Changing Patterns of Causation and the Use of Transplantation in the United Kingdom

Acute liver failure (ALF) is a rare condition in the United Kingdom. Comprehensive supportive intensive care of extra-hepatic organ failure and the early recognition of and use of transplantation for those who will not survive form the cornerstone of its management. Over the last 30 years there has been a reduction in the proportion of cases resulting from viral and seronegative hepatitis, and a progressive rise in those resulting from severe acetaminophen-induced hepatotoxicity. The latter cases mostly result from deliberate self-poisoning and formed the major cause of ALF hospital admissions and indication for emergency liver transplantation. The increasing misuse of acetaminophen has paralleled a rise in sales and greater availability of the drug. Introduction of legislation to restrict sales of acetaminophen has been followed by a fall in hospital admissions resulting from self-poisoning, a 20% reduction in deaths, and a 50% fall in the number of patients undergoing emergency liver transplantation. The reduction in acetaminophen-related ALF has been paralleled by an increase in the number of transplants performed in ALF of nonacetaminophen etiologies.

#

KEYWORDS

Acute liver failure - acetaminophen - self-poisoning - transplantation - hepatotoxicity

#

ALF IN THE UNITED KINGDOM: BACKGROUND AND ADVANCES IN MANAGEMENT

In the United Kingdom, ALF is a rare condition outside specialist centers. In England and Wales, chronic liver disease is reported as an underlying cause of death in nearly 5000 cases annually; ALF probably accounts for only a few hundred deaths.[1] Although the only therapy of proven benefit in advanced cases of ALF is that of emergency liver transplantation,[2] [3] it remains an infrequent indication for such surgery, accounting for less than 15% of all liver transplants in the United Kingdom and Ireland,[4] with between 75 and 100 transplants performed each year.[5]

The etiology of ALF shows marked worldwide variation: in the developing world, viral causes predominate, whereas drug-induced hepatotoxicity and “seronegative” hepatitis predominate in much of the western world (Table [1]).[2] [3] [6] [7] [8] [9] The importance of these differences in etiology lies in the fact that the frequency of complications and overall prognosis vary greatly with the underlying cause.[2] [3] Despite the frequent occurrence of cerebral edema and renal failure in so-called hyperacute ALF (exemplified by that resulting from acetaminophen and hepatitis A), survival without transplantation is relatively good. By contrast, the more indolent cases of “subacute” ALF (exemplified by seronegative hepatitis and many nonacetaminophen drug reactions) have very poor prognoses without necessarily the development of cerebral or renal failure.[2] [3] [10]

The management of these varying clinical scenarios is essentially supportive. It aims to identify and remove or ameliorate the insult that led to impairment of hepatic function while preventing or limiting the severity of the associated complications. Conditions needed for hepatic regeneration are optimized for a return to premorbid levels of hepatic function. In some patients with ALF, sufficient hepatic recovery may not be possible and the early recognition of such cases is essential, enabling transplantation to be performed before extra hepatic complications preclude transplantation.[11] [12] [13]

In the United Kingdom, most ALF cases result from acetaminophen-induced hepatotoxicity.[7] Acute liver failure in this setting is a short, intense illness, with patients progressing from isolated hepatic failure to the involvement of multiple extrahepatic organ systems failure with encephalopathy, renal failure, and cardiovascular collapse in a matter of hours.[13] [14] Fortunately the “superurgent” category within the U.K. transplant priority list allows ABO matched grafts to be available for most of these patients within 24 to 72 hours, and much current research activity is focused on aspects of the supportive care of unstable ALF patients as well as on finding better methods for the early detection of those patients who will require transplantation.[11] [15] [16] [17] [18]

Approaches to the supportive intensive care of the patient with ALF must address the multiple organ systems involved, and they have recently been reviewed.[19] Recent studies in other critical illnesses have reinforced the importance of specific aspects of the care of these patients.

Systemic cardiovascular dysfunction is likely to be a central mechanism for the development of extrahepatic organ failure in patients with acute hepatic dysfunction, and early monitored and aggressive restoration of circulating volume and systemic oxygen delivery may serve to limit the severity of organ failure that evolves.[20] The failure to respond to volume loading and the requirement for vasopressors is an ominous prognostic sign.[21] [22] Many such patients have relative adrenal insufficiency and may benefit from steroid supplementation,[23] and there is evidence from other critical illnesses that low-dose corticosteroids may reduce vasopressor requirements and improve survival.[24]

Renal failure is best treated with continuous rather than intermittent renal replacement therapy because this is associated with greater biochemical and hemodynamic stability and a lower incidence of intracranial hypertension.[25] [26] In the United Kingdom, continuous venovenous hemofiltration is used most commonly[27]; it is important that an adequate “dose” of filtration is administered. In other critical illnesses, higher volumes of hemofiltration are associated with benefits additional to the simple replacement of renal function, with improvements in hemodynamic stability and survival.[28] [29]

Advances in the understanding and treatment of encephalopathy associated with ALF are discussed elsewhere in this issue. On a practical level, our current practice is to maintain a low threshold for the endotracheal intubation to protect the airway in those patients with evolving encephalopathy. Ventilatory strategies should optimize oxygenation without the routine use of hyperventilation; its induction of cerebral vasoconstriction is ineffective in preventing cerebral edema and may worsen cerebral ischemia.[30] [31] [32] Muscle relaxants are not routinely administered because they may mask signs of seizure activity and in other critically ill patients have been linked to the development of critical illness neuropathy. The development of seizures may be prevented through the correction of electrolyte abnormalities, particularly of magnesium, calcium, and glucose. Hyponatremia may increase susceptibility to cerebral edema[33] [34] and serum sodium should be maintained between 140 and 150 mmol/L, and body temperature at 36°C or below.

All patients intubated for encephalopathy are monitored using jugular venous oximetry, a relatively noninvasive means of detecting abnormalities of global cerebral oxygen delivery and utilization.[35] Intracranial pressure monitoring is performed using the Camino extradural system, which is likely to have a lower complication rate than what was previously reported, but insertion is deferred until there is evidence from clinical signs or other forms of less-invasive monitoring of evolving intracranial hypertension or if the patient is to undergo transplantation.

Infection is common and of major prognostic importance in ALF, acting as a trigger for the systemic inflammatory response syndrome (SIRS) and precipitant of encephalopathy and cerebral edema.[36] [37] To minimize the risks of infection, early enteral feeding is administered when possible, and scrupulous asepsis is observed on insertion of vascular catheters, with the use of antimicrobially impregnated lines. The routine use of broad antimicrobial prophylaxis has not been shown to improve prognosis in ALF[36]; antimicrobial therapy (including antifungals) is restricted to patients displaying clinical signs of infection or SIRS or to those patients who have fulfilled transplantation criteria. Whenever possible, antimicrobial therapy is targeted to the causative organism, and frequent and appropriate microbiological cultures are taken.

#

CHANGES IN THE ETIOLOGY OF ALF IN THE UNITED KINGDOM

The etiology of ALF in the United Kingdom has changed over the last three decades. Two large ALF case series have been reported from the Institute of Liver Studies at King's College Hospital, London, covering the period from 1973 to 1997 (see Table [1]).[7] [38] [39] These show a major increase in the proportion of cases resulting from acetaminophen-induced hepatotoxicity and a corresponding reduction in those with a viral or presumed infective cause. More than 75% of a series of nearly 1000 cases admitted between 1991 and 1997 resulted from drug-induced hepatotoxicity, and, of these, more than 90% resulted from acetaminophen ingestion. No other single diagnostic group was responsible for more than 10% of admissions.

#

Nonacetaminophen-Induced ALF

The proportion of cases resulting from nonacetaminophen hepatotoxic drug reactions remained fairly constant between 1973 and 1997. In the more recent series, medication used for antituberculous therapy was implicated in nearly 30% of cases, and 20% resulted from reactions to the recreational drug Ecstasy (3,4 methylenedioxymethamphetamine).[40] Ecstasy is widely used in much of western Europe and is increasingly recognized as a cause of hepatotoxicity and ALF, particularly in those under 30 years of age.[41] [42] [43] No other single group of drugs predominates as a cause of ALF, with smaller numbers of patients developing hepatotoxicity from medication, including anticonvulsants, androgenic steroids, cocaine, nonsteroidal analgesics, and herbal remedies.

In the United Kingdom, the incidence of acute hepatitis A virus (HAV) and hepatitis B virus (HBV) infection has fallen dramatically since the 1980s, with particularly marked recent changes in relation to HAV infections (Fig. [1]). Currently, approximately 2000 acute infections are notified annually in England and Wales.[44] [45] Less than 0.05% of acute HAV[46] and HBV[47] infections result in ALF, and this patient group is currently responsible for less than 5% of all ALF admissions, a marked reduction from the 1970s and 1980s, when acute infections were much more common.[38] [48]

Seronegative or non-A-E hepatitis is the most common presumed viral cause in most of the western world,[3] but in the recent King's College series it accounted for less than 10% of all cases. This diagnosis remains one of exclusion, although doubt exists as to whether many or all of these cases are due to a viral infection.[3] [49] Cases are usually sporadic, and unidentified toxins or autoimmune processes may contribute to the causation of ALF in this group. In the United Kingdom, there is clinical suspicion that Ecstasy may play a role in some cases of subacute seronegative hepatic failure; a history of Ecstasy exposure is often obtained in younger patients. Unusual viral causes of ALF in the United Kingdom include herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus and hepatitis E (HEV).[39] [50] [51] The reduced proportion of seronegative cases in the recent King's College series is likely to reflect, in part, advances in case definition and viral diagnostic testing.

Miscellaneous causes are responsible for the remaining cases of ALF in the United Kingdom. These include ALF associated with pregnancy, acute Budd-Chiari syndrome, Wilson's disease, malignant infiltration, ischemic hepatitis, autoimmune hepatitis, and poisoning with the mushroom Amantia Phalloides.[3] Again, no single etiology predominates, with these rare causes individually responsible at most for only a small percentage of all cases.

#

Acetaminophen-Induced ALF: Acetaminophen-Induced Hepatotoxicity in the United Kingdom

Deliberate self-harm (DSH) is a major public health problem in the United Kingdom, with self-poisoning the most commonly used method, resulting in more than 60,000 hospital admissions annually.[52] Simple analgesics are among the most frequently used drugs for deliberate self-poisoning, and, of these drugs, acetaminophen is the most commonly consumed. Its use has increased dramatically over the last three decades.[53] [54] [55] Only a small proportion of patients who take an acetaminophen overdose are at risk of liver damage; less than 10% develop severe liver damage and only 1 to 2% will develop ALF, primarily because of the small doses absorbed and the efficacy of early antidotal therapy.[56] [57] Thus, although in 1997 more than 38,000 patients were admitted to U.K. hospitals as a result of acetaminophen poisoning, only 57 patients underwent emergency liver transplantation, and 562 deaths were reported in which acetaminophen ingestion was thought to have played a role.[52] [58]

Most cases of acetaminophen poisoning in the United Kingdom are likely to be as the result of deliberate rather than unintentional self-poisoning.[21] [59] The reasons for the popularity of acetaminophen for self-poisoning in the United Kingdom are not fully understood, although the ready availability of the over-the-counter (OTC) drug [60] [61] and the patients' limited knowledge of the possible consequences appear to be important factors.[62]

In the United Kingdom, acetaminophen self-poisoning is most common in young adults, most often women, and the drug is often consumed impulsively, with little serious suicidal intent.[21] [60] [63] The precipitants are most commonly problems with personal relationships, employment, or study,[53] and the rates of self-poisoning and acetaminophen-induced ALF are closely associated with measures of social deprivation and fragmentation.[64] [65] Patients whose self-poisoning results in a fatal outcome are more commonly older men and those consuming acetaminophen/opiate combinations[21] [66]

Whether chronic alcohol consumption is a major risk factor for the development of hepatotoxicity is controversial.[67] [68] [69] [70] Reports from the United Kingdom have suggested that a history of excessive alcohol consumption is common in patients who develop severe hepatotoxicity.[57] [59] [71] However, rather than reflecting an increased susceptibility to the drug, this seems likely to reflect the high rates of attempted suicide in those with alcohol problems.[59] [72] Few if any cases appear to result from “therapeutic misadventures,” and accidental overdose is rare.[59] Most of these patients have actually taken substantial overdoses or presented late, outside the “window” of effectiveness of antidotal therapy, or both. A worse outcome is seen only in those patients who are very heavy drinkers[57]; this may not necessarily reflect increased hepatotoxic effects[59] but rather the worse outcome seen in the malnourished with critical illnesses.[73]

#

UNITED KINGDOM ANALGESIC LEGISLATION

A number of strategies have been advocated to counter the rise in acetaminophen self-poisoning in the United Kingdom, including the promotion of alternative analgesic drugs[74]; the use of paracetamol-methionine combination tablets, which might have lower hepatotoxic potential[75]; or restriction of OTC availability.[61] [74] [76] Such restriction is recommended by the World Health Organization[77] when the use of specific substances for DSH is associated with significant mortality, and there are examples worldwide that this strategy may successfully reduce death rates.[78] [79] [80]

The increasing number of overdoses with acetaminophen has paralleled a rise in sales within the United Kingdom and, by implication, the greater availability of the drug.[61] This ready availability is likely to be a major factor in determining the drug's popularity for self-poisoning.[60] [62]

Some evidence suggests that restriction of acetaminophen availability might reduce rates of misuse and the severity of poisoning. There are clear differences in the availability of acetaminophen in different countries; in some (including until recently the United Kingdom), acetaminophen is freely available in large quantities from pharmacies and in smaller quantities from supermarkets and other retail outlets. Acetaminophen-related mortality appears to be highest in those countries in which unlimited quantities may be purchased; in countries in which it may only be purchased in pharmacies and in limited quantities, acetaminophen-related suicide is not commonly seen as a problem.[76] Increases in sales and availability appear to be associated with the increased use of acetaminophen for deliberate self-harm; in the United Kingdom, Denmark, and France, increases in sales have been accompanied by increases in fatal and nonfatal overdose.[61] [81] In France, however, where packet size is limited to 8 g, overdose is common, but severe hepatotoxicity and death are rare.[61]

Legislation introduced by the U.K. Medicines Control Agency on September 16, 1998,[82] to restrict the OTC availability of acetaminophen and aspirin (Table [2]) sought compromise between the inconvenience introduced to the many “safe” analgesic users and the apparent need to restrict the total amount of the drugs available to those taking overdoses. Given the impulsive nature of most self-poisonings, it seemed possible that even if it failed to reduce the total number of overdoses, the number of larger ingestions with significant hepatotoxicity as a result was likely to fall.[63] By reducing ease of purchase and residual quantities of these analgesics in the home, the dose taken at what are often impulsive overdoses should be lower.[63] [83]

Experience in other countries has suggested that the results of this approach might be limited or even deleterious. In Ireland the introduction of similar legislation had little effect on sales from nonpharmacy outlets and only a minor effect on rates of acetaminophen-related hospital admissions.[84] Selective restrictions of sale could also favor overdose, with the next most available drug or the increased use of more toxic multidrug combinations, transferring the burden of care and mortality from hepatology to other medical services.[83] [85] In Australia, a period of recall of acetaminophen products was not associated with a reduction in the rate of acetaminophen-related self-poisoning but with an apparent increase in poisoning with other OTC analgesics.[86]

Initial reports of the effects of this legislation have suggested that there may have been substantial changes in the incidence and severity of acetaminophen poisoning, with a reduction in deaths, hospital and liver unit admissions, and the number of emergency liver transplants performed.[87] [88] [89] In the remainder of this article, the changes that have occurred after the introduction of this legislation will be discussed, with particular emphasis on the utilization of emergency hepatology and transplantation services and the implications for other countries in which acetaminophen sales continue to be unrestricted.

#

Changes Observed in the United Kingdom After Introduction of Analgesic Legislation: Nonopiate Analgesic Sales

Commercial data are available for the sales of OTC analgesics to pharmacies and other outlets before and after the introduction of the legislation; these data cover 97% of all sales to pharmacies.[90] Sales of nonopiate analgesics changed dramatically in the years after the introduction of the legislation (Table [3]). By 2000, total sales of acetaminophen had fallen to 41% of their 1998 amount and of aspirin to 23%. These changes were accompanied by a parallel rise in sales of ibuprofen to 173% of their 1998 levels. There were no significant changes in the number of packs of acetaminophen or aspirin sold over this time period; the number of ibuprofen packs sold increased by nearly 20%.

#

Hospital Admissions and Acetaminophen-Related Deaths

Wilkinson and colleagues[52] examined changes in the rates of deliberate self-harm and the substances employed between 1995 and 2000, using the Hospital Episode Statistics (HES) database. The HES database collates data from all hospital admissions in England and Wales, accumulating some 12 million records per annum. Admissions resulting from self-harm of all causes rose from 1995 to 1996 until 1997 to 1998, with a 30% increase in the number of acetaminophen-related admissions. A reversal of this trend occurred in 1998 to 1999 and was maintained in 1999 to 2000. In the year from 1997 to 1998, 93,773 patients were admitted to the hospital after deliberate self-poisoning, 38,168 (41%) of these patients had consumed acetaminophen, a rate of 77 per 100,000 population. Acetaminophen-related admissions subsequently fell; in 1999 to 2000, the number had fallen to 34,481, or 67 per 100,000, a reduction of more than 10%.

The U.K. Office for National Statistics (ONS) data for deaths resulting from drug poisoning in England and Wales[58] showed a rise in all acetaminophen-related deaths of 21% between 1993 and 1997. This trend was reversed from 562 deaths in 1997 to 455 in 2000, a fall of 19%. It has been suggested that U.K. official figures of acetaminophen-related deaths may overestimate the actual number of cases directly resulting from acetaminophen-induced hepatic damage, with other drugs consumed at overdose playing a more important role.[91] However, ONS data show that deaths related to acetaminophen alone fell from 281 in 1997 to 187 in 2000, a reduction of more than 60%. Over the same time period, aspirin-related deaths showed a similar pattern, with a fall from 50 in 1997 to 24 in 2000, a reduction of 52%.[58]

#

ACETAMINOPHEN DOSE IN RELATION TO OCCURRENCE OF HEPATOTOXICITY

Hepatotoxicity is an uncommon consequence of acetaminophen overdose in part because most patients absorb less than 125 mg/kg of the drug (approximately 7.5 g of the drug in a 60-kg adult). This is likely to be the minimum dose capable of producing hepatic damage. The threshold dose that must be absorbed in order for there to be significant hepatic damage is approximately 250 mg/kg.[56]

The average dose of acetaminophen consumed at overdose may have fallen since supply was restricted. An analysis of nearly 1200 patients presenting to five general hospitals in Northern Ireland after overdose found a highly significant reduction in the dose consumed (to a median dose of 8 g), lower serum acetaminophen levels on admission, and fewer patients requiring administration of the antidote N-acetyl cysteine after the introduction of pack size restriction.[92] A study of more than 4500 patients presenting to seven hospitals in southern England found only a 7% reduction in the average number of tablets consumed but a 17% reduction in the numbers of patients consuming more than 16 g of acetaminophen.[87]

#

DRUG SUBSTITUTION FOR DELIBERATE SELF-POISONING

Since the sales restriction, there has been some evidence of increased use of acetaminophen as part of multidrug cocktails taken at overdose. One study found a small but significant increase in the proportion of patients self-poisoning with acetaminophen in conjunction with other drugs.[87] HES data from 1997 to 1998 and 1999 to 2000 showed a reduction in hospital admissions with acetaminophen poisoning as a main diagnosis by 16% from 30,918 to 26,096 admissions. However, a parallel 16% increase in admissions with acetaminophen poisoning as a subsidiary diagnosis occurred over this time period, from 7250 to 8385.[52]

An increase in multidrug self-poisoning may not be reflected by greater mortality. Although there has been a reduction in deaths related to acetaminophen alone since September 1998, there has been no increase in the number of deaths after poisoning with acetaminophen in combination with other drugs or alcohol.[58]

Whether substitution of acetaminophen for other OTC analgesic drugs in self-poisoning attempts has occurred is more difficult to determine because data are unavailable for rates of self-poisoning with ibuprofen, the next most popular OTC analgesic.[90] U.K. rates of self-poisoning with prescription psychotropic and sedative hypnotic drugs have been rising progressively since the early 1990s, prior to the introduction of legislation concerning analgesics.[58] With a reduction in rates of acetaminophen use, in 1998 to 1999 and 1999 to 2000 the number of hospital admissions resulting from self-poisoning with these drugs for the first time exceeded those resulting from acetaminophen,[52] but without a commensurate increase in the number of deaths.[58]

#

UNITED KINGDOM NATIONAL SUPERURGENT TRANSPLANTATION ACTIVITY

Patients with ALF who fulfill transplantation criteria and are not excluded by other considerations are registered for transplantation using the “Super-Urgent” listing scheme. Within the United Kingdom and Ireland, the central organization, U.K. Transplant, which manages all organ graft procurement and allocation, also maintains the National Transplant Database (NTD). The NTD includes details of all superurgent patient listings and the transplants performed. NTD data over the period 1995 to 1998 showed an increase of more than 75% in the number of patients with acetaminophen-induced ALF listed for transplantation. Between August 30, 1997, and August 29, 1998, 51 patients with acetaminophen-induced ALF were listed for transplantation, representing 40% of all superurgent listings. Thirty (59%) of these patients underwent transplantation, representing 38% of all superurgent transplants during this time period.[5]

The number of patients with acetaminophen-induced ALF subsequently fell and was lower in all 4 subsequent years. In 2001 to 2002, 27 patients were listed, 17 (63%) of whom received transplants, representing reductions to 53% and 56% of their 1997 to 1998 values, respectively (Fig. [2]). Between 1997 to 1998 and 2001 to 2002, the proportion of emergency transplants performed for acetaminophen-induced ALF also fell, from 38% of all transplants to 16%.

In parallel with the reduction in the number of patients undergoing transplantation for acetaminophen-induced ALF, there has been an increase in the number of patients listed as superurgent and receiving transplants for ALF from other etiologies. Between 1997 to 1998 and 2001 to 2002, the number of patients listed for acute graft failure after transplantation increased by more than 50% and those listed for seronegative hepatitis increased by more than 60% (Fig. [3]). During this time period, the total number of superurgent transplants performed increased from 79 transplants in 1997 to 1998 to 102 in 2001 to 2002.

This increase in the number of patients receiving transplants for acute graft dysfunction may relate to the greater use of marginal grafts in elective transplantation, but the changes seen in relation to transplants for seronegative hepatitis are more difficult to explain. It seems unlikely that this is as a consequence of a true increase in the incidence of seronegative hepatitis but rather that there may be greater recognition of this diagnostic group. Transplantation selection criteria are less well-defined for this group, and the thresholds for transplanting these patients may now be lower, possibly as a result of the greater availability of superurgent transplantation resources following the reduction in acetaminophen-related transplantation.

#

UNITED KINGDOM REGIONAL ACUTE HEPATOLOGY ACTIVITY

The Liver Intensive Therapy Unit (LITU) at King's College Hospital acts as a referral center for much of southeastern England, and its records show that during the 1980s and much of the 1990s there was a progressive rise in the numbers of patients transferred with severe acetaminophen-induced hepatotoxicity.[21] However, since September 1998, the number of patients admitted has fallen progressively.

Comparison of the period August 30, 1997, to August 29, 1998, with 2001 to 2002 shows an overall reduction by 72 % in the numbers of patients admitted and a 74% fall in the number who died or underwent transplantation (see Fig. [3]). Similar proportions of those admitted either died or underwent transplantation (32% of patients admitted in 1997 to 1998 and 30% of patients admitted in 2001 to 2002), suggesting no reduction in the overall severity of ALF.

These marked reductions in the incidence of severe acetaminophen-induced hepatotoxicity may not be reproduced elsewhere in the United Kingdom. Reports from Scotland[93] and northern England (M. Hudson, personal communication, October 2002) have suggested that in some areas the incidence of severe poisoning and hepatotoxicity may be unchanged, and the numbers of patients who die or are transplanted may actually be increasing. These differences may relate to the sociocultural factors that influence the popularity of the drug for overdose and the known effects of economic circumstance on rates of acetaminophen-related self-poisoning.[64] [65] The region served by the LITU benefited particularly from increased prosperity over the time period studied.

#

OVERVIEW OF ACETAMINOPHEN PACKAGE SIZE RESTRICTION

In assessing the data presented earlier, some important methodological issues should be considered. The studies follow a “before and after” design, and although they may show clinically and statistically significant changes, they cannot provide definitive evidence of causation; the findings are correlational, not experimental. Furthermore, before and after studies have difficulty accounting for underlying trends in outcomes, and the time period studied may be insufficient to demonstrate the eventual outcome of an intervention. It is also of concern that there is evidence of potentially important regional differences in the changes observed.[94] [95] [96] Nonetheless, the magnitude of changes in a variety of outcome measures in independent studies with national coverage would suggest that acetaminophen package size restriction has been successful in some of its aims to date.

To summarize the evidence, in the United Kingdom since September 1998, there has been

a marked reduction in the volume of sales of acetaminophen and a probable reduction in the doses consumed at self-poisoning;
a reversal of the trend of rising hospital admissions related to acetaminophen self-poisoning;
a reversal in the trend of increasing incidence of severe hepatotoxicity, with at least 20% fewer acetaminophen-related deaths and a fall of nearly 50% in the number of patients listed and undergoing transplantation for acetaminophen-induced ALF;
an increase in the number of patients undergoing transplantation for ALF of nonacetaminophen etiologies; and
little evidence for deleterious effects of drug substitution or increased use of multidrug cocktails.

The popularity of acetaminophen for deliberate self-poisoning in the United Kingdom is in many ways unique, with rates far higher than those seen elsewhere in the world.[76] [97] Few cases of severe hepatotoxicity result from inadvertent poisoning. However, a number of countries continue to allow unrestricted sales of acetaminophen,[76] and in some, acetaminophen-related hepatotoxicity may be an increasing problem. Extrapolation of the U.K. experience may be pertinent to these states.

For example, the sale of acetaminophen is unrestricted in the United States, and acetaminophen poisoning is increasingly common with 85% of cases involving the use of OTC formulations of acetaminophen.[98] Annually, it is responsible for nearly 60,000 emergency department (ED) visits, more than 26,000 hospitalizations, and in excess of 450 deaths.[98] Poison Center data suggest that there has been a nearly 100% increase in the number of acetaminophen-associated deaths since 1995.[99] Most cases of poisoning are a result of intentional rather than accidental ingestion of toxic quantities, with deliberate poisoning responsible for nearly 60% of acetaminophen-related ED visits.[98] “Therapeutic misadventures” may be more uncommon than was reported previously,[100] occurring in less than 15% of hospital admissions,[97] [101] [102] and less than a quarter of acetaminophen-related deaths can be attributed to unintentional overdose.[98] Acetaminophen is also the most common cause of ALF in the United States and may be increasing in importance, although as discussed elsewhere in this issue, the proportion of cases resulting from deliberate overdose seems to be lower. The demographic and clinical characteristics of those U.S. patients with apparently inadvertent severe hepatotoxicity closely resemble those of both U.K. and U.S. patients in whom poisoning is intentional and with delayed presentation and would suggest that many have in fact concealed deliberate overdoses.

The recent Food and Drug Administration recommendations[103] for more explicit warnings on acetaminophen packaging may be of only limited benefit in reducing the number of cases of poisoning and severe hepatotoxicity. Such changes are unlikely to have much effect on those who take the drug intentionally.[63] Some form of pack size restriction would seem, as we have learned, to be the only way forward.

#

ACKNOWLEDGMENTS

I thank Dr. Stephen Wilkinson (University of Bath, UK), Dr. Mark Hudson (University of Newcastle, UK), Dr. Natasha Crowcroft (Public Health Laboratory Service, UK); Alex Hudson and U.K. Transplant for supplementary data; and Dr Julia Wendon for her critical reading of the manuscript.

#

ABBREVIATIONS

ALFacute liver failure

DSHdeliberate self-harm

HESHospital Episode Statistics

LITULiver Intensive Therapy Unit

NTDNational Transplant Database

ONSOffice for National Statistics

OTCover-the-counter

SIRSsystemic inflammatory response syndrome

*Figure 1* Acute hepatitis A and hepatitis B in England and Wales 1990-2001. Hepatitis A, statutory hepatitis A virus infection notifications; hepatitis B, acute hepatitis B virus infection laboratory reports. From United Kingdom Public Health Laboratory Service, 2002.

*Figure 2* (A) Etiology of ALF of patients listed for super urgent liver transplantation in the United Kingdom from August 31, 1997, to August 31, 1998, and 2001 to 2002. (B) Etiology of ALF of patients undergoing super urgent liver transplants in United Kingdom from August 31, 1997, to August 31, 1998, and 2001 to 2002. From statistics prepared by the United Kingdom Transplant Database.[5]

*Figure 3* Number and outcome of patients admitted with severe acetaminophen-induced hepatotoxicity to the LITU, Kings College Hospital between September 1, 1996 and September 1, 2002.

#

REFERENCES

1 Mortality Statistics: cause. National Statistics. London: The Stationery Office; 1999

Search in Google Scholar
2 Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis . 1996; 16 343-348

Thieme Connect PubMed Search in Google Scholar
3 O'Grady J. Acute liver failure. In: O'Grady J, Lake J, Howdle P, eds. Comprehensive Clinical Hepatology, 1st ed London: Mosby 2000 : 30.1-30.20

Search in Google Scholar
4 Hartley P, Petruckvitch A, Reeves B. et al . The national liver transplantation audit: an overview of patients presenting for liver transplantation from 1994 to 1998. Br J Surg . 2001; 88 52-58

Crossref PubMed Search in Google Scholar
5 Statistics prepared by UK Transplant from the National Transplant Database maintained on behalf of transplant services in the UK and Republic of Ireland. October 2002
6 Dhiman R, Seth A, Jain S. et al . Prognostic evaluation of early indicators in fulminat hepatic failure by multivariate analysis. Dig Dis Sci . 1998; 43 1311-1316

Crossref PubMed Search in Google Scholar
7 Ellis A, Rhodes A, Jackson N. et al . Acute liver failure (ALF) in a specialist intensive care unit; a 7 year experience. Crit Care . 1998; 2(Suppl 1) P150

PubMed Search in Google Scholar
8 Ostapowicz G, Fontana R, Sciodt F. et al . Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med . 2002; 137 947-954

Crossref PubMed Search in Google Scholar
9 Trigo P, Lendoire J, Braslavsky G. et al . Etiology and outcome of 83 patients with fulminant hepatic failure in adults. Experience of an Argentinian liver transplant unit. Hepatology . 2001; 34 657A

PubMed Search in Google Scholar
10 O'Grady J, Schalm S, Williams R. Acute liver failure; redefining the syndromes. Lancet . 1993; 342 273-275

Crossref PubMed Search in Google Scholar
11 O'Grady J, Alexander G, Hayllar K, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology . 1989; 97 439-445

PubMed Search in Google Scholar
12 Anand A, Nightingale P, Neuberger J. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Kings's criteria. J Hepatol . 1997; 26 62-68

Crossref PubMed Search in Google Scholar
13 Bernal W, Wendon J, Rela M. et al . Use and outcome of liver transplantation in acetaminophen induced acute liver failure. Hepatology . 1998; 27 1050-1055

Crossref PubMed Search in Google Scholar
14 O'Grady J, Wendon J, Tan K. et al . Liver transplantation after paracetomol overdose. BMJ . 1991; 303 221-223

PubMed Search in Google Scholar
15 Mitchell I, Bihari D, Chang R. et al . Earlier identification of patients at risk from acetaminophen induced acute liver failure. Crit Care Med . 1998; 26 279-284

PubMed Search in Google Scholar
16 Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure. Lancet . 2002; 359 558-563

Crossref PubMed Search in Google Scholar
17 Pereira L M, Langley P G, Hayllar K M. et al . Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators. Gut . 1992; 33 98-102

PubMed Search in Google Scholar
18 Izumi S, Langley P G, Wendon J. et al . Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. Hepatology . 1996; 23 1507-1511

Crossref PubMed Search in Google Scholar
19 Sizer E, Bernal W, Wendon J. Acute liver failure in the intensive care unit. In: Vincent J, ed. 2003 Yearbook of Intensive Care and Emergency Medicine Berlin: Springer 2003

Search in Google Scholar
20 Rivers E, Nguyen B, Havstad S. et al . Goal-directed therapy for severe sepsis and septic shock. N Engl J Med . 2001; 345 1368-1377

Crossref PubMed Search in Google Scholar
21 Makin A, Wendon J, Williams R. A seven year experience of severe acetominophen-induced hepatotoxicity (1987-1993). Gastroenterology . 1995; 109 1907-1916

Crossref PubMed Search in Google Scholar
22 Bihari D, Gimson A, Lindridge J, Williams R. Lactic acidosis in fulminant hepatic failure: some aspects of pathogenesis and prognosis. J Hepatol . 1985; 1 405-416

PubMed Search in Google Scholar
23 Harry R, Ausinger G, Wendon J. Clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology . 2002; 36 395-402

Crossref PubMed Search in Google Scholar
24 Annane D, Sebille V, Charpentier C. et al . Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA . 2002; 288 862-871

Crossref PubMed Search in Google Scholar
25 Davenport A, Will E J, Davidson A M. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med . 1993; 21 328-338

Crossref PubMed Search in Google Scholar
26 Davenport A, Will E J, Davison A M. et al . Changes in intracranial pressure during haemofiltration in oliguric patients with grade IV hepatic encephalopathy. Nephron . 1989; 53 142-146

PubMed Search in Google Scholar
27 Forni L, Hilton P. Current concepts: continuous hemofiltration in the treatment of acute renal failure. N Engl J Med . 1997; 336 1303-1309

Crossref PubMed Search in Google Scholar
28 Bellomo R, Baldwin I, Ronco C. High volume hemofiltration. Curr Opin Crit Care . 2000; 6 442-445

PubMed Search in Google Scholar
29 Ronco C, Bellomo R, Homel P. et al . Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet . 2000; 355 26-30

PubMed Search in Google Scholar
30 Ede R, Gimson A, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral odema in fulminant hepatic failure. J Hepatol . 1986; 2 43-51

Crossref PubMed Search in Google Scholar
31 Wendon J A, Harrison P M, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology . 1994; 19 1407-1413

Crossref PubMed Search in Google Scholar
32 Strauss G, Hogh P, Knudsen G. et al . Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure. Hepatology . 1999; 30 1368-1373

Crossref PubMed Search in Google Scholar
33 Cordoba J, Gottstein J, Blei A. Chronic hyponatraemia exacerbates ammonia induced brain edema in rats after portocaval anastamosis. J Hepatol . 1998; 29 589-594

Crossref PubMed Search in Google Scholar
34 Murphy N, Wendon J. Serum sodium is inversely proportional to intracranial pressure in acute liver failure (Abst). Crit Care . 1999; 3(Suppl 1) 110

PubMed Search in Google Scholar
35 Schell R, Cole D. Cerebral monitoring: jugular venous oximetry. Anesth Analg . 2000; 90 559-566

PubMed Search in Google Scholar
36 Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infections in acute liver failure. Semin Liver Dis . 1996; 16 389-402

Thieme Connect PubMed Search in Google Scholar
37 Rolando N, Wade J, Davalos M. et al . The systemic inflammatory response in acute liver failure. Hepatology . 2000; 32 734-739

Crossref PubMed Search in Google Scholar
38 O'Grady J. Fulminant hepatitis in patients with chronic liver disease. J Viral Hepat . 2000; 7(Suppl 1) 9-10

Crossref PubMed Search in Google Scholar
39 Sallie R, Silva A E, Purdy M. et al . Hepatitis C and E in non-A non-B fulminant hepatic failure: a polymerase chain reaction and serological study. J Hepatol . 1994; 20 580-588

Crossref PubMed Search in Google Scholar
40 Jackson N, Ellis A, Rhodes A. et al . Non-paracetamol drug induced acute liver failure in a specialist liver intensive care unit: a seven year experience. Hepatology . 1998; 28 496A

PubMed Search in Google Scholar
41 Henry J A, Jeffreys K J, Dawling S. Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet . 1992; 340 384-387

Crossref PubMed Search in Google Scholar
42 Ellis A J, Wendon J A, Portmann B, Williams R. Acute liver damage and ecstasy ingestion. Gut . 1996; 38 454-458

PubMed Search in Google Scholar
43 Andreu V, Mas A, Bruguera M. et al . Ecstacy: a common cause of severe acute hepatotoxicity. J Hepatol . 1998; 29 394-397

PubMed Search in Google Scholar
44 Crowcroft N, Walsh B, Davidson K. et al . Guidelines for the control of hepatitis A infection. Communicable Disease and Public Health . 2001; 4 213-227

PubMed Search in Google Scholar
45 Goldberg D, McMenamin J. The United Kingdom's hepatitis B immunisation strategy-where now?. Communicable Disease and Public Health . 1998; 1 79-83

PubMed Search in Google Scholar
46 Melnick J. History and epidemiology of hepatitis A virus. J Infect Dis . 1995; 171(Suppl 1) S2-S8

PubMed Search in Google Scholar
47 Damme P V, Tormans G, Beutels P, Doorslaer E V. Hepatitis B prevention in Europe: a preliminary economic evaluation. Vaccine . 1995; 13 S54-S57

PubMed Search in Google Scholar
48 Kyrlagkitsis I, Cramp M, Smith H. et al . Acute hepatitis A virus infection: a review of prognostic factors from 25 years experience in a tertiary referral center. Hepatogastroenterology . 2002; 49 524-528

PubMed Search in Google Scholar
49 Gow P, Mutimer D. Non-A, non-B fulminant hepatic failure. Arch Intern Med . 2001; 161 1013-1014

Crossref PubMed Search in Google Scholar
50 Williams R, Riordan S. Acute liver failure: established and putatative hepatitis viruses and therapeutic implications. J Gastroenterol Hepatol . 2000; 15 G17-G25

Crossref PubMed Search in Google Scholar
51 McCrudden R, O'Connell S, Farrant T. et al . Sporadic acute hepatitis E in the United Kingdom: an underdiagnosed phenomenon?. Gut . 2000; 46 732-733

Crossref PubMed Search in Google Scholar
52 Wilkinson S, Taylor G, Templeton L. et al . Admissions to hospital for deliberate self-harm in England 1995-2000; an analysis of Hospital Episode Statistics. J Public Health Med . 2002; 24 179-183

PubMed Search in Google Scholar
53 Hawton K, Fagg J, Simkin S. et al . Trends in deliberate self harm in oxford, 1985-1995. Br J Psychiatry . 1997; 171 556-560

PubMed Search in Google Scholar
54 Shah R, Uren Z, Baker A, Majeed A. Trends in suicide from drug overdose in the elderly in England and Wales 1993-1999. Int J Geriatr Psychiatry . 2002; 17 416-421

PubMed Search in Google Scholar
55 McLoone P, Crombie I K. Hospitalisation for deliberate self-poisoning in Scotland from 1981 to 1993; trends in rates and types of drugs used. Br J Psychiatry . 1996; 169 81-85

PubMed Search in Google Scholar
56 Prescott L. Paracetamol overdose. In: Paracetamol (Acetaminophen) a Critical Bibliographic Review London: Taylor and Francis 1996: 401-473

Search in Google Scholar
57 Makin A J, Williams R. Acetaminophen-induced hepatotoxicity: predisposing factors and treatments. Adv Intern Med . 1997; 42 453-483

PubMed Search in Google Scholar
58 Deaths related to drug poisoning results for England and Wales, 1993 to 2000. Health Statistic Quarterly 2002; 13:76-82 www.statistics.gov.uk/downloads/theme health/ HSQ13 v4.pdf .
59 Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. QJM . 2000; 93 341-349

Crossref PubMed Search in Google Scholar
60 Townsend E, Hawton K, Harriss L. et al . Substances used in deliberate self poisoning 1985-1997; trend and associations with age, gender, repetition and suicidal intent. Soc Psychiatry Psychiatric Epidemiol . 2001; 36 228-234

Crossref PubMed Search in Google Scholar
61 Gunnell D, Hawton K, Murray V. et al . Use of paracetamol for suicide and non-fatal self poisoning in the UK and France: are restrictions on availability justified?. J Epidemiol Community Health . 1997; 51 175-179

Crossref PubMed Search in Google Scholar
62 Hawton K, Ware C, Mistry H. et al . Why patients choose paracetamol for self poisoning and their knowledge of its dangers. BMJ . 1995; 310 69-73

PubMed Search in Google Scholar
63 Hawton K, Ware C, Mistry H. et al . Paracetamol self-poisoning. Characteristics, prevention and harm reduction. Br J Psychiatry . 1996; 168 43-48

PubMed Search in Google Scholar
64 Newson P, Bathgate A, Henderson N. et al . Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland. Lancet . 2001; 358 1612-1613

Crossref PubMed Search in Google Scholar
65 Hawton K, Harriss L, Hodder K. et al . The influence of economic and social environment on deliberate self-harm and suicide: an ecological and person-based study. Psychol Med . 2001; 31 827-836

Crossref PubMed Search in Google Scholar
66 Neeleman J, Wessely S. Drugs taken in fatal and non-fatal self poisoning a study in south London. Acta Psychiatr Scand . 1997; 95 283-287

PubMed Search in Google Scholar
67 Prescott L. Paracetamol, alcohol and the liver. Br J Clin Pharmacol . 2000; 49 291-301

Crossref PubMed Search in Google Scholar
68 Schmidt L, Dalhoff K, Poulsen H. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology . 2002; 35 876-882

Crossref PubMed Search in Google Scholar
69 Kuffner E, Dart R, Bogdan G. et al . Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients. Arch Intern Med . 2001; 161 2247-2252

Crossref PubMed Search in Google Scholar
70 Whitcomb D, Block G. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA . 1994; 272 1845-1850

Crossref PubMed Search in Google Scholar
71 Read R B, Tredger J M, Williams R. Analysis of factors responsible for continuing mortality after paracetamol overdose. Hum Toxicol . 1986; 5 201-206

PubMed Search in Google Scholar
72 Foster T. Dying for a drink. BMJ . 2001; 323 817-818

Crossref PubMed Search in Google Scholar
73 Galanos A, Pieper C, Kussin P. et al . Relationship of body mass index to subsequent mortality among seriously ill hospitalised patients. Crit Care Med . 1997; 25 1962-1968

PubMed Search in Google Scholar
74 Sheen C, Dillon J, Bateman D. et al . Paracetamol toxicity: epidemiology, prevention and costs to the health-care system. QJM . 2002; 95 609-619

Crossref PubMed Search in Google Scholar
75 Jones A, Hayes P, Proudfoot A. et al . Should methionine be added to every paracetamol tablet?. BMJ . 1997; 315 301-304

PubMed Search in Google Scholar
76 Gunnell D, Murray V, Hawton K. Use of paracetamol (acetaminophen) for suicide and nonfatal poisoning: worldwide patterns of use and misuse. Suicide Life Threat Behav . 2000; 30 313-326

PubMed Search in Google Scholar
77 WHO. The world health report 2001. Mental health: new understanding, new hope. Geneva: World Health Organization 2001

Search in Google Scholar
78 Proudfoot A T, Park J. Changing pattern of drugs used for self-poisoning. BMJ . 1978; 1 90-93

PubMed Search in Google Scholar
79 Bowles J. Suicide prevention in western Samoa: an example of a suicide prevention program in a developing country. In: Diekstra R, Gulbinat W, Kienhorst I, Leo D, eds. Preventative Strategies on Suicide Leiden: EJ Brill 1995: 173-206

Search in Google Scholar
80 Oliver R, Hetzel B. An analysis of recent trends in suicide rates in Australia. Int J Epidemiol . 1973; 2 91-101

PubMed Search in Google Scholar
81 Ott P, Dalhoff K, Hansen P B. et al . Consumption, overdose and death from analgesics during a period of over-the-counter availability of paracetamol in Denmark. J Int Med . 1990; 227 423-428

Crossref PubMed Search in Google Scholar
82 Committee on Safety of Medicines, Medicines Control Agency. Paracetamol and aspirin. Current Problems in Pharmacovigilance . 1997; 23 9

PubMed Search in Google Scholar
83 Fagan E, Wannan G. Reducing paracetomol overdoses. BMJ . 1996; 313 1417-1418

PubMed Search in Google Scholar
84 Laffoy M, Byrne G, Scallan E. Paracetamol availability and overdose in Ireland. Irish Med J . 2001; 94 7

PubMed Search in Google Scholar
85 Thomas M, Jowett N. Restriction has not reduced admissions with self poisoning. BMJ . 2001; 322 553

Crossref PubMed Search in Google Scholar
86 Balit C, Isbister G, Peat J. et al . Paracetamol recall: a natural experiment influencing analgesic poisoning. Med J Aust . 2002; 176 163-166

PubMed Search in Google Scholar
87 Hawton K, Townsend E, Deeks J. et al . Effects of legislation restricting pack sizes of paracetamol and salycilate poisoning in the United Kingdom; before and after study. BMJ . 2001; 322 1203-1207

Crossref PubMed Search in Google Scholar
88 Prince M, Thomas S, James O, Hudson M. Reduction in incidence of severe paracetamol poisoning. Lancet . 2000; 355 2047-2048

Crossref PubMed Search in Google Scholar
89 Turvill J, Burroughs A, Moore K. Change in occurrence of paracetamol overdose in UK after introduction of blister packs. Lancet . 2000; 355 2048-2049

Crossref PubMed Search in Google Scholar
90 Sheen C, Dillon J, Bateman D. et al . Paracetamol pack size restriction: the impact on paracetamol poisoning and over-the-counter supply of paracetamol, asprin and ibuprofen. Pharmacoepidemiology and Drug Safety . 2002; 11 329-331

Crossref PubMed Search in Google Scholar
91 Spooner J, Harvey J. Paracetamol overdose; Facts not misconceptions. Pharmaceutical Journal . 1993; 252 706-707

PubMed Search in Google Scholar
92 Robinson D, Smith A, Johnston G. Severity of overdose after restriction of paracetamol availability: retrospective study. BMJ . 2000; 321 926-927

Crossref PubMed Search in Google Scholar
93 Sheen C, Dillon J, Bateman D. et al . The effect on toxicity on reducing the size of available paracetamol pack sizes. Gut . 2001; 48(Suppl 1) A105

PubMed Search in Google Scholar
94 Poulin C. Prevention of paracetamol poisoning. Lancet . 2000; 355 2009-2010

Crossref PubMed Search in Google Scholar
95 Hill A. The environment and disease: association or causation?. Proc R Soc Med . 1965; 295-300

PubMed Search in Google Scholar
96 Altman D. Practical Statistics for Medical Research. London: Chapman and Hall; 1991

Search in Google Scholar
97 Bond G R, Hite L. Population-based incidence and outcome of acetaminophen poisoning by type of ingestion. Acad Emerg Med . 1999; 6 1115-1120

PubMed Search in Google Scholar
98 Nourjah P, Willey M. Epidemiology of acetaminophen-related overdose. Department of Health and Human Services, Center for Drug Evaluation and Research, Food and Drug Administration, 2002. www.fda.gov/ohrms/dockets/ac/02/ briefing/3882b1.htm
99 Ahmad S. OPDRA safety review: review of acetaminophen poisoning exposures in Toxic Exposure Surveillance System (TESS). Department of Health and Human Services, Center for Drug Evaluation and Research, Food and Drug Administration, 2002. www.fda.gov/ohrms/dockets/ac/02 /briefing/3882b1.htm
100 Schiodt F, Atillasoy E, Shakil A. et al . Etiology and prognosis for 295 patients with acute liver failure in the US Liver Transplantation and Surgery . 1999; 5 29-34

PubMed Search in Google Scholar
101 Gyamlani G, Parikh C. Acetaminophen toxicity: suicidal versus accidental. Critical Care . 2002; 6 155-169

Crossref PubMed Search in Google Scholar
102 Prescott L. Therapeutic misadventure with paracetamol: fact or fiction?. American Journal of Therapeutics . 2000; 7 99-114

PubMed Search in Google Scholar
103 Food and Drug Administration. September 2002.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Nonprescription+Drugs/091902 acetaminophen/091902 AcetaminophenR.htm#.

#

REFERENCES

1 Mortality Statistics: cause. National Statistics. London: The Stationery Office; 1999

Search in Google Scholar
2 Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis . 1996; 16 343-348

Thieme Connect PubMed Search in Google Scholar
3 O'Grady J. Acute liver failure. In: O'Grady J, Lake J, Howdle P, eds. Comprehensive Clinical Hepatology, 1st ed London: Mosby 2000 : 30.1-30.20

Search in Google Scholar
4 Hartley P, Petruckvitch A, Reeves B. et al . The national liver transplantation audit: an overview of patients presenting for liver transplantation from 1994 to 1998. Br J Surg . 2001; 88 52-58

Crossref PubMed Search in Google Scholar
5 Statistics prepared by UK Transplant from the National Transplant Database maintained on behalf of transplant services in the UK and Republic of Ireland. October 2002
6 Dhiman R, Seth A, Jain S. et al . Prognostic evaluation of early indicators in fulminat hepatic failure by multivariate analysis. Dig Dis Sci . 1998; 43 1311-1316

Crossref PubMed Search in Google Scholar
7 Ellis A, Rhodes A, Jackson N. et al . Acute liver failure (ALF) in a specialist intensive care unit; a 7 year experience. Crit Care . 1998; 2(Suppl 1) P150

PubMed Search in Google Scholar
8 Ostapowicz G, Fontana R, Sciodt F. et al . Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med . 2002; 137 947-954

Crossref PubMed Search in Google Scholar
9 Trigo P, Lendoire J, Braslavsky G. et al . Etiology and outcome of 83 patients with fulminant hepatic failure in adults. Experience of an Argentinian liver transplant unit. Hepatology . 2001; 34 657A

PubMed Search in Google Scholar
10 O'Grady J, Schalm S, Williams R. Acute liver failure; redefining the syndromes. Lancet . 1993; 342 273-275

Crossref PubMed Search in Google Scholar
11 O'Grady J, Alexander G, Hayllar K, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology . 1989; 97 439-445

PubMed Search in Google Scholar
12 Anand A, Nightingale P, Neuberger J. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Kings's criteria. J Hepatol . 1997; 26 62-68

Crossref PubMed Search in Google Scholar
13 Bernal W, Wendon J, Rela M. et al . Use and outcome of liver transplantation in acetaminophen induced acute liver failure. Hepatology . 1998; 27 1050-1055

Crossref PubMed Search in Google Scholar
14 O'Grady J, Wendon J, Tan K. et al . Liver transplantation after paracetomol overdose. BMJ . 1991; 303 221-223

PubMed Search in Google Scholar
15 Mitchell I, Bihari D, Chang R. et al . Earlier identification of patients at risk from acetaminophen induced acute liver failure. Crit Care Med . 1998; 26 279-284

PubMed Search in Google Scholar
16 Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure. Lancet . 2002; 359 558-563

Crossref PubMed Search in Google Scholar
17 Pereira L M, Langley P G, Hayllar K M. et al . Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators. Gut . 1992; 33 98-102

PubMed Search in Google Scholar
18 Izumi S, Langley P G, Wendon J. et al . Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. Hepatology . 1996; 23 1507-1511

Crossref PubMed Search in Google Scholar
19 Sizer E, Bernal W, Wendon J. Acute liver failure in the intensive care unit. In: Vincent J, ed. 2003 Yearbook of Intensive Care and Emergency Medicine Berlin: Springer 2003

Search in Google Scholar
20 Rivers E, Nguyen B, Havstad S. et al . Goal-directed therapy for severe sepsis and septic shock. N Engl J Med . 2001; 345 1368-1377

Crossref PubMed Search in Google Scholar
21 Makin A, Wendon J, Williams R. A seven year experience of severe acetominophen-induced hepatotoxicity (1987-1993). Gastroenterology . 1995; 109 1907-1916

Crossref PubMed Search in Google Scholar
22 Bihari D, Gimson A, Lindridge J, Williams R. Lactic acidosis in fulminant hepatic failure: some aspects of pathogenesis and prognosis. J Hepatol . 1985; 1 405-416

PubMed Search in Google Scholar
23 Harry R, Ausinger G, Wendon J. Clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology . 2002; 36 395-402

Crossref PubMed Search in Google Scholar
24 Annane D, Sebille V, Charpentier C. et al . Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA . 2002; 288 862-871

Crossref PubMed Search in Google Scholar
25 Davenport A, Will E J, Davidson A M. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med . 1993; 21 328-338

Crossref PubMed Search in Google Scholar
26 Davenport A, Will E J, Davison A M. et al . Changes in intracranial pressure during haemofiltration in oliguric patients with grade IV hepatic encephalopathy. Nephron . 1989; 53 142-146

PubMed Search in Google Scholar
27 Forni L, Hilton P. Current concepts: continuous hemofiltration in the treatment of acute renal failure. N Engl J Med . 1997; 336 1303-1309

Crossref PubMed Search in Google Scholar
28 Bellomo R, Baldwin I, Ronco C. High volume hemofiltration. Curr Opin Crit Care . 2000; 6 442-445

PubMed Search in Google Scholar
29 Ronco C, Bellomo R, Homel P. et al . Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet . 2000; 355 26-30

PubMed Search in Google Scholar
30 Ede R, Gimson A, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral odema in fulminant hepatic failure. J Hepatol . 1986; 2 43-51

Crossref PubMed Search in Google Scholar
31 Wendon J A, Harrison P M, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology . 1994; 19 1407-1413

Crossref PubMed Search in Google Scholar
32 Strauss G, Hogh P, Knudsen G. et al . Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure. Hepatology . 1999; 30 1368-1373

Crossref PubMed Search in Google Scholar
33 Cordoba J, Gottstein J, Blei A. Chronic hyponatraemia exacerbates ammonia induced brain edema in rats after portocaval anastamosis. J Hepatol . 1998; 29 589-594

Crossref PubMed Search in Google Scholar
34 Murphy N, Wendon J. Serum sodium is inversely proportional to intracranial pressure in acute liver failure (Abst). Crit Care . 1999; 3(Suppl 1) 110

PubMed Search in Google Scholar
35 Schell R, Cole D. Cerebral monitoring: jugular venous oximetry. Anesth Analg . 2000; 90 559-566

PubMed Search in Google Scholar
36 Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infections in acute liver failure. Semin Liver Dis . 1996; 16 389-402

Thieme Connect PubMed Search in Google Scholar
37 Rolando N, Wade J, Davalos M. et al . The systemic inflammatory response in acute liver failure. Hepatology . 2000; 32 734-739

Crossref PubMed Search in Google Scholar
38 O'Grady J. Fulminant hepatitis in patients with chronic liver disease. J Viral Hepat . 2000; 7(Suppl 1) 9-10

Crossref PubMed Search in Google Scholar
39 Sallie R, Silva A E, Purdy M. et al . Hepatitis C and E in non-A non-B fulminant hepatic failure: a polymerase chain reaction and serological study. J Hepatol . 1994; 20 580-588

Crossref PubMed Search in Google Scholar
40 Jackson N, Ellis A, Rhodes A. et al . Non-paracetamol drug induced acute liver failure in a specialist liver intensive care unit: a seven year experience. Hepatology . 1998; 28 496A

PubMed Search in Google Scholar
41 Henry J A, Jeffreys K J, Dawling S. Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet . 1992; 340 384-387

Crossref PubMed Search in Google Scholar
42 Ellis A J, Wendon J A, Portmann B, Williams R. Acute liver damage and ecstasy ingestion. Gut . 1996; 38 454-458

PubMed Search in Google Scholar
43 Andreu V, Mas A, Bruguera M. et al . Ecstacy: a common cause of severe acute hepatotoxicity. J Hepatol . 1998; 29 394-397

PubMed Search in Google Scholar
44 Crowcroft N, Walsh B, Davidson K. et al . Guidelines for the control of hepatitis A infection. Communicable Disease and Public Health . 2001; 4 213-227

PubMed Search in Google Scholar
45 Goldberg D, McMenamin J. The United Kingdom's hepatitis B immunisation strategy-where now?. Communicable Disease and Public Health . 1998; 1 79-83

PubMed Search in Google Scholar
46 Melnick J. History and epidemiology of hepatitis A virus. J Infect Dis . 1995; 171(Suppl 1) S2-S8

PubMed Search in Google Scholar
47 Damme P V, Tormans G, Beutels P, Doorslaer E V. Hepatitis B prevention in Europe: a preliminary economic evaluation. Vaccine . 1995; 13 S54-S57

PubMed Search in Google Scholar
48 Kyrlagkitsis I, Cramp M, Smith H. et al . Acute hepatitis A virus infection: a review of prognostic factors from 25 years experience in a tertiary referral center. Hepatogastroenterology . 2002; 49 524-528

PubMed Search in Google Scholar
49 Gow P, Mutimer D. Non-A, non-B fulminant hepatic failure. Arch Intern Med . 2001; 161 1013-1014

Crossref PubMed Search in Google Scholar
50 Williams R, Riordan S. Acute liver failure: established and putatative hepatitis viruses and therapeutic implications. J Gastroenterol Hepatol . 2000; 15 G17-G25

Crossref PubMed Search in Google Scholar
51 McCrudden R, O'Connell S, Farrant T. et al . Sporadic acute hepatitis E in the United Kingdom: an underdiagnosed phenomenon?. Gut . 2000; 46 732-733

Crossref PubMed Search in Google Scholar
52 Wilkinson S, Taylor G, Templeton L. et al . Admissions to hospital for deliberate self-harm in England 1995-2000; an analysis of Hospital Episode Statistics. J Public Health Med . 2002; 24 179-183

PubMed Search in Google Scholar
53 Hawton K, Fagg J, Simkin S. et al . Trends in deliberate self harm in oxford, 1985-1995. Br J Psychiatry . 1997; 171 556-560

PubMed Search in Google Scholar
54 Shah R, Uren Z, Baker A, Majeed A. Trends in suicide from drug overdose in the elderly in England and Wales 1993-1999. Int J Geriatr Psychiatry . 2002; 17 416-421

PubMed Search in Google Scholar
55 McLoone P, Crombie I K. Hospitalisation for deliberate self-poisoning in Scotland from 1981 to 1993; trends in rates and types of drugs used. Br J Psychiatry . 1996; 169 81-85

PubMed Search in Google Scholar
56 Prescott L. Paracetamol overdose. In: Paracetamol (Acetaminophen) a Critical Bibliographic Review London: Taylor and Francis 1996: 401-473

Search in Google Scholar
57 Makin A J, Williams R. Acetaminophen-induced hepatotoxicity: predisposing factors and treatments. Adv Intern Med . 1997; 42 453-483

PubMed Search in Google Scholar
58 Deaths related to drug poisoning results for England and Wales, 1993 to 2000. Health Statistic Quarterly 2002; 13:76-82 www.statistics.gov.uk/downloads/theme health/ HSQ13 v4.pdf .
59 Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. QJM . 2000; 93 341-349

Crossref PubMed Search in Google Scholar
60 Townsend E, Hawton K, Harriss L. et al . Substances used in deliberate self poisoning 1985-1997; trend and associations with age, gender, repetition and suicidal intent. Soc Psychiatry Psychiatric Epidemiol . 2001; 36 228-234

Crossref PubMed Search in Google Scholar
61 Gunnell D, Hawton K, Murray V. et al . Use of paracetamol for suicide and non-fatal self poisoning in the UK and France: are restrictions on availability justified?. J Epidemiol Community Health . 1997; 51 175-179

Crossref PubMed Search in Google Scholar
62 Hawton K, Ware C, Mistry H. et al . Why patients choose paracetamol for self poisoning and their knowledge of its dangers. BMJ . 1995; 310 69-73

PubMed Search in Google Scholar
63 Hawton K, Ware C, Mistry H. et al . Paracetamol self-poisoning. Characteristics, prevention and harm reduction. Br J Psychiatry . 1996; 168 43-48

PubMed Search in Google Scholar
64 Newson P, Bathgate A, Henderson N. et al . Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland. Lancet . 2001; 358 1612-1613

Crossref PubMed Search in Google Scholar
65 Hawton K, Harriss L, Hodder K. et al . The influence of economic and social environment on deliberate self-harm and suicide: an ecological and person-based study. Psychol Med . 2001; 31 827-836

Crossref PubMed Search in Google Scholar
66 Neeleman J, Wessely S. Drugs taken in fatal and non-fatal self poisoning a study in south London. Acta Psychiatr Scand . 1997; 95 283-287

PubMed Search in Google Scholar
67 Prescott L. Paracetamol, alcohol and the liver. Br J Clin Pharmacol . 2000; 49 291-301

Crossref PubMed Search in Google Scholar
68 Schmidt L, Dalhoff K, Poulsen H. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology . 2002; 35 876-882

Crossref PubMed Search in Google Scholar
69 Kuffner E, Dart R, Bogdan G. et al . Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients. Arch Intern Med . 2001; 161 2247-2252

Crossref PubMed Search in Google Scholar
70 Whitcomb D, Block G. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA . 1994; 272 1845-1850

Crossref PubMed Search in Google Scholar
71 Read R B, Tredger J M, Williams R. Analysis of factors responsible for continuing mortality after paracetamol overdose. Hum Toxicol . 1986; 5 201-206

PubMed Search in Google Scholar
72 Foster T. Dying for a drink. BMJ . 2001; 323 817-818

Crossref PubMed Search in Google Scholar
73 Galanos A, Pieper C, Kussin P. et al . Relationship of body mass index to subsequent mortality among seriously ill hospitalised patients. Crit Care Med . 1997; 25 1962-1968

PubMed Search in Google Scholar
74 Sheen C, Dillon J, Bateman D. et al . Paracetamol toxicity: epidemiology, prevention and costs to the health-care system. QJM . 2002; 95 609-619

Crossref PubMed Search in Google Scholar
75 Jones A, Hayes P, Proudfoot A. et al . Should methionine be added to every paracetamol tablet?. BMJ . 1997; 315 301-304

PubMed Search in Google Scholar
76 Gunnell D, Murray V, Hawton K. Use of paracetamol (acetaminophen) for suicide and nonfatal poisoning: worldwide patterns of use and misuse. Suicide Life Threat Behav . 2000; 30 313-326

PubMed Search in Google Scholar
77 WHO. The world health report 2001. Mental health: new understanding, new hope. Geneva: World Health Organization 2001

Search in Google Scholar
78 Proudfoot A T, Park J. Changing pattern of drugs used for self-poisoning. BMJ . 1978; 1 90-93

PubMed Search in Google Scholar
79 Bowles J. Suicide prevention in western Samoa: an example of a suicide prevention program in a developing country. In: Diekstra R, Gulbinat W, Kienhorst I, Leo D, eds. Preventative Strategies on Suicide Leiden: EJ Brill 1995: 173-206

Search in Google Scholar
80 Oliver R, Hetzel B. An analysis of recent trends in suicide rates in Australia. Int J Epidemiol . 1973; 2 91-101

PubMed Search in Google Scholar
81 Ott P, Dalhoff K, Hansen P B. et al . Consumption, overdose and death from analgesics during a period of over-the-counter availability of paracetamol in Denmark. J Int Med . 1990; 227 423-428

Crossref PubMed Search in Google Scholar
82 Committee on Safety of Medicines, Medicines Control Agency. Paracetamol and aspirin. Current Problems in Pharmacovigilance . 1997; 23 9

PubMed Search in Google Scholar
83 Fagan E, Wannan G. Reducing paracetomol overdoses. BMJ . 1996; 313 1417-1418

PubMed Search in Google Scholar
84 Laffoy M, Byrne G, Scallan E. Paracetamol availability and overdose in Ireland. Irish Med J . 2001; 94 7

PubMed Search in Google Scholar
85 Thomas M, Jowett N. Restriction has not reduced admissions with self poisoning. BMJ . 2001; 322 553

Crossref PubMed Search in Google Scholar
86 Balit C, Isbister G, Peat J. et al . Paracetamol recall: a natural experiment influencing analgesic poisoning. Med J Aust . 2002; 176 163-166

PubMed Search in Google Scholar
87 Hawton K, Townsend E, Deeks J. et al . Effects of legislation restricting pack sizes of paracetamol and salycilate poisoning in the United Kingdom; before and after study. BMJ . 2001; 322 1203-1207

Crossref PubMed Search in Google Scholar
88 Prince M, Thomas S, James O, Hudson M. Reduction in incidence of severe paracetamol poisoning. Lancet . 2000; 355 2047-2048

Crossref PubMed Search in Google Scholar
89 Turvill J, Burroughs A, Moore K. Change in occurrence of paracetamol overdose in UK after introduction of blister packs. Lancet . 2000; 355 2048-2049

Crossref PubMed Search in Google Scholar
90 Sheen C, Dillon J, Bateman D. et al . Paracetamol pack size restriction: the impact on paracetamol poisoning and over-the-counter supply of paracetamol, asprin and ibuprofen. Pharmacoepidemiology and Drug Safety . 2002; 11 329-331

Crossref PubMed Search in Google Scholar
91 Spooner J, Harvey J. Paracetamol overdose; Facts not misconceptions. Pharmaceutical Journal . 1993; 252 706-707

PubMed Search in Google Scholar
92 Robinson D, Smith A, Johnston G. Severity of overdose after restriction of paracetamol availability: retrospective study. BMJ . 2000; 321 926-927

Crossref PubMed Search in Google Scholar
93 Sheen C, Dillon J, Bateman D. et al . The effect on toxicity on reducing the size of available paracetamol pack sizes. Gut . 2001; 48(Suppl 1) A105

PubMed Search in Google Scholar
94 Poulin C. Prevention of paracetamol poisoning. Lancet . 2000; 355 2009-2010

Crossref PubMed Search in Google Scholar
95 Hill A. The environment and disease: association or causation?. Proc R Soc Med . 1965; 295-300

PubMed Search in Google Scholar
96 Altman D. Practical Statistics for Medical Research. London: Chapman and Hall; 1991

Search in Google Scholar
97 Bond G R, Hite L. Population-based incidence and outcome of acetaminophen poisoning by type of ingestion. Acad Emerg Med . 1999; 6 1115-1120

PubMed Search in Google Scholar
98 Nourjah P, Willey M. Epidemiology of acetaminophen-related overdose. Department of Health and Human Services, Center for Drug Evaluation and Research, Food and Drug Administration, 2002. www.fda.gov/ohrms/dockets/ac/02/ briefing/3882b1.htm
99 Ahmad S. OPDRA safety review: review of acetaminophen poisoning exposures in Toxic Exposure Surveillance System (TESS). Department of Health and Human Services, Center for Drug Evaluation and Research, Food and Drug Administration, 2002. www.fda.gov/ohrms/dockets/ac/02 /briefing/3882b1.htm
100 Schiodt F, Atillasoy E, Shakil A. et al . Etiology and prognosis for 295 patients with acute liver failure in the US Liver Transplantation and Surgery . 1999; 5 29-34

PubMed Search in Google Scholar
101 Gyamlani G, Parikh C. Acetaminophen toxicity: suicidal versus accidental. Critical Care . 2002; 6 155-169

Crossref PubMed Search in Google Scholar
102 Prescott L. Therapeutic misadventure with paracetamol: fact or fiction?. American Journal of Therapeutics . 2000; 7 99-114

PubMed Search in Google Scholar
103 Food and Drug Administration. September 2002.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Nonprescription+Drugs/091902 acetaminophen/091902 AcetaminophenR.htm#.

Permissions and Reprints