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HYPOPHOSPHATAEMIA AND PHOSPHATURIA IN PARACETAMOL POISONING
608
Toxicology HYPOPHOSPHATAEMIA AND PHOSPHATURIA IN PARACETAMOL POISONING A. F. TONES1,2
J. M. HARVEY1 J.
A. VALE1,2
West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham B18 7QH;1 and University of Birmingham2
a continuous flow multiple channel analyser (SMA 2, Technicon Instruments, Tarrytown, New York, USA) with commercial Inorganic phosphate reagents (Technicon Instruments).
concentration was measured with acidic ammonium molybdate, bilirubin concentration by diazotisation, potassium concentration by flame photometry, creatinine concentration with alkaline picrate, and aspartate aminotransferase activity (AST) by the oxidation of NADH with oxaloacetate. Paracetamol was measured with a commercial fluorescence polarisation immunoassay (’TDX’ Abbott
Diagnostics, Maidenhead, UK). In a separate group of 40 patients the renal phosphate threshold concentration TmPO4/GFR (the ratio of the maximum rate of renal tubular phosphate reabsorption to the glomerular filtration rate) determined from measurements of serum and urinary creatinine and phosphate in specimens collected after an overnight fast.9 Differences in patients’ clinical characteristics were assessed by Student’st test, in biochemical and haematological indices by analysis of variance, and in laboratory measurements by linear was
Summary
To find
whether the
hypophosphataemia in paracetamol poisoning is due to renal loss of phosphate, serum phosphate concentrations were correlated with indices of hepatotoxicity in 273 patients who had taken an overdose of paracetamol, and the renal handling of phosphate was examined in another 40 patients. Hypophosphataemia was a feature of paracetamol poisoning, whether hepatotoxicity was present or not. It correlated with the degree of hepatic damage and was not influenced by glucose infusions. Serum phosphate correlated with renal threshold phosphate concentration, so out
renal loss rather than intracellular redistribution of phosphate seems to be the reason for the hypophosphataemia in paracetamol overdose, and it correlates well with other indices of severity of poisoning. INTRODUCTION
HYPOPHOSPHATAEMIA, a recognised feature of acute liver failure,l,2 may contribute to morbidity and mortality by inducing mental confusion, irritability, coma, abnormalities of platelet, white cell, and erythrocyte function, and rhabdomyolysis.3 Low serum phosphate concentrations have been reported in patients with severe paracetamol poisoning-in 7 of 12 patients with acute hepatic encephalopathy4 and in 8 of 15 with hepatorenal failure (including 12 with grade 4 encephalopathy).5 The cause of hypophosphataemia in acute liver failure has not been established. It has been attributed variously to intracellular movement of phosphate in systemic alkalosis, the effects of treatment with intravenous glucose, the breakdown of intracellular organic phosphates in the presence of intracellular acidosis, and phosphate loss in the urine.5 Paracetamol may produce renal tubular toxicity, even in the absence of fulminant liver damage 6and tubular absorption of phosphate may be impaired.4,8If renal wasting of phosphate were a feature of paracetamol poisoning, hypophosphataemia could occur even in the absence of fulminant hepatic failure. To investigate this possibility we have studied the relation between serum phosphate concentration and clinical and laboratory indices of toxicity in 273 patients with paracetamol poisoning, and the correlation between renal handling of phosphate and degree of hypophosphataemia in a further group of 40.
regression. RESULTS
There was no biochemical indication of hepatic toxicity in 125 patients (AST < 45 IU/1). 63 of these 125 patients took insufficient paracetamol to warrant treatment with Nacetylcysteine (group 1); the remaining 62 (group 2) were given N-acetylcysteine within 12 h of ingestion of paracetamol because their plasma concentrations of paracetamol fell above the "treatment line".1O The 148 patients with evidence of liver damage (AST > 45 IU/1) were divided into two groups: group 3 (n=131) without hepatic encephalopathy and group 4 (n = 17) with. Groups 3 and 4 presented later than did groups 1 and 2 (table); groups did not differ in age or sex. The groups differed significantly in mean minimum serum phosphate concentrations (table). Mean minimum serum phosphate concentration correlated inversely with mean maximum AST activity (r 0-38; p < 0-001), mean maximum bilirubin concentration (r = - 0-36; p< 0-001), and mean maximum prothrombin ratio (r = - 0-40; p < 0-001 ). It correlated positively with mean minimum potassium concentration (r + 0 38 p < 0-001). Since intravenous infusions of glucose may lead to a fall in serum phosphate concentration due to redistribution to the intracellular compartment, further comparison was made between patients in group 2 (n 62) and those in group 3 (n = 80) who received N-acetylcysteine and therefore dextrose. Mean minimum serum phosphate concentration was lower (p < 0-00001) in group 3 (0-66 [SD 026] mmol/1) than in group 2 (0-89 [SD 0.23] mmol/1), which suggests that glucose infusion did not account for the =
=
=
hypophosphataemia. CLINICAL AND BIOCHEMICAL FEATURES
SUBJECTS AND METHODS 273 patients admitted consecutively to the West Midlands Poisons Unit between January, 1987, and June, 1988, with biochemically proven overdoses of paracetamol were included. Some of these patients were referred to the unit because of severe hepatic damage. Age, sex, and time of presentation after the overdose, treatment, and complications were noted. Biochemical investigations and tests of coagulation were done on admission and every day of the hospital stay. Serum was analysed biochemically on
-
*p < 000p1compared with group 1. tp < 000001 compared with group 2. tp < 00005 compared with group 3.
609 clinical consequences of poisoning it should be such patients and the need for phosphate considered.
sought in repletion
We thank Mr R. Holder, Department of Statistics, University of Birmingham, for statistical advice.
Correspondence should be addressed to J. A. V. REFERENCES 1. Knell
AJ, Pratt OE, Curzon G, Williams R. Changing ideas in hepatic encephalopathy. In: Neale G, ed. Eighth symposium on advanced medicine. London: Pitman Medical, 1972: 156-70. 2. Moore KP, Williams R. Hypophosphataemia in acute liver failure. Br Med J 1988; 296: 131. 3. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977; 137: 203-20. 4. Dawson DJ, Babbs C, Warnes TW, Neary RH. Hypophosphataemia in acute liver failure. Br Med J 1987; 295: 1312-13. 5. Davenport A, Will EJ. Hypophosphataemia in acute liver failure. Br Med J 1988; 296: 131.
Relation between serum phosphate concentration and renal phosphate threshold concentration (TmPO,/GFR).
(y=0’S6x+0’25, r=0’S7, p < 0001 ).
Of the 40 patients whose renal handling of phosphate was investigated, 12 had raised AST activity. Serum phosphate concentration correlated with TmP04/GFR (r = + 0-87,
accompanying figure). TmP04/GFR was (p < 0-001 ) in patients with raised transaminase activity (045+023 mmol/1) than in those without biochemical evidence of hepatotoxicity (0-82 ::!:: 0.28 mmol/1. p<0001,
see
lower
6. Cobden I, Record CO, Ward MK, Kerr DNS. Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Br Med J 1982; 284: 21-22. 7. Davenport A, Finn R. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. Nephron 1988; 50: 55-56. 8. Dabbagh S, Chesney RW. Acute renal failure related to acetaminophen (paracetamol) overdose without fluminant hepatic disease. Int Paed J Nephrol 1985; 6: 221-24. 9. Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; ii. 309-10. 10. Prescott LF, Illingworth RN, Cntchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; ii: 1097-100. 11. Record CO, Iles RA, Cohen RD, Williams R. Acid-base and metabolic disturbances in fulminant hepatic failure. Gut 1975; 16: 144-49. 12. Gray TA, Buckley BM, Vale JA. Hyperlactataemia and metabolic acidosis following paracetamol overdose. Q J Med 1987; 246: 811-21.
DISCUSSION
Reports of hypophosphataemia in paracetamol poisoning have included only patients with hepatic encephalopathy. Our findings confirm previous reports and, in addition, show that hypophosphataemia is a biochemical feature of paracetamol overdose in general. The degree of hypophosphataemia correlates with severity of poisoning as indicated by biochemical and haematological markers of hepatic injury. Hypophosphataemia has been attributed to an intracellular shift of phosphate in systemic alkalosis which may occur in hepatic failure." However, this hypothesis is unlikely to be correct because, firstly, metabolic acidosis is the more common acid-base disturbance in paracetamol overdose12 and, secondly, hypophosphataemia may occur in the absence of clinical or biochemical evidence of liver toxicity, as this study has shown. Although glucose may displace phosphate and potassium intracellularly, the difference in mean phosphate concentration between patients in group 2 and those in group 3, who received equivalent quantities of dextrose, renders this explanation unlikely despite the correlation between serum phosphate and potassium concentrations. A preliminary study in 40 patients has demonstrated low renal thresholds for phosphate in patients poisoned with paracetamol: the threshold correlated closely with degree of hypophosphataemia, so renal loss of phosphate, rather than intracellular redistribution, seems to be the main cause of hypophosphataemia and has been described previously in isolated cases.4.8 Renal tubular dysfunction or necrosis has been reported rarely in paracetamol poisoning and may occur in the absence of fulminant hepatic failure.6,7 If phosphaturia accounts for the hypophosphataemia of paracetamol poisoning, renal tubular abnormalities seem to be far more common than previously recognised. Since hypophosphataemia occurs frequently after paracetamol overdose and may account for some of the
Point of View DRUG TRIALS: WHO TAKES THE RISK? VICTOR TUNKEL
Faculty of Laws, Queen Mary College, University of London, London E1 4NS
ARE
we
doing
all
we can to
protect
patients
in clinical
trials, within the limits of all reasonable medical and legal safeguards? The answer, I fear, is no. Let us consider a hypothetical case. A patient, given the usual information, agrees to take part in a trial of a new drug which is being sponsored by the manufacturer. He subsequently has adverse physical effects, apparently from the drug. Everyone is sympathetic but no one accepts any blame. Has he a legal right to compensation?. THE
QUEST FOR COMPENSATION
a patient show that the drug is only one of one or possible causes of his condition, he will fail, according to the House of Lords. Even if a scheme of no-fault liability is introduced for personal injuries, causation will always remain a difficulty. Once causation is established, the patient then has to show fault on someone’s part. The new European Community code of product liability,2 enacted in the UK by the Consumer Protection Act, 1987, now seemingly imposes a higher standard of care on manufacturers of products (including drugs). If a person injured can show damage caused by a defect in a product, he is well on the way to getting judgment. However, the UK Government, unlike other EC countries, allows manufacturers an inevitable development risks defence: section 4 (le) of the 1987 Act allows companies to avoid liability by proving: "that the state of scientific and technical knowledge at the relevant time was not such that a producer of products of the same description as the product in question might
Should such
more
Toxicology HYPOPHOSPHATAEMIA AND PHOSPHATURIA IN PARACETAMOL POISONING A. F. TONES1,2
J. M. HARVEY1 J.
A. VALE1,2
West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham B18 7QH;1 and University of Birmingham2
a continuous flow multiple channel analyser (SMA 2, Technicon Instruments, Tarrytown, New York, USA) with commercial Inorganic phosphate reagents (Technicon Instruments).
concentration was measured with acidic ammonium molybdate, bilirubin concentration by diazotisation, potassium concentration by flame photometry, creatinine concentration with alkaline picrate, and aspartate aminotransferase activity (AST) by the oxidation of NADH with oxaloacetate. Paracetamol was measured with a commercial fluorescence polarisation immunoassay (’TDX’ Abbott
Diagnostics, Maidenhead, UK). In a separate group of 40 patients the renal phosphate threshold concentration TmPO4/GFR (the ratio of the maximum rate of renal tubular phosphate reabsorption to the glomerular filtration rate) determined from measurements of serum and urinary creatinine and phosphate in specimens collected after an overnight fast.9 Differences in patients’ clinical characteristics were assessed by Student’st test, in biochemical and haematological indices by analysis of variance, and in laboratory measurements by linear was
Summary
To find
whether the
hypophosphataemia in paracetamol poisoning is due to renal loss of phosphate, serum phosphate concentrations were correlated with indices of hepatotoxicity in 273 patients who had taken an overdose of paracetamol, and the renal handling of phosphate was examined in another 40 patients. Hypophosphataemia was a feature of paracetamol poisoning, whether hepatotoxicity was present or not. It correlated with the degree of hepatic damage and was not influenced by glucose infusions. Serum phosphate correlated with renal threshold phosphate concentration, so out
renal loss rather than intracellular redistribution of phosphate seems to be the reason for the hypophosphataemia in paracetamol overdose, and it correlates well with other indices of severity of poisoning. INTRODUCTION
HYPOPHOSPHATAEMIA, a recognised feature of acute liver failure,l,2 may contribute to morbidity and mortality by inducing mental confusion, irritability, coma, abnormalities of platelet, white cell, and erythrocyte function, and rhabdomyolysis.3 Low serum phosphate concentrations have been reported in patients with severe paracetamol poisoning-in 7 of 12 patients with acute hepatic encephalopathy4 and in 8 of 15 with hepatorenal failure (including 12 with grade 4 encephalopathy).5 The cause of hypophosphataemia in acute liver failure has not been established. It has been attributed variously to intracellular movement of phosphate in systemic alkalosis, the effects of treatment with intravenous glucose, the breakdown of intracellular organic phosphates in the presence of intracellular acidosis, and phosphate loss in the urine.5 Paracetamol may produce renal tubular toxicity, even in the absence of fulminant liver damage 6and tubular absorption of phosphate may be impaired.4,8If renal wasting of phosphate were a feature of paracetamol poisoning, hypophosphataemia could occur even in the absence of fulminant hepatic failure. To investigate this possibility we have studied the relation between serum phosphate concentration and clinical and laboratory indices of toxicity in 273 patients with paracetamol poisoning, and the correlation between renal handling of phosphate and degree of hypophosphataemia in a further group of 40.
regression. RESULTS
There was no biochemical indication of hepatic toxicity in 125 patients (AST < 45 IU/1). 63 of these 125 patients took insufficient paracetamol to warrant treatment with Nacetylcysteine (group 1); the remaining 62 (group 2) were given N-acetylcysteine within 12 h of ingestion of paracetamol because their plasma concentrations of paracetamol fell above the "treatment line".1O The 148 patients with evidence of liver damage (AST > 45 IU/1) were divided into two groups: group 3 (n=131) without hepatic encephalopathy and group 4 (n = 17) with. Groups 3 and 4 presented later than did groups 1 and 2 (table); groups did not differ in age or sex. The groups differed significantly in mean minimum serum phosphate concentrations (table). Mean minimum serum phosphate concentration correlated inversely with mean maximum AST activity (r 0-38; p < 0-001), mean maximum bilirubin concentration (r = - 0-36; p< 0-001), and mean maximum prothrombin ratio (r = - 0-40; p < 0-001 ). It correlated positively with mean minimum potassium concentration (r + 0 38 p < 0-001). Since intravenous infusions of glucose may lead to a fall in serum phosphate concentration due to redistribution to the intracellular compartment, further comparison was made between patients in group 2 (n 62) and those in group 3 (n = 80) who received N-acetylcysteine and therefore dextrose. Mean minimum serum phosphate concentration was lower (p < 0-00001) in group 3 (0-66 [SD 026] mmol/1) than in group 2 (0-89 [SD 0.23] mmol/1), which suggests that glucose infusion did not account for the =
=
=
hypophosphataemia. CLINICAL AND BIOCHEMICAL FEATURES
SUBJECTS AND METHODS 273 patients admitted consecutively to the West Midlands Poisons Unit between January, 1987, and June, 1988, with biochemically proven overdoses of paracetamol were included. Some of these patients were referred to the unit because of severe hepatic damage. Age, sex, and time of presentation after the overdose, treatment, and complications were noted. Biochemical investigations and tests of coagulation were done on admission and every day of the hospital stay. Serum was analysed biochemically on
-
*p < 000p1compared with group 1. tp < 000001 compared with group 2. tp < 00005 compared with group 3.
609 clinical consequences of poisoning it should be such patients and the need for phosphate considered.
sought in repletion
We thank Mr R. Holder, Department of Statistics, University of Birmingham, for statistical advice.
Correspondence should be addressed to J. A. V. REFERENCES 1. Knell
AJ, Pratt OE, Curzon G, Williams R. Changing ideas in hepatic encephalopathy. In: Neale G, ed. Eighth symposium on advanced medicine. London: Pitman Medical, 1972: 156-70. 2. Moore KP, Williams R. Hypophosphataemia in acute liver failure. Br Med J 1988; 296: 131. 3. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977; 137: 203-20. 4. Dawson DJ, Babbs C, Warnes TW, Neary RH. Hypophosphataemia in acute liver failure. Br Med J 1987; 295: 1312-13. 5. Davenport A, Will EJ. Hypophosphataemia in acute liver failure. Br Med J 1988; 296: 131.
Relation between serum phosphate concentration and renal phosphate threshold concentration (TmPO,/GFR).
(y=0’S6x+0’25, r=0’S7, p < 0001 ).
Of the 40 patients whose renal handling of phosphate was investigated, 12 had raised AST activity. Serum phosphate concentration correlated with TmP04/GFR (r = + 0-87,
accompanying figure). TmP04/GFR was (p < 0-001 ) in patients with raised transaminase activity (045+023 mmol/1) than in those without biochemical evidence of hepatotoxicity (0-82 ::!:: 0.28 mmol/1. p<0001,
see
lower
6. Cobden I, Record CO, Ward MK, Kerr DNS. Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Br Med J 1982; 284: 21-22. 7. Davenport A, Finn R. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. Nephron 1988; 50: 55-56. 8. Dabbagh S, Chesney RW. Acute renal failure related to acetaminophen (paracetamol) overdose without fluminant hepatic disease. Int Paed J Nephrol 1985; 6: 221-24. 9. Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; ii. 309-10. 10. Prescott LF, Illingworth RN, Cntchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; ii: 1097-100. 11. Record CO, Iles RA, Cohen RD, Williams R. Acid-base and metabolic disturbances in fulminant hepatic failure. Gut 1975; 16: 144-49. 12. Gray TA, Buckley BM, Vale JA. Hyperlactataemia and metabolic acidosis following paracetamol overdose. Q J Med 1987; 246: 811-21.
DISCUSSION
Reports of hypophosphataemia in paracetamol poisoning have included only patients with hepatic encephalopathy. Our findings confirm previous reports and, in addition, show that hypophosphataemia is a biochemical feature of paracetamol overdose in general. The degree of hypophosphataemia correlates with severity of poisoning as indicated by biochemical and haematological markers of hepatic injury. Hypophosphataemia has been attributed to an intracellular shift of phosphate in systemic alkalosis which may occur in hepatic failure." However, this hypothesis is unlikely to be correct because, firstly, metabolic acidosis is the more common acid-base disturbance in paracetamol overdose12 and, secondly, hypophosphataemia may occur in the absence of clinical or biochemical evidence of liver toxicity, as this study has shown. Although glucose may displace phosphate and potassium intracellularly, the difference in mean phosphate concentration between patients in group 2 and those in group 3, who received equivalent quantities of dextrose, renders this explanation unlikely despite the correlation between serum phosphate and potassium concentrations. A preliminary study in 40 patients has demonstrated low renal thresholds for phosphate in patients poisoned with paracetamol: the threshold correlated closely with degree of hypophosphataemia, so renal loss of phosphate, rather than intracellular redistribution, seems to be the main cause of hypophosphataemia and has been described previously in isolated cases.4.8 Renal tubular dysfunction or necrosis has been reported rarely in paracetamol poisoning and may occur in the absence of fulminant hepatic failure.6,7 If phosphaturia accounts for the hypophosphataemia of paracetamol poisoning, renal tubular abnormalities seem to be far more common than previously recognised. Since hypophosphataemia occurs frequently after paracetamol overdose and may account for some of the
Point of View DRUG TRIALS: WHO TAKES THE RISK? VICTOR TUNKEL
Faculty of Laws, Queen Mary College, University of London, London E1 4NS
ARE
we
doing
all
we can to
protect
patients
in clinical
trials, within the limits of all reasonable medical and legal safeguards? The answer, I fear, is no. Let us consider a hypothetical case. A patient, given the usual information, agrees to take part in a trial of a new drug which is being sponsored by the manufacturer. He subsequently has adverse physical effects, apparently from the drug. Everyone is sympathetic but no one accepts any blame. Has he a legal right to compensation?. THE
QUEST FOR COMPENSATION
a patient show that the drug is only one of one or possible causes of his condition, he will fail, according to the House of Lords. Even if a scheme of no-fault liability is introduced for personal injuries, causation will always remain a difficulty. Once causation is established, the patient then has to show fault on someone’s part. The new European Community code of product liability,2 enacted in the UK by the Consumer Protection Act, 1987, now seemingly imposes a higher standard of care on manufacturers of products (including drugs). If a person injured can show damage caused by a defect in a product, he is well on the way to getting judgment. However, the UK Government, unlike other EC countries, allows manufacturers an inevitable development risks defence: section 4 (le) of the 1987 Act allows companies to avoid liability by proving: "that the state of scientific and technical knowledge at the relevant time was not such that a producer of products of the same description as the product in question might
Should such
more