesting, a few patients also had neutropenia as well.

Evans Syndrome (ES) includes the following features: Coombs-positive warm autoimmune hemolytic anemia (IgG), and immune thrombocytopenia (ITP). Some patients also have autoimmune neutropenia. Interestingly, the antibodies that play a role in hemolysis are different from those that result in the destruction of platelets:

• Antibodies involved in RBC destruction: directed against a base protein found in the Rh blood group
• Antibodies that destroy platelets: often directed against GPIIb/IIIa                                                                    NOTE: The typical course is one that is chronic and relapsing.

Etiology: the etiology is not completely understood, but it is postulated to involve non-cross reacting autoantibodies directed against antigens specific to RBCs, platelets, and neutrophils 

• Many cases: idiopathic
• Associations: SLE, lymphoproliferative disorders, autoimmune lymphoproliferative syndrome, common variable immunodeficiency, hypogammaglobulinemia, post-allogenic hematopoietic cell transplant

Treatment: medical management can be challenging, with varying response to therapy even within the same individual patient throughout their disease course!

• First line: course of glucocorticoid (i.e. Prednisone 1-2 mg/kg/day)
• IVIG may help those that are dependent on steroids
• Second line: studies in small case series à danazol, cyclophosphamide, azathioprine
•  Third line: Consideration of Rituximab (chimeric human/mouse monoclonal antibody that targets CD20 on lymphocytes)
•  Splenectomy
•  Hematopoietic cell transplantation

NOTE: there are no randomized controlled trials (RCTs) on the treatment of ES. There is insufficient information in the literature to choose one agent over the other. Recent literature includes more support for success with the use of Rituximab

Resources:

 Blood (2009). Michel, M. et al. “The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases”