Altered Mental Status: The Mystery of the Empty Container

L. SPACK, C. WEIGLE
Department of Pediatrics
Section of Critical Care
Medical College of Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin
lspack@post.its.mcw.edu

REPORT OF CASE

A 16 month old previously healthy male was transported from a
referring hospital emergency department with dehydration and a possible
intracranial bleed.

He presented to a local emergency department on the morning of
admission with complaints of vomiting for 2 hours and a questionable
shaking episode at home. The informant also reported the possibility
of some abnormal breathing. There was no history of diarrhea or fever.
Mild upper respiratory infection symptoms were present for one day.
There were no other complaints, and no previous hospitalizations. There
was no history of ingestion of toxic substances.

On arrival to the emergency department he was awake, alert, playful
and interactive. His temperature was 38.1 C., heart rate 110 bpm,
respiratory rate 50 per minute, oxygen saturation 98% on room air.
Blood pressure was within normal limits for age. His physical exam was
unremarkable except for some mild retractions and tachypnea. Breath
sounds were reported to be equal without wheezing. He was given an
Albuterol aerosol secondary to his respiratory difficulty despite no
evidence of bronchospasm. No clinical change was appreciated after the
Albuterol. One dose of Tylenol was given. There was no evidence of
any external trauma. Approximately 45 minutes after arrival to the
emergency department he developed a generalized tonic clonic seizure
lasting 3 -5 minutes, at which point one dose of Ativan (0.05 mg/kg) and
Dilantin (10 mg/kg) intravenous was given. Computed tomography of the
head was reported to show a right occipital bleed and an undefined
nodular lesion in the right temporal lobe. The child awoke shortly
after but remained slightly lethargic. Laboratory findings: sodium 142
mEq/L; potassium 3.9 mEq/L; chloride 111 mEq/L; bicarbonate 12 mEq/L;
glucose 191 mq/dl; blood urea nitrogen 23 mg/dl; creatinine 0.4 mg/dl;
white blood count 20,000; platelet 431,000 /mm3; urinalysis specific
gravity 1.030, positive for ketones. The child was given Rocephin after
blood cultures were obtained, and arrangements were made for transport
to our facility.

On arrival of our transport team at the referring hospital the
child was assessed to be lethargic with Kussmaul respirations, heart
rate was 180 - 190 bpm, blood pressure 126/58 mm/Hg with cool
extremities and delayed capillary refill. The child developed
increased lethargy with decreased respiratory effort and his trachea was
subsequently intubated without incident using atropine (0.15 mg),
versed (0.1 mg/kg), fentanyl(3 mcg/kg), and vecuronium (0.1 mg/kg). His
heart rate decreased after he received 20 ml/kg of Lactated Ringer's
solution. Coffee ground material was obtained after placing an
nasogastric tube. He was transported without further event to our
intensive care unit.

On arrival at our PICU, his blood pressure was 100/60 mm/Hg, heart
rate was 180 -200 bpm; respirations were deep, at 60 per minute; rectal
temperature was 41 degrees Celsius . His head and neck exam showed an
old healed abrasion of the left forehead, pupils equal and reactive to
light, no evidence of retinal hemorrhage or external trauma. His heart
exam was unremarkable. The child was tachypneic with deep retractions
but had clear breath sounds. Abdominal exam was normal. Neurologically
he was unresponsive with a Glasgow Coma Score of 3 (GCS). Computed
tomography scan of his head was reviewed and thought to be normal.
Cerebrospinal fluid obtained by lumbar puncture was normal. Initial
laboratory values: arterial blood pH 7.35, PCO2 22 mmHg, PO2 191 mmHg
(FiO2 = 0.40), bicarbonate 12 mEq/L, base deficit 12 mEq/dl; white blood
count 18,000 /mm3 (65% segmented neutrophils, 8% bands, 12%
lymphocytes); hematocrit 35.6%; sodium 146 mEq/L; potassium 4.9 mEq/L;
chloride 111 mEq/L; bicarbonate 16 mEq/L; glucose 5 mg/dl; blood urea
nitrogen 21 mg/dl; creatinine 0.5 mg/dl; lactate 13 mg/dl.

The child's symptomatology and presentation was felt to be
consistent with a toxic ingestion, most likely salicylate. The child was
given charcoal via nasogastric tube, intravenous bicarbonate, high rate
of intravenous glucose infusion, and hyperventilation. Subsequent
laboratory tests showed a prothrombin time of 17 seconds (control 10.8
- 13.0); partial thromboplastin time 27.4 seconds (control 21.4 - 34.0);
ionized calcium 2.52 mg/dl (normal 4.5 - 5.3 mg/dL) ; phosphate 1.4
md/dL; AST 54 U/Liter; ALT 43 U/Liter; LDH 5028 IU/Liter; ammonia 59
micromol/Liter; The Salicylate level was 91.5 mcg/dl. A hemodialysis
catheter was placed. Salicylate level just prior to initiating dialysis
was 72 mcg/dl. After dialysis, the salicylate level was 33.
Subsequently, the lactate level rose to 71 mg/dl.

The following morning the childs neurologic exam had improved. He
was responsive to stimuli, moving all extremities (GCS 9), breathing
more comfortably on his own, pupils still equal and reactive to light.
The lactate was 29 md/dl and electrolytes were normal. The salicylate
level was 48 mcg/dl and hemodialysis was repeated. Halfway through
hemodialysis the patient developed a bradycardic rhythm (rate in 70's)
with no other changes. He soon developed fixed and dilated pupils, with
a GCS of 3 and hypertension. Mannitol was given. A CT scan revealed
massive cerebral edema with effaced basilar cisterns (approximately 12
hours after initial normal CT). A ventriculostomy was placed in an
attempt to decompress the brain. Only a few drops of CSF was obtained.
Pressure readings were unobtainable. The child expired the next morning
meeting brain death criteria. Postmortem examination by the medical
examiner was performed without organ microscopic examination.

Subsequent to the death of our patient, investigations at his home
found an empty container of aspirin. It is still not clear, however,
how the child obtained or received the aspirin tablets.

DISCUSSION

Despite ongoing educational efforts directed at childproofing the
home with respect to medications and chemicals, children still sustain
significant morbidity and mortality from accidental ingestions in the
home. Salicylate intoxication in children, although decreased in
incidence (1), is still seen as a result of accidental ingestion in the
home. Perhaps this is because salicylates are frequently overlooked, as
they are integrated into more than 200 formulations used in the home (2,3).

Although patients with salicylate intoxication are at risk of
developing pulmonary edema, coagulopathy, hepatic compromise (4) and
even complete cardiovascular collapse (5), there is evidence that many
patients who die do so with signs and symptoms suggesting primary
central nervous system dysfunction (6). As serum salicylate levels
increase, tinnitus followed by diminished auditory acuity occurs. Other
early CNS responses may include vertigo and hyperventilation, with a
variety of altered mental states including hyperactivity, agitation,
delirium, or hallucinations. Typically in the face of salicylate
toxicity, a respiratory alkalosis develops. The presence of a
respiratory acidosis suggests either CNS depression or pulmonary edema.
In addition, patients with significant salicylate ingestion may exhibit
lethargy, stupor, coma, and may develop cerebral edema. Coma is rare
and is generally seen in massive ingestions (4). McGuigan found nervous
system abnormalities postmortem in 18% of patients. These included
cerebral edema and hemorrhage (7). Hypoglycemia results from increased
glucose utilization from the increased metabolic demands.

Once a salicylate ingestion has either been confirmed or suspected
it is imperative that immediate aggressive management be undertaken to
enhance clearance of salicylate from the body, possibly of most
importance to keep salicylate away from the brain. Salicylate acts as
an uncoupler of oxidative phosphorylation (8 - 10 ) and causes rapid
swelling of mitochondria (11). The ability of salicylate to cause
mitochondrial uncoupling and/or swelling relates to the symptomatology
we see in salicylate poisoning. Hyperthermia and lactic acidosis
commonly seen in salicylate intoxication is secondary to decreased ATP
synthesis and unchanged oxygen utilization, both a result of uncoupling
of oxidative phosphorylation. (12). Salicylates in addition inhibit
dehydrogenases and aminotransferases (2). Liver histology and the
gross cerebral pathology seen in children with Reye's syndrome have been
found to be similar to that observed from children who died from
salicylate intoxication (13). Cerebral pathologic findings have
included gross brain swelling with swelling of the astrocytes and
oligoglia without evidence of herniation or cerebral or meningeal
inflammation (13). Others have reported non-inflammatory cerebral edema
as a feature of Reye's syndrome (14 - 16).

At normal therapeutic dosages and blood levels, salicylate in
plasma is about 90% protein bound. Salicylates are excreted by the
liver after undergoing biotransformation (75%) and excreted unchanged in
the urine (10%). When taken in toxic doses less salicylate is protein
bound and the liver's capacity to biotransform salicylate is easily
saturated. Thus, larger amounts of free salicylate are available to
enter the interstitial fluid, cerebrospinal fluid, and intracellular
compartment, where they can exert damaging effects. An increasing
proportion of the drug must be removed via the kidneys which are far
less efficient than the liver. This increases the half-life of
salicylate from 3 -12 hours to 15 - 30 hours. Renal elimination of
salicylate increases with increased GFR, increased urine flow rate, and
with an alkaline urine (salicylate is a weak acid with a low pK and
remains in the ionized form at an alkaline pH) (17). Interpretation of
the plasma salicylate level should keep in mind the possibilities of the
distribution of salicylate in the body (i.e., a falling salicylate level
in the plasma may not necessarily reflect increased clearance, it may
represent increased tissue distribution with resultant increased
toxicity).

The management of salicylate intoxication should include the
following key elements. Emptying the gastrointestinal tract in acute
intoxication will remove any unabsorbed salicylate and prevent further
absorption. Administration of activated charcoal with a cathartic
promptly will aid in preventing any further gastrointestinal absorption.
Correction of hypovolemia, insuring adequate urine output of at least 2
cc/kg/hr, should be a mainstay of therapy. Included in this regimen,
should be maintenance of adequate serum glucose to prevent central
nervous system hypoglycemia, addition of potassium supplementation
which will prevent intracellular hypokalemia, and the generous use of
bicarbonate. The use of bicarbonate will prevent central nervous
system diffusion of salicylate, correction of metabolic acidosis,
and alkalinize the urine which will enhance clearance of salicylate.
Adequate ventilation must be maintained especially for the moderate to
severe intoxications. For severe intoxications hemodialysis is
warranted as this modality enhances salicylate clearance, helps correct
fluid/electrolyte imbalance, and corrects acid/base disorder. Although
central nervous system findings including cerebral edema and hemorrhage
are rare, therapy should nevertheless be directed at minimizing
diffusion of salicylate into the brain which include avoiding
interventions that may compromise respiratory alkalosis or worsen
metabolic acidosis. It remains unclear the reason why our patient showed
neurologic improvement, only to develop massive cerebral edema which
became clinically evident during hemodialysis. It may have been caused
by the anaerobic cerebral metabolic damage with late 'neuronal dropout',
similar to that seen following global cerebral ischemia. It is
reasonable, however, to conclude that the development of his cerebral
edema was only coincidentally related to hemodialysis.

REFERENCES

1. Rumack BH: Chemical and Drug Poisoning, in Nelson: Textbook of
Pediatrics; 15th Edition: 2016 - 2018.

2. Sainsbury SJ: Fatal salicylate toxicity from bismuth subsalicylate.
West J Med 1991; 155:637-639.

3. Leist E, Banwell J: Products containing aspirin. N Engl J Med 1974;
291: 710-712.

4. Goldfranky LR, Bresnitz EA, Hartnett L, Flomenbaum NE: Salicylates,
in Goldfrank's Toxicologic Emergencies 4th Edition 1990 261 - 269.

5. Berk WA, Andersen JC: Salicylate Associated Asystole: Report of Two
Cases. American J Med 1989;85(4): 505 - 506.

6. Hill JB. Current Concepts: Salicylate Intoxication. N Engl J Med
1973;288: 1110-1113.

7. McGuigan MA: A Two Year Review of Salicylate Deaths in Ontario. Arch
Intern Med 1987;147: 510 - 512.

8. Brody TM. Action of sodium salicylate and related compounds on
tissue metabolism in vitro. J. Pharmacol 1956;117: 39-51.

9. Haas R. et al Salicylate induced loose coupling: Protonmotive force
measurements. Biochem Pharmacol 1985;34: 900 - 902.

10. Whitehouse MW Biochemical Properties of anti-inflammatory drugs:
III. Uncoupling of oxidative phosphorylation in a connective tissue
(cartilage) and liver mitochondria by salicylate analogues. Biochem
Pharmacol 1964;13: 319 - 336.

11. You K. Salicylate and mitochondrial injury in Reye's Syndrome.
Science 1983;221: 163 - 165.

12. Smith MHG, Jeffrey SW: The effects of salicylate on oxygen and
carbohydrate metabolism in the isolated rat diaphragm. Biochem J 1956;
63;524-529.

13. Starko KM, Mullick FG: Hepatic and Cerebral Pathology Findings in
Children With Fatal Salicylate Intoxication: Further Evidence For A
Causal Relation Between Salicylate And Reye's Syndrome. Lancet 1983;
1: 326 - 329.

14. Chang LW, Gilbert EF, Tanner W, Moffat HL. Reye's Syndrome. Light
and electron microscopic studies. Arch Pathol 1973; 96:127 - 32.

15. Norman MG. Encephalopathy and fatty degeneration of the viscera in
childhood: I. Review of cases at the Hospital for Sick Children, Toronto (1954 - 1966)
Can Med Ass J 1968; 99: 522 - 26.

16. Johnson GM, Scurletis TD, Carroll NB. A study of sixteen fatal cases
of encephalitis - like disease in North Carolina children. N Carolina
Med J 1963; 24: 464 - 73.

17. Garella S: Extracorporeal techniques in the treatment of exogenous
intoxications (clinical conference ), Review. Kidney International 1988;
33(3) : 735 -754.

Permission to report this case has been given by the patient's family.

Accepted for publication September 24, 1996

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