aDivision of Toxicology, Albert Einstein Medical Center, 5501 Old York Road,
bThomas Jeﬀerson University Hospital, Philadelphia, PA 19141, USA
cChildren’s Hospital of Philadelphia, Philadelphia, PA 19141, USA
dPhiladelphia Poison Control Center, Philadelphia, PA 19141, USA
The term salicylate refers to any of a group of chemicals that are derived
from salicylic acid. The best known is acetylsalicylic acid (aspirin). Acetyl-salicylic acid is metabolized to salicylic acid (salicylate) after ingestion.
The salicylates originally were derived from salicin, the active ingredientin willow bark, which Hippocrates used 2500 years ago for treating painand fever . Salicylates also occur naturally in many plants such as straw-berries, almonds, and tomatoes .
Poisoning by aspirin is common and is under-represented in poison cen-
ter data, because it is often not recognized The in-hospital mortalityfor unrecognized chronic aspirin poisoning is reportedly three times higherthan if the diagnosis is made in the emergency department Familiaritywith the clinical presentation during the various stages of acute and chronicaspirin poisoning is important for the practice of emergency medicine. Themost challenging aspect of the clinical evaluation and management of theaspirin-poisoned patient may be recognition of the subtle signs and symp-toms of chronic, nonintentional aspirin overdose (
Salicylate poisoning continues to be an important overdose that fre-
quently presents to emergency departments . There were over 21,000
* Department of Emergency Medicine, Albert Einstein Medical Center, 5501 Old York
0733-8627/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
Box 1. Pitfalls in the emergency department managementof salicylate–poisoned patients
Failure to recognize the presence of salicylate toxicityFailure to appreciate the presence of continued absorption of
Misinterpreting clinical significance of serum salicylate levels,
Reliance on one or two serum levels of salicylate that may not
describe a trend of decreasing total body burden of aspirinclearly
Misinterpretation of low serum salicylate levels as nontoxic and
failure to comprehend the changing acid–base status of thepatient
Waiting until serum salicylate levels are determined before
Accidentally adding bicarbonate to isotonic saline (creating a
hypertonic solution) rather than intravenous dextrose/watersolutions to alkalinize the urine
Forgetting to add potassium to the urinary alkalinization infusionFailure to recognize the emergent need for definitive therapy
(hemodialysis) on the basis of impending end organ injury().
Inappropriately or prematurely initiating intubation and
mechanical ventilation without hyperventilation and withoutsimultaneous hemodialysis
Prematurely discharging patients without demonstrating
metabolic stability, declining salicylate levels, and the absenceof an aspirin bezoar
aspirin and nonaspirin salicylate exposures reported to the United Statespoison centers in 2004, with 43 deaths and 12,968 patients requiring hospitaltreatment Because poison center data are collected passively, that sta-tistic is certainly an underestimate of the true incidence of salicylate poison-ing occur in the United States. One half of the reported exposures (10,786)were categorized as intentional overdoses. The incidence of chronic aspirinpoisoning is not known, but it is misdiagnosed frequently .
In recent years, packaging strategies such as child-resistant packaging
and reducing the amount of medication in each package of over-the-counteranalgesics have impacted the incidence of poisoning. It is estimated that theuse of child-resistant packaging for salicylate-containing medications has re-sulted in a 34% reduction in the salicylate-related child mortality rate .
In England, Australia, and Ireland, analgesics are packaged and sold in
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
small amounts (ie, 4 g of acetaminophen). This has resulted in a 30%decrease in the number of patients requiring liver transplantation for acet-aminophen-induced hepatic failure and a 22% reduction in suicidal deathsfrom acetaminophen and salicylate . Large aspirin overdoses werereduced by 39% on average in the countries in which the limited packageformulation is required
Salicylate is a metabolic poison. Understanding the pathophysiology of its
metabolic eﬀects can help to understand the clinical manifestations of toxic-ity. The metabolic derangements induced by salicylate poisoning are multifac-torial, but the principal pathophysiologic mechanism in salicylate poisoningis interference with aerobic metabolism by means of uncoupling of mitochon-drial oxidative phosphorylation This leads to the interruption of a se-ries of enzyme-mediated mitochondrial functions and increased anaerobicmetabolism with cellular conversion of pyruvate to lactate and rapid develop-ment of lactic acidosis The ineﬃciency of anaerobic metabolism re-sults in less energy being used to create ATP and release of the energycreated during the metabolism of glucose in the electron transport chain asheat, so salicylate poisoned patients may become febrile The absenceof fever, however, does not rule out salicylate poisoning.
The acidosis is caused by anaerobic metabolism and the inability to
buﬀer hydrogen ions, which is reﬂected by the accumulation of lactate.
The presence of acetasalicylic acid or salicylate molecules probably contrib-utes little to the acidotic state
Interference with oxidative phosphorylation by salicylate also will impact
glucose homeostasis negatively by causing glycogen depletion, gluconeogen-esis, and catabolism of proteins and free fatty acids, the end result being lowserum glucose levels and central nervous system (CNS) hypoglycemia rela-tive to serum glucose levels
The pharmacokinetic proﬁle of aspirin is unique and explains the unique
characteristics of clinical poisoning. The ionization constant (pKa) of aspi-rin is 3, which means that at a pH of 3, approximately half of the availablechemical is in the ionized state. In an acidic environment like the stomach,more of the drug will be absorbed compared with tissues at a higher pH The absorption of aspirin from the stomach can be delayed by the presenceof food in the stomach and the formulation of the aspirin, (eg, enteric coat-ing of pills may create concretions and bezoars that limit available surfacearea for absorption) . Aspirin is thought to cause spasm of the pyloricsphincter, increasing gastric transit time and prolonging the time that aspi-rin is in the acidic environment of the stomach, favoring increased
absorption . Salicylates also are absorbed readily in the unionized formfrom the small intestine
Dermal salicylate formulations typically do not result in tissue penetra-
tion much deeper than 3 to 4 mm in animal studies and human vol-unteer experiments . Methyl salicylate has less dermal absorption thaneither camphor or menthol, with lower mean plasma levels and shorterelimination half-life than either compound in people Signiﬁcantamounts of salicylate typically are not absorbed through the skin exceptin select patients, such as children and patients with compromised skinsuch as burn patients or patients who have severe psoriasis
In therapeutic doses, the major route of salicylate biotransformation is
conjugation with glycine in the liver. A small amount of aspirin is excretedunchanged in the urine In overdose, the liver’s ability to metabolizethe drug is overwhelmed, and unchanged salicylate excretion through thekidney becomes a much more important elimination route.
Salicylate toxicity initially will create a pure respiratory alkalosis because
of direct stimulatory eﬀects on the respiratory centers of the cerebral me-dulla. This is characterized in the blood gas by a decrease in the partial pres-sure of dissolved CO2 accompanied by an elevated pH and normal toslightly lower levels of serum HCO3 . There is some controversy as towhether pediatric aspirin poisoned patients demonstrate this phase ofacid–base derangement. Pediatric patients may present later in the courseof the poisoning, or the centrally mediated hyperventilatory phase of aspirinpoisoning may be so subtle in children that it often is missed
As the poisoning progresses and more of the aspirin is absorbed into the
serum and is incorporated into the mitochondria, uncoupling oxidativephosphorylation, lactic acid accumulates in the serum, and metabolic com-pensatory mechanisms are initiated Hyperventilation becomes a truecompensatory mechanism in addition to the byproduct of central medullarystimulation This phase is characterized metabolically by a continueddecrease in the pCO2, marked decline in measured HCO3 and possibly a de-crease in serum pH, depending on the ability of the patient to maintain therespiratory demands of the developing acidosis and to retain bicarbonate inthe kidney A common error at this stage of the poisoning is to acknowl-edge that the serum pH is close to 7.4 or slightly higher than 7.4, and assumethat the patient is compensating adequately for the acidosis.
As the ability to compensate for the acidosis is overwhelmed, pH drops;
lactic acid accumulates, and serum bicarbonate is consumed. Patients who
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
reach the stage of aspirin poisoning where pH is less than 7.4 with decreasedpCO2 and low serum bicarbonate are dangerously unstable, likely todecompensate hemodynamically and will begin to demonstrate other symp-toms of end-organ injury
The triad of salicylate poisoning consists of hyperventilation, tinnitus,
and gastrointestinal (GI) irritation Physicians should remain awarethat patients may hyperventilate with a normal respiratory rate by increas-ing tidal volume (hyperpnea) and should make it a habit to observe respira-tory patterns carefully. Ototoxicity is a well-described phenomenon withsalicylism, and it is thought to be secondary to interference with chloridechannels in the cochlear hair cells that transmit sound waves . Theototoxicity is most noticeable in the range of serum salicylate from 20 to40 mg/dL . Aspirin, especially enteric-coated formulations, areknown to develop concretions and bezoars in the stomach and act as a directGI irritant leading to nausea, vomiting, and abdominal pain .
Patients who present early in the course of salicylate poisoning may have
modest symptoms, and the hyperventilation may be mistaken for emotionalexcitation or anxiety. GI irritation may or may not be present, and tinnitusor other symptoms of ototoxicity may be overlooked unless the physicianspeciﬁcally tests for them with direct questioning or confrontational hearingtesting. Vital signs may reﬂect emotional agitation and CNS stimulationwith tachycardia, increased work of breathing (increased minute ventila-tion), and overall autonomic up-regulation. Early in the course of acute poi-soning, fever generally will be absent Clinical symptoms will be variableif the patient ingested more than one drug, or the ingested aspirin formula-tion contained a CNS depressant, which might blunt the expected hyperven-tilation and respiratory alkalosis .
Laboratory values early in the course of aspirin poisoning will be largely
normal or will reﬂect the direct stimulatory eﬀect of salicylate on the cere-bral respiratory center. Serum aspirin levels may be elevated modestly (20to 40 mg/dL), and blood gas analysis may demonstrate pure respiratory al-kalosis with elevated pH and low pCO2 with normal or near-normal HCO3The decision to determine serum salicylate concentrations is not diﬃ-cult. Although serum salicylate levels may not be required to screen everyasymptomatic overdose, liberal use of the laboratory to make the diagnosisand follow resuscitative eﬀorts is advisable .
As salicylate enters the mitochondria, dramatic changes in vital signs and
clinical stability occur. Serum salicylate levels alone are not adequate to ac-curately assess and follow seriously poisoned patients Serum salicylatelevels do not reﬂect the total body burden of salicylate, and so to evaluatethe rapidly changing acid base status of an aspirin poisoned patient, serialsalicylate levels should be accompanied by serial blood gas analysis .
Patients who present in the late phases of salicylate toxicity often are mis-diagnosed as sepsis myocardial infarction or as agitated or other-wise psychiatrically disturbed
The progression to death from salicylate poisoning is particularly tumul-
tuous. The toxic eﬀects of the salicylate molecule on mitochondrial functionand subsequent basement membrane leakage overwhelm the compensatorycapacity of the organism. This leads to marked metabolic acidosis with de-velopment of pulmonary and cerebral edema. Myocardial depression andhypotension secondary to the acidosis and volume deﬁcit occur, and CNSdepression with seizures secondary to hypoxia, hypoglycemia, and directCNS toxicity often precedes cardiopulmonary arrest
In one study, nearly half (45%) of the patients who died from salicylate
poisoning arrived at the emergency department alert and deteriorated whilethere . In another study, 39% of the patients who had severe salicylatepoisoning requiring ICU management arrived alert with minimal symptoms. Mean postmortem salicylate serum levels on 16 patients who presenteddead on arrival after aspirin overdose were 51 mg/dL (range 17 to 101 mg/dL). Postmortem examination of salicylate-poisoned patients demonstratedseveral unique ﬁndings including myocardial necrosis suggestive of toxicmyocarditis , pulmonary congestion, hemorrhagic gastritis with unab-sorbed salicylate and GI ulceration, cerebral edema, and paratonia (extrememuscle rigidity)
Emergency department evaluation of the salicylate-poisoned patient
The aspirin nomogram, commonly referred to as the Done nomogram,
after its creator Done was ﬁrst published in 1960. Data from pedi-atric patients who ingested a one-time dose of aspirin were plotted overtime to create an instrument to predict toxicity. Several important limita-tions exist with regards to the development of the Done nomogram thatlimit its generalizability, including the fact that patients who had polydrugingestion were included in the analysis, making the clinical correlationdiﬃcult to interpret. In addition, the nomogram assumed an elimination
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
half-life of 20 hours in all patients and did not allow for the change fromﬁrst-order to zero-order elimination kinetics that occurs when serum levelsexceed the elimination enzyme systems . Although innovative and oftenaccurate for the intended (pediatric) population, the Done nomogram hasbeen demonstrated to have very limited applicability and usefulness formost aspirin-poisoned patients, and its routine use is discouraged
Physicians should make liberal use of blood tests in the evaluation of po-
tentially aspirin-poisoned patients. Diﬀerent clinical laboratories may reportsalicylate levels in diﬀerent units of measure (mg/dL versus mmol/L). Clini-cians should maintain consistent use of the respective units of measure toavoid confusion. Seriously aspirin-poisoned patients may display symptomsthat allow an astute practitioner to perform comparative serial examinationsand assess developing toxicity. Accurate recognition of worsening signs oftoxicity, however, is an inexact science with uncertain sensitivity and speci-ﬁcity, especially in the event of polypharmaceutical ingestion or pediatricpatients Serum salicylate levels frequently do not reﬂect the se-verity of the poisoning. Depending on the time since ingestion, presenceof food in the stomach, coingestants, and presence of concretions, amongother variables, symptoms may or may not correlate with serum salicylatelevels. Symptomatic patients suspected of aspirin ingestion or salicylate poi-soning should have serial aspirin levels and blood gas analysis performeduntil a clear trend toward decreasing (not plateau or modestly increasing)levels and metabolic stability as described by the blood gas is present.
Radiographic evaluation of the aspirin poisoned patient is rarely helpful,
except for seriously ill patients who may have pulmonary edema or patientswho have altered mental status that might require CT scanning of the headto eliminate the possibility of an alternative cause for a changed level of con-sciousness. Large bezoars of ingested enteric-coated aspirin tablets may ormay not be visible on a radiograph, and the absence of opacity on an ab-dominal radiograph is not adequate to rule out the presence of a largeamount of salicylate in the gut
Treatment of the salicylate-poisoned patient
Depending on the acuity of the poisoning and the presence of end-organ
injury and hemodynamic instability, patients may require early, aggressiveresuscitation and treatment. Most patients who have consequential aspirinoverdose will be somewhat volume deﬁcient because of ﬂuid losses causedby increased respiration, fever, and metabolic activity Volume resus-citation with alkalinized intravenous ﬂuids is reasonable and advisable and
should be initiated early in the course of the patient’s treatment so that valu-able time is not lost waiting for laboratory conﬁrmation of elevated salicy-late levels Begin by placing a suﬃcient volume of sodium bicarbonate(three ampules NaHCO3 with 44 mEq Naþ/ampule) into a liter of a glu-cose-containing hypotonic solution, such as 5% dextrose and water and in-fusing at 2 to 3 mL/kg per hour to promote brisk urine output. A total of 40mEq of KCl per liter should be added to prevent hypokalemia.
Salicylate-poisoned patients who require advanced airway management
are particularly challenging. Salicylate-intoxicated patients who have de-pressed mental status from the salicylate-induced cerebral hypoglycemiaor acidosis or coingestants who require endotracheal intubation andmechanical ventilation pose a clinical no-win situation for emergency physi-cians, because positive pressure ventilation simply cannot maintain therespiratory rate and metabolic demands of seriously salicylate-poisonedpatients. Hemodynamic instability and worsening of acid–base status willalmost deﬁnitely be the consequence Patients who require endotrachealintubation for airway protection and maintenance almost always should behemodialyzed simultaneously to remove salicylate and the accumulated or-ganic acids. Careful attention to maintaining a favorable acid–base statusthrough the judicious manipulation of ventilator settings should occur soas not to allow hypoventilation and the accumulation of CO2.
The unique characteristics of aspirin in the stomach make gastric decon-
tamination particularly problematic. Gastric irritation, induction of nausea,and decreased mental alertness all combine to put the salicylate-poisoned pa-tient at substantial risk for vomiting and aspiration from any attempt at GIdecontamination. Clinicians must weigh the very real risk of aspiration ver-sus the possible beneﬁts from any method of gastric decontamination.
Activated charcoal has been demonstrated to be eﬀective in decreasing
the area under the curve for absorbed aspirin, and it is the most widelyused method of gastric decontamination for salicylate-poisoned patients. Multidose activated charcoal similarly has been shown to reduce ab-sorption of aspirin and results in decreased serum levels, but this has nottranslated into an improved morbidity or mortality rate Given thatmultiple doses of activated charcoal are quite safe and generally well toler-ated and seem to result in lower total body burden of aspirin, it is reasonableto recommend 25 g of activated charcoal without sorbitol given orally every3 hours while the patient is being monitored with serial aspirin and bloodgas measurements. Before each 25 g dose of activated charcoal, bowelsounds should be checked, and if absent, the activated charcoal shouldnot be withheld.
Whole-bowel irrigation is not recommended in aspirin-poisoned patients,
because there are very little data to support its use in salicylate poisoning.
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
What data do exist do not demonstrate an improved outcome Whole-bowel irrigation with balanced electrolyte solutions decreases guttransit time but may increase total surface area available for absorptionand possibly lead to increased serum levels of aspirin. It is universally poorlytolerated and diﬃcult to perform .
Gastric lavage largely has been abandoned in the management of poi-
soned patients with the possible exception of overdose with a life-threaten-ing drug and early presentation of the patient in the course of the poisoning. Serious aspirin poisoning is certainly a life threat and given theunique potential of enteric-coated aspirin to form concretions and remainin the stomach due to pylorospasm , it is reasonable to consider gastriclavage with a large-bore endogastric tube (36 French or larger) if substantialsalicylate poisoning is suspected, and there is no likelihood of airway com-promise .
Restoring intravascular volume and alkalinization of the serum and
urine is an important ﬁrst-line treatment for acetasalicylic acid toxicity. Bi-carbonate diuresis is the mainstay and ﬁrst-line treatment for aspirin tox-icity, and it should be initiated early in every case of moderate salicylatepoisoning . The (pKa) is a logarithmic function, so a small change inurine pH will have a disproportionately larger eﬀect on salicylate clearance,so theoretically elimination of salicylic acid is increased substantially in al-kaline urine The most practical method of creating an isotonic alka-line solution in the emergency department is to add sodium bicarbonateto 5% dextrose in water. In general, one 50 mL ampule of 40% sodiumbicarbonate should contain 43 mEq of sodium. By putting three ampules(150 mL total volume) of sodium bicarbonate into one liter of D5W, theresulting solution should have 132 mEq of sodium, which is essentially0.9% (normal) saline . A total of 40 mEq of KCl per liter should beadded to prevent hypokalemia. This solution should be infused rapidly ata rate of at least 2 to 3 mL/kg/hour to maintain a brisk urine output of1 to 2 mL/kg/hr. The enhanced excretion of salicylate requires not justraising the pH of the urine, but also increasing the glomerular ﬁltrationrate
The development of cerebral or pulmonary edema following salicylate
poisoning is an important consideration, but a concern for possibly causingthese complications should not lead to inadequate or ineﬃcient urinaryalkalinization or intravascular volume restoration. Patients who developworsening respiratory function with increased work of breathing and hyp-oxia consistent with pulmonary edema or who develop altered or decreasedmental status consistent with cerebral edema should have their hydrationand urinary alkalinization interrupted and be evaluated immediately fordeﬁnitive treatment (hemodialysis).
Box 2. Indications for hemodialysis in salicylatedpoisonedpatients
Severe acidosis or hypotension refractory to optimal supportive
care (regardless of absolute serum aspirin concentration)
Evidence of end-organ injury (ie, seizures, rhabdomyolysis,
Renal failureHigh serum aspirin concentration (>100 mg/dL) despite relatively
Consider for patients who require endotracheal intubation unless
that indication for mechanical ventilation is respiratorydepression secondary to a coingestant.
Potassium replacement long has been an important aspect of urinary
alkalinization despite a paucity of clinical evidence to support the routinepractice Chronic potassium depletion causes increased reabsorptionof bicarbonate in the proximal renal tubules and diﬃculty achieving an al-kaline urine. The eﬀects of acute potassium depletion on urinary excretionof bicarbonate are uncertain It seems reasonable to infuse potassiumand NaHCO3 simultaneously, especially in patients who are already hypo-kalemic. Urinary alkalinization should be delayed while attempts are madeto replace the serum potassium
Hemodialysis is the deﬁnitive treatment to prevent and treat salicylate-
induced end-organ injury Indications for dialysis are listed in .
Hemodialysis will remove aspirin in the serum and lactate eﬃciently .
Patients may have metabolized their aspirin and have a low measured serumconcentration of salicylate, but they still may beneﬁt from hemodialysis toremove the byproducts of mitochondrial poisoning. Charcoal hemoperfu-sion is not practical in most circumstances , and hemodialysis hasbecome the preferred method of enhanced elimination of excess serumsalicylate.
Aspirin carries both signiﬁcant adverse eﬀects in therapeutic doses and
a substantial risk in overdose, for which there is no antidote. Its risk-beneﬁtproﬁle is probably the poorest of all analgesics currently available over thecounter; this is reﬂected in current trends in analgesic use and overdose ﬁg-ures Emergency physicians must have a healthy respect for the erraticand unpredictable absorption and elimination kinetics of aspirin, the devas-tating physiologic eﬀects of aspirin overdose and the subtle manifestations,
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
presentation, and increased mortality of chronic aspirin toxicity. Consulta-tion with the regional poison control center is advised to assist with themanagement and follow-up of all poisoned patients.
 Hedner T, Everts B. The early clinical history of salicylates in rheumatology and pain. Clin
 Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development,
and directions for the future. Circulation 1994;89(1):432–49.
 Hare LG, Woodside JV, Young IS. Dietary salicylates. Journal of Clinical Pathology 2003;
 Fink CW. Acute versus chronic salicylate poisoning. Pediatrics 1983;71(5):862–3.
 Flomenbaum N. Salicylates. In: Goldfrank LR, Flomenbaum N, Lewin N, editors. Gold-
frank’s toxicologic emergencies. 7th edition. New York: McGraw-Hill Medical PublishingDivision; 2003. p. 513.
 Vivian AS, Goldberg IB. Recognizing chronic salicylate intoxication in the elderly. Geriat-
 Anderson RJ, Potts DE, Gabow PA, et al. Unrecognized adult salicylate intoxication. Ann
 Jones A. Over-the-counter analgesics: a toxicologic perspective. Am J Ther 2002;9(3):
 Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to
hospital: prospective analysis of 18,820 patients. BMJ 2004;329(7456):15–9.
 Wazaify M, Kennedy S, Hughes CM, et al. Prevalence of over-the-counter drug-related over-
doses at accident and emergency departments in Northern Irelandda retrospective evalua-tion. J Clin Pharm Ther 2005;30(1):39–44.
 Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2004 Annual report of the American Asso-
ciation of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med2005;23(5):589–666.
 Gittelman DK. Chronic salicylate intoxication. South Med J 1993;86(6):683–5.
 Rodgers GB. The eﬀectiveness of child-resistant packaging for aspirin. Arch Pediatr Adolesc
 Hawton K, Simkins S, Decks J, et al. UK legislation on analgesic packs: before-and-after
study of long-term eﬀect on poisonings. BMJ 2004;329(7474):1076.
 Sheen CL, Dillon JF, Bateman DN, et al. Paracetamol pack size restriction: the impact on
paracetamol poisoning and the over-the-counter supply of paracetamol, aspirin, and ibupro-fen. Pharmacoepidemiol Drug Saf 2002;11(4):329–31.
[15a] Yip L, Dart RC, Gabrow PA. Concepts and controversies in salicylate toxicity. Emerg Med
 Petrescu I, Tarba C. Uncoupling eﬀects of diclofenac and aspirin in the perfused liver and
isolated hepatic mitochondria of rat. Biochim Biophys Acta 1997;1318(3):385–94.
 Krause DS, Wolf BA, Shaw LM. Acute aspirin overdose: mechanisms of toxicity. Ther Drug
 Temple AR. Pathophysiology of aspirin overdosage toxicity, with implications for manage-
ment [review]. Pediatrics 1978;62(5 Pt 2 Suppl):873–6.
 Leatherman JW, Schmitz PG. Fever, hyperdynamic shock, and multiple-system organ fail-
ure. A pseudo-sepsis syndrome associated with chronic salicylate intoxication. Chest 1991;100(5):1391–6.
 Schwartz R, Landy G. Organic acid excretion in salicylate intoxication. J Pediatr 1965;66:
 Hill JB. Salicylate intoxication. N Engl J Med 1973;288:1110–3.
 Rivera W, Kleinschmidt KC, Velez LI, et al. Delayed salicylate toxicity at 35 hours without
early manifestations following a single salicylate ingestion. Ann Pharmacother 2004;38(7–8):1186–8.
 Myers B, Evans DN, Rhodes J, et al. Metabolism and urinary excretion of 5-amino salicylic
acid in healthy volunteers when given intravenously or released for absorption at diﬀerentsites in the gastrointestinal tract. Gut 1987;28:196–200.
 Schanker LS, Tocco DJ, Brodie BB, et al. Absorption of drugs from the rat small intestine.
J Pharmacol Exp Ther 1958;123(1):81–8.
 Singh P, Roberts MS. Dermal and underlying tissue pharmacokinetics of salicylic acid after
topical application. J Pharmacokinet Biopharm 1993;21(4):368–70.
 Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-
inﬂammatory drugs after topical application. J Pharmacol Exp Ther 1994;268(1):144–51.
 Cross SE, Anderson C, Roberts MS. Topical penetration of commercial salicylate esters and
salts using human isolated skin and clinical microdialysis studies. Br J Clin Pharmacol 1998;46(1):29–35.
 Martin D, Valdez J, Boren J, et al. Dermal absorption of camphor, menthol, and methyl
salicylate in humans. J Clin Pharmacol 2004;44:1151–7.
 Bell AJ, Duggin G. Acute methyl salicylate toxicity complicating herbal skin treatment for
psoriasis. Emerg Med (Fremantle) 2002;14(2):188–90.
 Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol 1999;38(1):
 Taylor JR, Halprin KM. Percutaneous absorption of salicylic acid. Arch Dermatol 1975;
 Martin L. All you really need to interpret arterial blood gases. 2nd edition. Philadelphia:
Lippincott, Williams and Wilkins; 1999.
 Chrichton JU, Elliott GB. Salicylateda dangerous drug in infancy and childhood. Can Med
 Done AK. Treatment of salicylate poisoning: review of personal and published experiences.
 Gaudreault P, Temple AR, Lovejoy FH. The relative severity of acute versus chronic salic-
ylate poisoning in children: a clinical comparison. Pediatrics 1982;70:567–8.
 Jepsen F, Ryan M. Poisoning in children. Current Paediatrics 2005;15(7):563–8.
 Wrathall G, Sinclair R, Moore A, et al. Three case reports of the use of haemodiaﬁltration in
the treatment of salicylate overdose. Hum Exp Toxicol 2001;20(9):491–5.
 Grabe DW, Manley HJ, Kim JS, et al. Respiratory distress caused by salicylism conﬁrmed by
lung biopsy. Clin Drug Investig 1999;17(1):79–81.
 Proudfoot AT. Toxicity of salicylates. Am J Med 1983;75(Suppl):100–2.
 Cazals Y. Auditory sensori-neural alterations induced by salicylate. Prog Neurobiol 2000;
 Wecker H, Laubert A. Reversible hearing loss in acute salicylate intoxication. HNO 2004;
 Mongan E, Kelly P, Nies K, et al. Tinnitus as an indication of therapeutic serum salicylate
 Taylor JR, Streetman, DS, Castle SS. Medication bezoars: a literature review and report of
a case. Ann Pharmacother 1998;32(9):940–6.
 Stack PE, Thomas E. Pharmacobezoar: an evolving new entity. Dig Dis 1995;13(6):356–64.
 Gabow PA, Anderson RJ, Potts DE, et al. Acid–base disturbances in the salicylate-intoxi-
cated adult. Arch Intern Med 1978;138:1482–3.
 Dale C, Aulaqi AA, Baker J, et al. Assessment of a point-of-care test for paracetamol and
salicylate in blood. QJM 2005;98(2):113–8.
 Graham CA, Irons AJ, Munro PT. Paracetamol and salicylate testing: routinely required for
all overdose patients? Eur J Emerg Med 2006;13(1):26–8.
MANAGEMENT OF THE SALICYLATE-POISONED PATIENT
 Wood DM, Dargan PI, Jones AL. Measuring plasma salicylate concentrations in all patients
with drug overdose or altered consciousness: is it necessary? Emerg Med J 2005;22(6):401–3.
 Dugandzic RM, Tierney MG, Dickinson GE, et al. Evaluation of the validity of the Done
nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989;18:1186–90.
 Chalasani N, Roman J, Jurado RL. Systemic inﬂammatory response syndrome caused by
chronic salicylate intoxication. South Med J 1996;89(5):479–82.
 Paul BN. Salicylate poisoning in the elderly: diagnostic pitfalls. J Am Geriatr Soc 1972;20:
 Bailey RB, Jones SR. Chronic salicylate intoxication: a common cause of morbidity in the
elderly. J Am Geriatr Soc 1989;37:556.
 Steele TE, Morton WA. Salicylate-induced delirium. Psychosomatics 1986;27:455–6.
 Dargan PI, Wallace CI, Jones AL. An evidence-based ﬂowchart to guide the management of
acute salicylate (aspirin) overdose. Emerg Med J 2002;19:206–9.
 McGuigan MA. A two-year review of salicylate deaths in Ontario. Arch Intern Med 1987;
 Thisted B, Krantz T, Stroom J. Acute salicylate self-poisoning in 177 consecutive patients
treated in ICU. Acta Anaesthesiol Scand 1987;31(4):312–6.
 Pena-Alonso YR, Montoya-Cabrera MA, Bustos-Cordoba E. Aspirin intoxication in a child
associated with myocardial necrosis: Is this a drug-related lesion? Pediatr Dev Pathol 2003;3:342–7.
 Done AK. Salicylate intoxication: signiﬁcance of measurements of salicylate in blood in
cases of acute ingestion. Pediatrics 1960;26:805–6.
 Done AK. Aspirin overdosage: incidence, diagnosis, and management. Pediatrics 1978;
 Kulig K. Salicylate intoxication: is the Done nomogram reliable? [Comment in AACT] Clin-
ical Toxicology UPDATE 1990;3(2):2–3.
 Chabali R. Diagnostic use of anion and osmolal gaps in pediatric emergency medicine.
Pediatr Emerg Care 1997;13(3):204–10.
 Litovitz T, Manoguerra A. Comparison of pediatric poisoning hazards: an analysis of 3.8
million exposure incidents. A report from the American Association of Poison ControlCenters. Pediatrics 1992;89(6 Pt 1):999–1006.
 Mitchell AA, Lovejoy FH Jr, Slone D, et al. Acetaminophen and aspirin. Prescription, use,
and accidental ingestion among children. Am J Dis Child 1982;136(11):976–9.
 Erzurumlu K, Malagirt Z, Bektas A, et al. Gastrointestinal bezoars: a retrospective analysis
of 34 cases. World J Gastroenterol 2005;11(12):1813–7.
 Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol
 Greenberg MI, Hendrickson RG, Hofman M. Deleterious eﬀects of endotracheal intubation
in salicylate poisoning. Ann Emerg Med 2003;41(4):583–4.
 Kirshenbaum LA, Mathews SC, Sitar DS, et al. Does multiple-dose charcoal therapy
enhance salicylate excretion? Arch Intern Med 1990;150(6):1281–3.
 Park GD, Spector R, Goldberg MJ, et al. Expanded role of charcoal therapy in the poisoned
and overdosed patient. Arch Intern Med 1986;146(5):969–73.
 Vale JA, Krenzolak E, Barceloux GD. Position statement and practice guidelines on the use
of multidose activated charcoal in the treatment of acute poisoning. American Academy ofClinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
J Toxicol Clin Toxicol 1999;37(6):731–51.
 Lheureux P, Tenenbein M. Position paper: whole bowel irrigation. J Toxicol Clin Toxicol
 Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical
Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J ToxicolClin Toxicol 1997;35(7):753–62.
 Daly FF, Little M, Murray L. A risk assessment-based approach to the management of acute
poisoning. Emerg Med J 2006;23(5):396–9.
 Heard K. The changing indications of gastrointestinal decontamination in poisonings. Clin
 Worthley LI. Clinical toxicology: part I. Diagnosis and management of common drug
overdosage. Crit Care Resusc 2002;4(3):192–215.
 Heard K. Gastrointestinal decontamination. Med Clin North Am 2005;89(6):1067–78.
 Osterhoudt KC, Durbin D, Alpern ER, et al. Risk factors for emesis after therapeutic use of
activated charcoal in acutely poisoned children. Pediatrics 2004;113(4):806–10.
 Proudfoot AT, Krenzelok EP, Brent J, et al. Does urinary alkalinization increase salicylate
elimination? If so, why? Toxicol Rev 2003;22(3):129–36.
 Chang YL, Biagi B, Giebish G. Control mechanism for bicarbonate transport across the rat
proximal convoluted tubule. Am J Physiol 1982;242:532–43.
 Lund B, Seifert SA, Mayersohn M. Eﬃcacy of sustained low-eﬃciency dialysis in the treat-
ment of salicylate toxicity. Nephrol Dial Transplant 2005;20(7):1483–4.
 Higgins RM, Connolly JO, Hendry BM. Alkalinization and hemodialysis in severe salicylate
poisoning: comparison of elimination techniques in the same patient. Clin Nephrol 1998;50(3):178–83.
 Shalkham AS, Kirrane BM, Hoﬀman RS, et al. The availability and use of charcoal hemo-
perfusion in the treatment of poisoned patients. Am J Kidney Dis 2006;48(2):239–41.
IL SANTUARIO DELL’<<ARA DELLA REGINA>> 1. Topografia e prime evidenze archeologiche Il santuario è situato sul margine sud della zona centrale della città antica e domina sia la vallata sotto il fosso di San Savino sia il colle occupato dalla Tarquinia etrusca e Il tempio venne scavato da Pietro Romanelli nel 1938 e nel 1946 e pubblicato parzialmente nel 1948; altri scavi
The Times The Sunday Times From The Sunday Times February 14, 2010 How to do India with kids (part 1) In the first of two missives from a three-month adventure, everything seems to be going surprisingly well for our writer Michael Booth Of other holidays, one might perhaps recall the beaches or the shopping, but in the run-up to my family’s three-month circumnavigation of India, al