Intoxication plasma SA
Intoxication plasma SA
(600 mg aspirin)
Salicylic acid phenol glucuronide 11 ± 1 23 ± 2 15 ± 4
Total salicylates (mg salicylic acid equivalent) 246 ± 8 2999 ± 374 8092 ± 1470
Salicylic acid phenol glucuronide 11 ± 1 23 ± 2 15 ± 4
Total salicylates (mg salicylic acid equivalent) 246 ± 8 2999 ± 374 8092 ± 1470
Note the increased % excretion of nonmetabolized salicylic acid and the reduced % excretion of salicyluric acid with increasing severity of poisoning, indicating the saturation of the salicyluric acid pathway (glycine conjugation) .
of breath standstills from 42 to 28 apneas/h. This was accompanied by a decrease in pCO2 and an increase in pO2. However, because of possible side effects, this high-dose treatment was not recommended for general clinical use .
Salicylate-induced noncardiogenic pulmonary edema occurs in both severe acute aspirin intoxication and long-term overdosing of the substance . The edema occurs only at advanced stages of intoxication and may be lethal. The incidence according to recent surveys was 7% (29) in 397 patients with salicylate intoxication. At the same time, there might be proteinuria, indicating a generally increased vascular permeability [26-29]. Renalfailure is rare and usually restricted to patients with preexisting renal diseases, specifically elderly persons with hypoalbuminemia (Section 3.2.2).
Toxic symptoms of the central nervous system dominate the clinical picture with increasing severity of poisoning. The initial cerebral excitation is converted into an increased cerebral depression. Finally, there is stupor, coma with cardiovascular failure, and death from respiratory arrest.
Laboratory Findings Laboratory findings are mainly the consequence of uncoupling of oxidative phosphorylation and inhibition of b-oxidation of (long-chain) fatty acids by high-level salicylates (Section 2.2.3). In this situation, metabolic CO2 production exceeds its respiratory elimination. This effect is further enhanced by the depressive action of high salicylate levels on the respiratory center. With increasing inhibition of oxidative phosphorylation, there is also increasing accumulation of acids from the disturbed energy metabolism (lactate, pyruvate, and others) with further aggravation of acidosis and dehydration. Eventually, this results in anion-gap acidosis . Salicylate itself contributes only minimally to the anion gap: about 3 mval/l at serumlevels of500 mg/ml . There is an increased renal excretion of bicarbonate (followed by K+ and Na+) and impaired kidney function, possibly alsorelated to disturbedenergymetabolism within the tubular cells. Water and electrolyte imbalance as well as heat production (sweating!) may cause dehydration. This and the decreased renal blood flow, if untreated, will result in oliguria and finally renal failure. Disturbances in the acid-base equilibrium are most prominent in babies and toddlers .
Another typical symptom of salicylate overdosing is the changes in blood glucose levels, mostly hypoglycemia . This is due to enhanced insulin secretion as result of activation of the NFkB pathway in the pancreas by high-dose salicylate (Section 2.2.2). This might result in low glucose levels in the liquor, which require glucose substitution. However, hyperglycemia has also been reported .
Salicylate Intoxication in Children In relation to the discussion on the relationship between aspirin toxicity and Reye's syndrome, the signs and symptoms of salicylate intoxication are of particular interest in children. Similar to adults, toxic salicylate effects in children are also determined by the extreme prolongation of salicylate half-life, the markedly increased plasmalevels, and its enhanced distribution into cells and tissues with decreasing pH.
Aspirin overdosing in children becomes clinically evident as a consequence of uncoupling of oxidative phosphorylation. Conventional light microscopic examination of liver biopsies of children with severe salicylate intoxication showed intrahepatocytic microvesicular steatosis without inflammation or necrosis but with depletion of glycogen stores. Findings of this kind in 10 out of 12 children who died from assumed salicylate intoxication and had cerebral edema (according to a review of records) suggested a causal relationship between aspirin intoxication and the occurrence of Reye's syndrome in a frequently cited paper . However, ultrastructural microscopy of liver biopsies (not done in this particular study) of children with Reye's syndromeis different from that ofchildren with salicylate intoxication , andacausal relationship between aspirin and Reye's syndrome in children has never been established  (Section 3.3.3).
Uncoupling of oxidative phosphorylation is compensated by an increase in metabolic turnover and associated with increased oxygen consumption, depletion in liver glycogen, and increased production of heat. This increased production of heat is responsible for the dangerous hyperpyrexia that is a prominent symptom of salicylate poisoning in infants .
Hyperpyrexia in salicylate poisoning is somehow difficult to understand because salicylates were frequently and effectively used as antipyretic analgesics in children until the Reye's syndrome discussion was started. The possible explanation is that salicylates "reset" the disturbed temperature regulation in the hypothalamus via their interaction with endogenous pyrogens (Section 2.3.2) but are unable to block the production of "extra" heat as a consequence of uncoupling of oxidative phosphorylation in peripheral organs (Section 2.2.3).
Physical temperature control functions by the production of large quantities of sweat as long as enough fluid for sweat production is available. When this mechanism becomes exhausted because of large water losses and dehydration, unbalanced hyperpyrexia develops because the "upregulation" of temperature control by endogenous pyrogens is still in function. Dehydration is also associated with convulsions, in particular, at severe intoxication of children below 2 years of age .
These metabolic disturbances, including respiratory alkalosis and metabolic acidosis, arethemost important life-threatening effects of salicylates. In children, metabolic acidosis usually predominates over respiratory alkalosis whereas the opposite is seen in adults [3, 12, 36].
Chronic Overdosing Chronic salicylate intoxication in adults (salicylism) usually results from iatrogenic overdosing during long-term aspirin treatment and is frequently overlooked because of the absence of specific symptoms . Symptoms of chronic overdosing are tinnitus, multiple neurological deficits, including headache (!), confusion and central excitation, sweating, hyperventilation, gastrointestinal bleeding, and ulcers. GI side effects appear to dominate in younger age whereas tinnitus and other audiovestibular toxicities (Section 3.2.4) are more frequent in the elderly. Reversible hepatic injury as another feature of long-term aspirin overdosing was, in principle, only seen in patients with a pathologic immune status, for example, rheumatoid arthritis, where the patients required long-term aspirin treatment at high doses  (Section 3.2.3). However, because of available therapeutic alternatives in this indication, this finding is now more of historical interest.
Severe salicylate poisoning is an acute life-threatening, though rarely fatal, medical emergency situation. The treatment is entirely symptomatic because no specific antidote is available. As with other systemic intoxications, there are two basic therapeutic principles: reduction or prevention of absorption and stimulation of excretion of salicy-lates. Both measures are supported by symptomatic treatment of functional and metabolic disturbances. An actual evidence-based consensus guideline for out-of-hospital treatment of salicylate poisoning  as well as recommendations for emergency department management [20, 39] is available. However, obviously, not all recommendations at least in the past were identical.
A survey on recommendations by health professionals for optimum treatment of acute aspirin poisoning by retarded-release formulations provided interesting results. Seventy-six poison-control centers of North America were asked for their recommendations to treat a hypothetical case of an adult male patient presented 1 h after ingestion of 500mg/kg enteric-coated aspirin with normal vital signs.
There was a considerable variability between the center-based recommendations. Some of the 36 (!) different recommended courses of action were considered potentially harmful .
Inhibition of Absorption Treatment of the "conventional" oral intoxication starts with an interruption of further salicylate uptake from the GI tract since intestinal absorption in the presence of toxic doses still continues for several hours and might be even longer in the case of enteric-coated preparations because of their retarded absorption . Usual procedures for preventing further absorption include gastric lavage and administra tion of activated charcoal . As to be expected, the earlier they can be started the more effective these procedures are. An optimum time frame would be within 1 h after ingestion.
This study and most of the other pharmacoki-netic studies on the modification of aspirin kinetics used aspirin doses between 1.5 and 3.0 g. These doses are far below those where toxic effects had to be expected and, therefore, may not sufficiently reflect the reality of salicylate poisoning. Nevertheless, the data indicate that charcoal treatment will reduce the aspirin absorption if it is started early and charcoal is given at sufficiently high doses. In addition, charcoal may recoat the surface of aspirin concretions within the stomach  and thus reduce ongoing absorption. Administration of repeated doses of charcoal may be particularly useful in patients who have ingested overdoses of enteric-coated or other slow-release formulations [41, 45]. Thus, repeated charcoal doses (4 x 50 g in 1 h intervals to adults or 1 g/kg body weight to children) are recommended until the plasma salicylate reaches peak levels . In the postabsorption phase, there is no accelerated clearance of plasma salicylate by charcoal [46, 47] and no change in the prolonged half-life .
Stimulation of Elimination Determinations of salicylate plasma levels by any suitable method (Section 1.2.2) and ofthe acid-base equilibrium to detect ionic gaps are helpful because most of the clinical symptoms of salicylate poisoning are well correlated with these parameters. Measurements of salicylate plasma levels should be done initially and should be repeated at appropriate time intervals until peak plasma levels are obtained. The combined metabolic/respiratory acidosis should be corrected by appropriate treatment with sodium bicarbonate together with 20-40 mM K+ i.v. over 3 h under control of kidney function and rehydration . This procedure works with several mechanisms: inhibition of reabsorption of salicylate in the kidney by alkaline diuresis and improvement of the acid-base equilibrium in blood with normali-zationofplasmapH. This facilitates therediffusion of (acetyl) salicylic acid from tissues in the blood. Particularly important is rediffusion from the central nervous system. An urinary pH of 7.5 or higher is suggested whereas the pH of blood should not exceed 7.55. Renal salicylate clearance is stimulated about 20-fold when the urinary pH increases from 6.1 to 8.1 , indicating that renal clearance of salicylates depends much more on urinary pH than on the renal flow rate . An additional approach to stimulate salicylate clearance is conversion into salicyluric acid by substitution of glycine .
Severe acute poisoning, that is, plasma salicylate levels above 1200 or 1000 mg/ml 6 h after ingestion, refractory acidosis or other symptoms of severe intoxication (Table 3.1), volume overload, and renal failure are indications for hemodialysis. In chronic overdose, hemodialysis may be considered in symptomatic patients with serum salicylate levels above 600 mg/ml . Hemodialysis has been shown to reduce both morbidity and mortality of salicylate poisoning . An actual flowchart on algorithms for the treatment of acute salicylate poisoning was published by Dargan et al.  (Figure 3.1). Further details and dose recommendations can be found in the original publication.
Further Measures Hyperthermia and dehydration require immediate treatment, that is, cooling and fluid uptake. Ketoacidosis and hypoglycemia additionally require the administration of glucose
In one prospective trial, 13 healthy adults received 1.9 g aspirin (24 tablets, each containing 81 mg aspirin). In a randomized crossover design, each subject received additionally 50 g charcoal as a single dose, two times or three times in a 4 h interval. Urinary salicylate excretion was measured and each protocol repeated in weakly intervals.
In the absence of charcoal, 91 ± 6% (mean ± SD) of total salicylate was recovered in urine. This amount was reduced to 68 ± 12, 66 ± 13, and 49 ± 12% after one, two, and three single 50 g doses of charcoal, respectively. All of these changes were significant and document for this model a 30-50% reduction in salicylate absorption by charcoal .
(see  for details). Administration of dextrose may help to avoid low cerebrospinal glucose level . Pulmonary edema usually resolves quickly with standard supportive therapy, though it might also be lethal (see above) .
The many tons of aspirin consumed every year worldwide have occasionally led to the opinion that the drug is habit forming. However, it is generally accepted that antipyretic analgesics, such as aspirin or acetaminophen in contrast to morphine-type analgesics, do not cause physical dependence. This is also confirmed by the scarcity of reports on "addiction" or "habituation" to salicylates. There might be some psychological desire for drug intake, for example, regular use for pain relief, but only to the extent that frequent use of any substances that gives relief, real or imaginary, from pain, is a habit .
In contrast, there might be abuse of aspirin if used in (fixed) combinations with other constituents of analgesic mixtures, most notably, caffeine and codeine. A separate issue is the few reports on abuse of aspirin at high doses when toxic effects, such as salicylism with exaltation and deafness, were used for "therapeutic" purposes.
A 59-year-old man took about 100 tablets of aspirin within 2 weeks for "encouragement." A 30-year-old man with eplilepsy and alcoholic problems took 20-30 tablets of aspirin within 1 h for the same purpose and a 58-year-old female with alcoholic problems took up to 100 aspirin tablets against crapulousness and also because she was unable to tolerate the noise at her working place (after ).
Taken together, there is no evidence that aspirin as a single preparation has a habit-forming potential.
Acute life-threatening salicylate intoxication in adults occurs at doses of about 12-15 g and above and 3 g and above in children. This is equivalent to plasma levels of >300 mg/ml or >2mM. Initial symptoms are nausea and vomiting, tinnitus, and tachypnea with respiratory alkalosis and central excitation, eventually resulting in combined respiratory/metabolic acidosis. At severe intoxications, there are increasing central nervous dysfunctions (hallucinations, stupor, and coma), renal failure, and, finally, death from respiratory arrest. All of these symptoms are caused by salicy-late accumulation in organs and tissues, most notably, in the central nervous system, and probably due to salicylate actions on cellular metabolism. Despite large interindividual variability, the salicylate plasma levels correlate well with clinical symptoms.
Treatment of salicylate poisoning is symptomatic. Reduced absorption by repeated administration of activated charcoal is an effective measure in early stages of intoxication, that is, as long as absorption from the GI tract is not completed. With ingestion of enteric-coated aspirin, this interval is longer than that with plain compounds. Renal salicylate excretion can be considerably enhanced by correction ofacidosis and appropriate alkalinization of urine by sodium bicarbonate. The final outcome is largely determined by an early diagnosis, that is, beginning of the treatment. Under optimum conditions, mortality of severe intoxications amounts to <5% but may increase to 15-20% if the beginning of treatment is delayed.
There is no evidence for addiction or habitua-tion with salicylates, even at long-term use. The risk of persistent injuries of liver or kidney function, the main sites of salicylate metabolism and excretion, respectively, is very small and clinically only relevant at preexisting diseases, for example, high-dose long-term treatment of inflammatory disorders with an altered immune status, such as rheumatoid arthritis. However, this is currently no indication of aspirin use.
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