A 45 year old male who had recently been diagnosed with depression after losing his job presented to the Emergency Department complaining of nausea, abdominal pain, and one episode of blood -tinged vomitus. He also complained of mild shortness of breath and a slight ringing in his ears. Three hours earlier he took approximately fifty 325 mg aspirin tablets. There was no significant past medical history.
On physical examination he appeared nauseated and diaphoretic. His pulse was 110, blood pressure 140/80, respiratory rate 26, and temperature 38.2 . The lungs were clear to auscultation and the abdomen was mildly, diffusely tender.
1)What are the principles of immediate evaluation and treatment ?
2)How is salicylate use quickly confirmed ?
3)How should this patient be treated ?
Salicylates
Plain ASA is rapidly absorbed with peak levels obtained at 4 hours. The therapeutic dose is 15 mg/kg and the dose where life-threatening toxicity can occur is approximately 150 mg/kg. In overdose situations it causes an uncoupling of oxidative phosphorylation resulting in decreased ATP, increased catabolism and oxidation, increased heat release with hyperthermia, increased O2 consumption, increased CO2 production, increased substrate demand, increased gluconeogenesis, lipid breakdown, and ketosis. Kreb’s cycle enzyme inhibition leads to anaerobic metabolism and lactic acidosis. Furthermore, it causes direct stimulation of the respiratory center resulting in respiratory alkalosis. The mixed acid-base disturbance of respiratory alkalosis and an anion gap metabolic acidosis is suggestive of salicylate toxicity.
Initial assessment of a patient who has ingested an overdose of salicylates should include a careful assessment of vital signs , paying particular attention to the depth and rate of respirations as well as the temperature. Since aspirin is a GI irritant, early onset of nausea, abdominal pain, and blood-tinged vomitus is characterisitic. The presence of tinnitus and lethargy indicate that a significant quantity of salicylate has entered into the CNS. The additional presence of confusion, coma, seizures, or any nonspecific neurological presentation should further heighten the suspicion of salicylate overdose. The lungs should be auscultated carefully because noncardiogenic pulmonary edema can occur with large salicylate ingestions and its presence will limit treatment with sodium bicarbonate.
A simple bedside test can be performed to confirm the usage of salicylates while awaiting a serum level. Two drops of ferric chloride ( FeCl3) placed in one ml of urine will turn a purple color if the patient has ingested a minimum of one aspirin in the past 24 hours. This test confirms that salicylates have been taken, but does not confirm that an overdose has been ingested. Furthermore, a bedside urine ketone determination will usually be positive due to the increased fatty acid metabolism caused by salicylate overdose. The arterial blood gas typically shows a mixed pattern of a respiratory alkalosis (due to respiratory center stimulation) and a metabolic acidosis.
The combination of these symptoms, signs, and rapidly obtainable tests allows the clinician to rapidly confirm a salicylate ingestion and start early therapeutic interventions while a salicylate level is pending. Patients who are severely ill on presentation should be placed on oxygen, a pulse oximeter, a cardiac monitor, and have intravenous access and a Foley catheter placed. Maintenance of the airway is essential. The protective nature of the induced hyperventilation in maintaining alkalemia must be recognized. Maintaining an alkalemic pH is critical in preventing the drug from leaving the bloodstream and entering the CNS. The administration of a sedative agent that blunts respiratory drive, such as a benzodiazepine, has lead to rapid death. If the patient is to be intubated, care should be taken to maintain the often profound respiratory alkalosis during and following intubation
Fluid and electrolyte replacement is also essential, as volume loss secondary to vomiting, hyperventilation, and diaphoresis is common. All salicylate poisoned patients are at risk for hypoglycemia and dextrose should be supplied in the iv fluids. Gastric lavage may be very useful for large ingestions who present early, but by the time most patients present the administration of activated charcoal is probably more important.
Sodium bicarbonate is a key therapeutic tool in the management of salicylate toxicity. Acidemia from any etiology must be treated aggressively, as it facilitates the entry of salicylate into the brain and other tissues and may lead to rapid deterioration. Alkalinization of the urine with bicarbonate increases the less mobile non-permeable ionized form of salicylate in the urine since salicylic acid is a weak acid ( pKa 3.5 ). This "traps " the salicylic acid in the urine where it is excreted, thus greatly enhancing elimination of salicylate from the body. When the urine pH increases from 5 to 8, the renal clearance of salicylate increases 10 to 20 times. Any patient manifesting signs or symptoms of salicylism with a level above the therapeutic range ( 2.2 mMol/L ) should have alkalinization begun. Two ampules ( 1 - 2 mEq/Kg) of sodium bicarbonate should be given immediately, then 3 ampules of NaHCO3 ( 132 mEq ) in 1 litre of D5W should be run at a 1.5 to 2 times maintenance fluid range. The goal is to maintain the urine pH at 7.5 to 8 and the urine pH should be followed hourly. The ABG’s should also be followed to avoid an arterial pH greater than 7.55. If difficulty in achieving urinary alkalinization occurs, hypokalemia, volume depletion, or excretion of organic acids are possible etiologies. Alkalinization is contraindicated when the volume load cannot be tolerated because of congestive heart failure, renal failure, cerebral edema, or non-cardiogenic pulmonary edema. Patients with these complications and toxicity should receive dialysis. Other indications for hemodialysis include failure to respond to alkalinization satisfactorily, persistant CNS disturbance, progressive deterioration in vital signs, severe acid-base or electrolyte disturbances, or a level greater than 7.2 mMol/L at 6 hours post-ingestion. Any patient with an initial level greater than 8.7 mMol/L should be considered for immediate hemodialysis.
Admission to hospital is recommended for any patient with an acute intoxication and significant symptoms irrespective of levels, or any arterial blood gas abnormality.
Infants with any clinical evidence of salicylism as well as adults who are chronically on salicylates and have clinical evidence of salicylism are at particularly high risk and should be admitted. Failure of serum levels to fall on serial determinations is also an indication for admission.
The correlation between toxicity and serum salicylate levels is unfortunately poor. The widely used Done normogram is useful only in certain narrowly defined situations and generally should not be used. It was developed in a pediatric population to be used only 6 hours after a single acute ingestion of non-enteric coated aspirin, when the serum pH is known to be 7.4. The normogram has been demonstrated to have a poor predictive value in adult populations. Because there are numerous case reports of patients with presumably benign initial salicylate determinations who deteriorated afterwards, repeat testing of serum levels is mandatory every 2 to 4 hours after ingestion until a peak level is determined and there is consistent evidence of a dropping level. Delayed absorption can occur due to pylorospasm, pyloric stenosis, or gastric outlet obstruction induced by the salicylate. Fatalities can definitely occur within 6 hours so a level should be drawn immediately upon presentation. A concurrent arterial blood gas should be drawn so that the level can be interpreted in light of the serum pH. When the patient is acidemic, more of the drug leaves the bloodstream to enter the tissues and CSF. Thus a falling serum level may reflect redistribution with increasing toxicity rather than increased drug clearance with decreasing toxicity. In summary, the patients clinical signs and symptoms are given the highest priority, the serum salicylate level is used in conjunction with the ABG pH, and levels should be followed serially until it is clear a peak level has been reached and drug elimination from the body is occurring.
Salicylates
Pharmacokinetics
- plain ASA rapidly absorbed with peak levels at 4 hours
- ECASA needs alkaline environment to dissolve
- pylorospasm at large doses with bezoar formation delays peak levels
- conjugated and renally excreted ( !st order at low doses, zero order at high
- albumin binding saturated at low doses
- T1/2 can increase to 15 - 30 hours
- therapeutic dose = 15 mg/kg
- toxic dose 150 mg/kg
Pathophysiology
1) uncouples oxidative phosphorylation
( decreased ATP, increased catabolism and oxidation, increased heat release, increased O2 consumption, increased CO2 production, increased substrate demand,
increased gluconeogenesis, lipid breakdown, ketosis )
2) direct stimulation of the respiratory center ( resp alkalosis )
3) Krebs cycle enzyme inhibition ( anaerobic metabolism - lactate )
4) adrenal medullary stimulation - hyperglycemia unless depleted glycogen stores
cerebral hypoglycemia may be present despite normal serum glucose
Net results
hyperthermia
glucosuria, ketonemia, hypo/hyperglycemia
ABG show resp alk and AGMA unless co-ingestants
lytes - low Na, H,K, volume due to vomiting
alkalosis - renal losses of Na, K, HCO3
direct effects on tubules - increase loss of K
uncoupling - decreased ATP, increased Na/H2O intracell/ K extracell
Clinical
- 3 groups of Sx acutely
1) tinnitus/ impaired hearing
2) hyperventilation ( increased Vt ), vomiting, dehydration, hyperthermia, CNS disturbances
3) Pulmonary edema, ARF, GI bleed
- tinnitus, decreased auditory acuity, deafness
- vertigo
- hyperventilation
- GI upset - n, v
- AMS - hyperactivity, agitation, delirium, hallucinations, convulsions, lethargy, stupor, coma(rare)
brain metabolic acidosis
uncoupling leads to anaerobic metabolism
CNS hypoglycemia
cerebral edema is cause of death
- any increase in temperature is an indicationn of severe toxicity ( uncoupled ox phos )
- CNS stimulant - hyperV ( increased Vt,RR, sighs, resp alkalosis)
- intereferance with Kreb’s cycle ( ? Mg chelation) with increased lactate production and ketosis leads to metabolic acidosis
- metabolic acidosis due to lactate and ketones
- mixed acid-base changes ( resp and met acidosis is terminal and almost always a mixed OD )
barbs, BZ, EtOH, TCA all blunt resp response, if pure ASA OD, then resp acidosis suggests either NCPE or severe CNS depression
- acidemia from any cause must be treated agressively for it facilitates entry into brain/tissues
- volume depletion may be prominant secondary to tachypnea, fever, vomiting, diaphoresis
- ketoacids, hypoglycemia, hyperglycemia
- hyperthermia from uncoupling of oxidative phosphorylation
- decreased CSF glucose vs plasma
- hematologic - decreased prothrombin, PLT dysfn
- NCPE - ( Ddx )
aspiration
post-ictal and neurogenic
ASA intox with hypoxia ( mechanism obscure )
PE, uremia, opioid, cocaine, high altitude, eclampsia, toxic inhalants
- NCPE ( risk factors )
age > 30, chronic ingestion, smoker, MA, CNS Sx,
- experimentally there appears to be a critical CSF salicylate level that correlates with mortality. Systemic acidosis enhances the rise in brain salicylate levels across the BBB. Therefore, alkalinization of both blood and urine is important.
Five minute evaluation
1) abnormal VS - increased RR,increased Vt, Temp
2) mental status - tinnitus, lethargy, AMS, confusion
3) noncardiogenic pulmonary edema
4) abdominal Sx - n,v, pain, blood-tinged vomitus, gross hematemesis
5) urine - FeCl3, ketones - confirms usage, not overdosage
6) Chemstrip - hypoglycemia is uncommon but serious
7) ABG - resp alkalosis, met acidosis ( mixed disturbance )
8) ASA level, electrolytes
- FeCL3 - several drops 10% FeCl3 in one ml urine - purple color
detects 1 ASA last 24 hours
false pos with ketones, phenothiazines
confirms usage, not overdosage
- phenastix - turn brown with ASA or phenothiazines
less reliable than FeCl3
Correlation between toxicity and serum salicylate levels
- poor correlation with serum levels
- repeat testing of levels mandatory q2-4h with concurrent ABG
- falling [] may reflect redistribution rather than clearance
- the patients clinical signs and symptoms are given the highest priority and the serum salicylate level is used in conjunction with the ABG pH
Done Normogram
- single dose, single drug
- known time of ingestion
- normal renal fn
- plain ASA only
- assumes first order elimination
-does not account for pH
- developed for pediatr8ic population and is of limited value
- stratifications of severity are poor - lethargy and coagulopathy are mild or moderate
- serum pH 7.4 ( always do concurrent ABG )
- not for ECASA, methyl salicylate
- at least 6 hours post-ingestion
- the level of consciousness and the presence of acidosis are much more important than any level
- acidemia means more salicylate leaves the blood into tissues, CSF . Interpretation of plasma levels should always take into account the blood pH and resultant distribution. A falling [serum] may reflect either increased tissue distribution ( increased toxicity ) or increased clearance ( decreased toxicity ).
- delayed absorption with pylorospasm, pyloric stenosis, gastric outlet obstruction
- T1/2 increases at toxic levels for 2 out of 5 pathways ( zero order kinetics )
- decreased protein binding and increased Vd
Ion Trapping
1) salicyclic acid has pKa = 3 ( 99.99 % ionized at pH 7
2) non-ionized form crosses lipid membranes ( cells, BBB, renal tubules )
3) non-ionized form equilibrates across membranes
4) drugs concentrate in compartment in which they are most highly ionized
Treatment
1) oxygen, O2 sat, cardiac monitor, NIBP, iv line, Foley
cbc, smac, pt/ptt, APAP, ASA levels, ABG, FeCL3 test, urinalysis
lavage and charcoal
1) hydration - volume loss secondary to v, sweating, hyperpnea, excretion of solute load, Temp
titrate volume to urine output
2) alkalinize urine and give K+
level > 35 mg %, ABG abnormal, Sx
2-3 amps NaHCO3 push , then infuse 3 amps/1L D5W at 2 times maintenance
follow urine pH hourly, aim for pH 7.5 - 8.0
follow ABG - avoid pH > 7.55
3) glucose - all at risk of hypoglycemia, may have CNS hypoglycemia with normal plasma glu
increased brain O2 and glucose consumption
D5W to provide substrate
D10W if hypoglycemic or CNS Sx
4) gastric emptying and charcoal - MDAC ( need 10:1 )
5) dialysis- early
sever CNS Sx
renal failure
pulmonary edema
failure to respong to treatment
severe AB imbalance
level > 100 mg% at 6 hr in acute, 60 in chronic
6) maintain low PCO2 - avoid precipitous rise in PCO2 without giving bicarb due to risk of more ASA shifting into brain; if sedate ( BZ ) without maintaining PCO2 they will die; if patient crashes due to resp fatigue they will die; require quick intubation and hyperventilation; anyone with metabolic acidosis and pH < 7.4 is in impending respiratory failure ( NCPE, severe CNS)
intubate with ketamine
7) Admit
chronic intox with Sx, irrespective of levels
infants with any clinical evidence of salicylism
any ABG abnormality
significant Sx
failure of levels to fall
8) consider Vt K in all significant ingestions ( inhibition of V, VII, X, II )
9) Airway management - risk of sedation and respiratory depression, protection of resp alk
Diuretics and Alkalinization
- forced saline diuresis little better than oral fluids
- acetazolamide causes metabolic acidosis
- acidosis increases [] of freely diffusable unionized molecule
- alkalinization with NaHCO3 sb considered in all cases where salicylate levels exceed 35 mg % or until level is known
increased ionized fraction of ASA
decreased renal reabsorption
decreasing salicylate entry into brain and other tissues
- alkalinization of the blood and urine will keep ASA away from the brain in addition to enhancing urinary excretion
- salicylic acid is a weak acid pHa 3.5 - ionized and less mobile in alkaline media ( ion trapping )
- increasing urine pH from 5 to 8 increases urine clearance 10 to 20 times
- risk of VOL ( CHF, renal failure, cerebral edema )
- must correct hypokalemia or this will prevent urine alkalinization,
alkalosis shifts K intracellularly
loss in urine anf vomiting
- maintain urine pH 7.5 to 8
- maintain blood pH < 7.5 ( alkalemia shifts O2 curve to left )
Extracorporeal Removal
- PD only 10 - 25 % as efficient as HD or HP
- HD is most ideal - rapid correction of volume, lytes, A-B
- HP has better clearance
Indications for HD
- renal failure
- CHF
- NCPE
- persistant CNS disturbance
- progressive deterioration in VS
- severe AB or lytes disturbance despite agressive appropriate treatment
- hepatic compromise
- coagulopathy
- T0 level > 120 mg% ( 8.7 mMol/L )
- T6 level > 100 ( 7.2 mMol/L )
arbitrary level is 100 mg%
end-organ manifestations ( CNS, kidney, lung )
AMS
renal failure ( Can’t get rid of it, bad lytes, acidosis )
NCPE ( can’t give fluids and HCO3 )
very ill, very high level, can’t eliminate, severe fluid and electrolyte
References: Salicylates
1) Done AK : Salicylate intoxication: Significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics 26 : 800-807,1960
2) Dugandzic RM, Tierney MG, et al: Evaluation of the validity of the Done normogram in the management of acute salicylate intoxication. Ann Emerg Med 18:1186-1190,1989
3) Hrnicek G, Skelton J, et al: Pulmonary edema and salicylate intoxication.
JAMA 230:866-867,1974
4) Gabow PA, Anderson RJ, et al: Acid-base disturbances in the salicylate poisoning in adults. Arch Intern Med 138:1481-1484,1978.
5) Wortzman DJ, Grunfeld A: Delayed absorption following enteric coated aspirin overdose. Ann Emerg Med 16:434-436,1987