`J. Inherit. Metab. Dis. 23
`(2000)
`(
`SSIEM and Kluwer Academic Publishers. Printed in the Netherlands
`
`Three cases of intravenous sodium benzoate and
`sodium phenylacetate toxicity occurring in the
`treatment of acute hyperammonaemia
`V. PRAPHANPHOJ1, S. A. BOYADJIEV1, L. J. WABER2, S. W. BRUSILOW1 and
`M. T. GERAGHTY1
`1 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore,
`Maryland; 2 University of T exas Southwestern Medical School, Dallas, T exas, USA
`* Correspondence: Department of Pediatrics, Blalock 1008, Johns Hopkins University
`School of Medicine, 600 N. W olfe St., Baltimore, MD 21287-4922, USA
`
`MS received 24.12.98 Accepted 13.08.99
`
`Summary: Intravenous sodium benzoate and sodium phenylacetate have been
`used successfully in the treatment of acute hyperammonaemia in patients with
`urea cycle disorders. They provide alternative pathways for waste nitrogen dis-
`posal and help maintain nitrogen homeostasis. However, we report three
`patients with hyperammonaemia who received inappropriate doses of intra-
`venous sodium benzoate and sodium phenylacetate that resulted in severe com-
`plications. Ambiguous medical prescriptions and inadequate cross-checking of
`drug dosage by physicians, nurses and pharmacists were the main causes of
`these incidents. All the patients presented with alteration in mental status,
`Kussmaul respiration and a partially compensated metabolic acidosis with an
`increased anion gap. Two patients developed cerebral oedema and hypotension
`and died. The third survived after haemodialysis. Plasma levels of benzoate and
`phenylacetate were excessively high. The possible mechanisms of toxicity, man-
`agement and safety measures are discussed.
`
`Intravenous sodium benzoate and sodium phenylacetate have been used successfully
`in the treatment of episodic hyperammonaemia in patients with urea cycle disorders
`(Brusilow et al 1984). These drugs provide alternative pathways to ureagenesis for
`waste nitrogen disposal and help maintain nitrogen homeostasis in these patients.
`Sodium benzoate is conjugated with glycine to form hippurate, while sodium phenyl
`acetate is conjugated with glutamine to form phenylacetylglutamine. Both of these
`metabolites are rapidly excreted in urine via glomerular —ltration and tubular secre-
`tion. The recommended dose of intravenous sodium benzoate and sodium phenyl-
`acetate is 250 mg/kg each infused over 90 min, followed thereafter by 250 mg/kg each
`infused over 24 h. Theoretically, administration of 250 mg/kg per day of each drug
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`will lead to an excretion of 24 mg/kg per day of hippurate nitrogen or 44 mg/kg per
`day of phenylacetylglutamine nitrogen (Brusilow and Maestri 1996).
`These investigational drugs have been used in the treatment of patients with urea
`cycle defects for almost 20 years and the e(cid:134)ectiveness and safety of this therapy is
`widely accepted. The success of the drugs in decreasing plasma ammonium levels in
`these disorders has led to their wider application to the treatment of hyper-
`ammonaemia from other causes (Mendenhall et al 1986; Tse et al 1991). Known
`side-e(cid:134)ects of the drugs include nausea and vomiting during the infusion and hypo-
`kalaemia secondary to urinary loss enhanced by the excretion of the non-absorbable
`anions
`(hippurate and phenylacetylglutamine)
`(Batshaw et al 1982). Hyper-
`chloraemic acidosis may occur as a consequence of arginine-HCl administration.
`No serious side-e(cid:134)ects have been reported when the drugs are used in the recom-
`mended doses. However, we report here three cases of hyperammonaemic patients
`who received excessive doses of intravenous sodium benzoate and sodium phenyl-
`acetate, resulting in devastating complications.
`
`MATERIALS AND METHODS
`We reviewed the hospital charts of three patients who received accidental overdose
`with intravenous sodium benzoate and sodium phenylacetate. All three patients had
`known urea cycle defects and were being treated for intercurrent acute hyper-
`ammonaemia at the time the overdose occurred. Two cases occurred at one hospital
`and the third at a separate hospital. The clinical courses, relevant laboratory results
`including blood gases, electrolytes and ammonium levels, details of drug dosage,
`and drug and drug metabolite levels were summarized.
`Plasma ammonium was measured by a cation-ion exchange method (Brusilow
`1991). In our laboratory, the normal plasma ammonium levels are less than
`30 kmol/L. Where possible, blood for determination of drug levels and drug metab-
`olites was obtained. Plasma benzoate, hippurate, phenylacetate and phenylacylglu-
`tamine were determined by reversed-phase high-pressure liquid chromatography
`(Batshaw et al 1982).
`
`PATIENT 1
`J.H., a 3-year-old girl with known ornithine transcarbamylase de—ciency, presented
`with a 2-day history of upper respiratory tract infection. Subsequently, she became
`irritable with decreased mental alertness. At the time of admission her diet was
`protein restricted (1 g/kg per day natural protein) and she was taking 2.5 g/day of
`sodium benzoate and sodium phenylacetate and 3.6 g/day of citrulline. On admis-
`sion her weight was 11.6 kg. Initial laboratory results showed a plasma ammonium
`of 82 kmol/L. Serum electrolytes were sodium 141 mEq/L, potassium 4.0 mEq/L,
`chloride 103 mEq/L, bicarbonate 21 mEq/L and glucose 67 mg/dL. At that time her
`showed glutamine 1056 kmol/L (337¨673), glycine
`quantitative amino acids
`296 kmol/L (87¨323), alanine 948 kmol/L (136¨440), citrulline 0 kmol/L (10¨34),
`ornithine 108 kmol/L (22¨94), arginine 20 kmol/L (15¨115); normal
`laboratory
`values are shown in parentheses. Because of altered mental status, a priming intra-
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`Benzoate and phenylacetate toxicity
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`131
`
`venous dose of 250 mg/kg of sodium benzoate and sodium phenylacetate with
`2 ml/kg of 10% arginine-HCl was ordered to be given over 90 min, followed by the
`same dose over 24 h. Her plasma ammonium level decreased to 44 kmol/L and
`54 kmol/L at 4 and 7 h, respectively, after starting treatment. Plasma amino acids 4 h
`after starting treatment showed glutamine 745 kmol/L (337¨673), glycine 85 kmol/L
`(87¨323), alanine 998 kmol/L (136¨440), citrulline trace (10¨34), ornithine 237 kmol/
`L (22¨94), arginine 776 kmol/L (15¨115). However, during this time she became
`more irritable and somnolent, and developed tachypnoea with Kussmaul respir-
`ation. A repeat venous blood gas 7 h after starting the intravenous drugs showed a
`pCO2
`pH of 7.21 and
`of 5 torr. Serum electrolytes at that time were sodium
`146 mEq/L, potassium 3.7 mEq/L, chloride 104 mEq/L and bicarbonate 4 mEq/L,
`with a calculated anion gap of 42. She was transferred to the intensive care unit,
`where her condition worsened. Her plasma ammonium levels increased to 158 kmol/
`L and 232 kmol/L at 22 and 26 h, respectively, despite continuous infusion of both
`medications. Serum electrolytes at 26 h were sodium 152 mEq/L, potassium
`2.9 mEq/L, chloride 107 mEq/L and bicarbonate 16 mEq/L, with a calculated anion
`gap of 32. Haemodialysis was required to correct her acid¨base balance and hyper-
`ammonaemia. Plasma ammonium decreased below 100 kmol/L and her anion gap
`normalized within 24 h. Plasma ammonium levels were normal by 48 h.
`Plasma taken 4 h after the priming dose was ordered, and at the time of the
`increased anion gap, revealed levels of benzoate and phenylacetate far above those
`reported for the recommended doses (Table 1). Retrospective review of the medical
`record revealed that the patient had received three priming doses intravenously fol-
`lowed by an incorrect maintenance infusion dose. In total the patient received
`915 mg/kg of sodium benzoate and sodium phenylacetate over 12 h. The written
`orders were ambiguous and the abnormal dose went unrecognized by pharmacists,
`nurses and physicians. She recovered from the event and was discharged home after
`17 days of admission. She is now 19 years of age with an overall DQ of 35. She
`continues to have occasional episodes of hyperammonaemia despite treatment with
`a protein-restricted diet (0.75 g/kg per day) supplemented with sodium phenylbuty-
`rate (500 mg/kg per day) and citrulline.
`
`PATIENT 2
`
`S.P., a boy aged 6 years and 8 months with known late-onset ornithine trans-
`carbamylase de—ciency, presented with vomiting and a possible viral illness. His
`weight on admission was 21 kg. Prior to admission the patient was on a protein-
`restricted diet with citrulline supplementation. However, the family was noncom-
`pliant. His initial plasma ammonium was 326 kmol/L. Serum electrolytes were
`sodium 141 mEq/L, potassium 4.7 mEq/L,
`chloride 103 mEq/L, bicarbonate
`23 mEq/L, with an anion gap of 20. Plasma amino acids were not obtained. He was
`admitted and treated with a priming dose of 250 mg/kg of sodium benzoate and
`sodium phenylacetate with 2 ml/kg of 10% arginine-HCl infused over 2 h. This
`resulted in a decline of the plasma ammonium to 78 kmol/L one hour after com-
`
`J. Inherit. Metab. Dis. 23 (2000)
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`Table 1 Drug levels and metabolites obtained in patients 1 and 3
`
`T ime (h)
`Patient 1
`0
`4
`12
`Patient 3
`6
`9
`13
`15
`19
`28
`Normal values
`0
`3
`12
`17
`20
`27
`32
`
`BA (mmol/L)
`
`PA (mmol/L)
`
`HA (mmol/L)
`
`PAG (mmol/L)
`
`0.002
`10.60
`1.80
`
`5.07
`5.58
`3.37
`2.53
`0.321
`0.034
`
`0
`2.6
`1.5
`0.2
`0
`0
`0.4
`
`ND
`10.0
`2.71
`
`8.19
`9.07
`7.67
`8.16
`7.59
`1.79
`
`0
`3.4
`4.5
`3.5
`3.0
`2.2
`1.5
`
`0.007
`0.292
`0.294
`
`0.399
`0.395
`0.362
`0.412
`0.566
`0.189
`
`0
`0.25
`0.35
`0.25
`0.15
`0.15
`0.15
`
`ND
`ND
`0.097
`
`0.341
`0.341
`0.292
`0.319
`0.475
`0.677
`
`0
`0
`0
`0.40
`0.50
`0.50
`0.45
`
`For comparison, values are shown from a single patient who received 250 mg/kg over 90 min followed by
`250 mg/kg over 24 h
`BA, benzoate; PA, phenylacetate; HA, hippurate; PAG, phenylacetylglutamine; ND, not determined.
`
`pletion of the priming infusion. Since he was unable to take his oral medication, a
`24 h infusion of the same dose of each medication was ordered. At 16 h of this
`infusion, he was found to be obtunded and unresponsive to painful stimuli and had
`Kussmaul respiration. His plasma ammonium was 113 kmol/L. A venous gas
`pCO2
`showed a pH of 7.38,
`of 9 torr and a calculated bicarbonate of 5 mEq/L.
`Serum electrolytes were sodium 151 mEq/L, potassium 2.7 mEq/L, chloride 97 mEq/
`L and bicarbonate \5 mEq/L. The calculated anion gap was 52 mEq/L. An over-
`dose of intravenous sodium benzoate and sodium phenylacetate was suspected at
`that time and the infusion was stopped at approximately 18 h. He was then treated
`with intravenous (cid:209)uids and sodium bicarbonate. However, his plasma ammonium
`increased to 915 kmol/L. At that time his venous blood gas showed a pH of 7.35 and
`pCO2
`a
`of 12 torr. His serum electrolytes were sodium 152 mEq/L, potassium
`3.5 mEq/L, chloride 101 mEq/L and bicarbonate 6 mEq/L. The calculated anion gap
`was 49 mEq/L. Haemodialysis was started and his acid¨base balance and ammo-
`nium levels were normalized after two rounds of dialysis. Despite this, his neuro-
`logical status worsened, a CT scan of his brain showed cerebral oedema and he had
`—xed and dilated pupils. He was pronounced dead on the third day of admission.
`A review of the medical record revealed that the patient had received the entire
`24 h continuous infusion dose repeating every 3 h resulting in a total dose of
`1750 mg/kg of sodium benzoate and sodium phenylacetate over an 18 h period.
`
`J. Inherit. Metab. Dis. 23 (2000)
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`Benzoate and phenylacetate toxicity
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`133
`
`Again medical orders were ambiguous and the excessive doses were not recognized
`by pharmacists, nurses or physicians. He had received seven times the desired dose
`within 18 h until the time his clinical condition deteriorated and the infusion was
`stopped. Drug levels were not available.
`
`PATIENTS 3
`
`D.D., a boy aged 2 years and 9 months with known neonatal-onset ornithine trans-
`carbamylase de—ciency, was admitted following 1 week of upper respiratory tract
`infection and 2 days of emesis and irritability. At the time of his illness his diet
`consisted of 1.28 g/kg per day of protein, of which 0.5 g/kg per day was given as
`essential amino acids (UCD2, Milupa). Additionally, he was taking 600 mg/kg per
`day of phenylbutyrate and 3 g/day of citrulline. On admission he was alert and
`active with stable vital signs. His weight was 13 kg. The initial plasma ammonium
`was 84 kmol/L. A venous blood gas showed a pH of 7.38, and
`pCO2
`of 35 torr.
`Serum electrolytes were sodium 142 mEq/L, potassium 4.4 mEq/L, chloride
`110 mEq/L, bicarbonate 22 mEq/L and a calculated anion gap of 14. Quantitative
`plasma amino acids showed glutamine 1446 kmol/L (337¨673), glycine 390 kmol/L
`(87¨323), alanine 2198 kmol/L (136¨440), citrulline 0 (10¨34), ornithine 50 kmol/L
`(22¨94), arginine 39 kmol/L (15¨115). Because of continued vomiting, a priming dose
`of 250 mg/kg sodium benzoate, 250 mg/kg sodium phenylacetate and 2 ml/kg 10%
`arginine-HCl was started. Maintenance with the same doses and medications was
`ordered to run over 24 h after the priming dose was completed. Six hours after
`starting the priming dose, the patientˇs plasma ammonium had decreased to
`32 kmol/L. Plasma amino acids at that time showed glutamine 806 kmol/L (337¨
`673), glycine 60 kmol/L (87¨323), alanine 995 kmol/L (136¨440), citrulline 0 (10¨34),
`ornithine 148 kmol/L (22¨94), arginine 377 kmol/L (15¨115). However, after 9 h of
`treatment he was noted to be lethargic and irritable and had Kussmaul respiration.
`Serum electrolytes at that time were sodium 137 mEq/L, potassium 4.2 mEq/L, chlo-
`ride 97 mEq/L, and bicarbonate 5 mEq/L. The calculated anion gap was 39 mEq/L.
`At that time it was discovered that he was receiving an incorrect maintenance dose.
`The medications were immediately stopped but despite vigorous (cid:209)uid and electro-
`lyte resuscitation he developed cerebral oedema and respiratory depression
`requiring ventilatory support. The patient developed disseminated intravascular
`coagulation, became hypotensive and died within 36 h of admission.
`Drug levels (Table 1) revealed toxic levels of benzoate, phenylacetate and their
`metabolites. Review of the medical record revealed that the patient received a total
`of 750 mg/kg of the drugs over 10 h. The orders for the drugs were wrongly tran-
`scribed and the mistake was not recognized by pharmacists, nurses or physicians.
`
`DISCUSSION
`
`The recommended dose of intravenous sodium benzoate and sodium phenylacetate
`is 250 mg/kg each infused over 90 min, followed by 250 mg/kg each infused over 24 h
`
`J. Inherit. Metab. Dis. 23 (2000)
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`Praphanphoj et al
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`thereafter. We report three patients who accidentally received these drugs far in
`excess of these doses. Patients 1 had received 915 mg/kg over 12 h, patient 2 received
`1750 mg/kg over 18 h, and patient 3 received 750 mg/kg over 10 h. Plasma levels of
`benzoate and phenylacetate were measured as 10.6 mmol/L and 10 mmol/L at 4 h
`after infusion in patient 1 and 5.58 mmol/L and 9.07 mmol/L at 9 h in patient 3.
`Using a priming infusion of 250 mg/kg over 90 min, plasma benzoate levels generally
`reach peak levels of 3 mmol/L at 4¨6 h while phenylacetate reaches peak levels of
`4 mmol/L at the same time (Table 1). Plasma hippurate and phenylacetylglutamine
`levels are generally below 600 kmol/L when treatment is with these doses (Brusilow
`et al 1984). The clinical presentation of toxicity was similar in all cases. The patients
`initially became agitated and confused even as the plasma ammonium decreased.
`Kussmaul respiration was prominent in all cases. Biochemical indices in blood
`showed that all patients developed a partially compensated metabolic acidosis with
`an increased anion gap (42, 52 and 27 in patients 1, 2 and 3, respectively). Accumu-
`lation of benzoate and phenylacetate may represent another cause of an increased
`anion gap. Plasma ammonium levels decreased in all patients after the priming dose
`but rebounded in patient 1 to 232 kmol/L and in patient 2 to 915 kmol/L once the
`intravenous drugs were discontinued. Mental status was depressed in all patients.
`Cerebral oedema was evident in patients 2 and 3 before they died. Hypotension and
`cardiovascular collapse were late signs of intoxication. Patients 2 and 3 died despite
`intensive therapy. Patient 1 survived after prompt haemodialysis.
`Adverse reactions have been noted before in patients receiving sodium benzoate
`and sodium phenylacetate for the treatment of urea cycle defects (Brusilow et al
`1984). These include nausea and vomiting. An increased anion gap may be observed
`due to the accumulation of benzoate, phenylacetate and their conjugation products
`in plasma, the sum of which may attain levels of 7 mmol/L. Other electrolyte
`changes that may be seen include hypernatraemia and hyperosmolarity (because of
`the high sodium content of the drugs), hypokalaemia as a result of increased urinary
`loss and hyperchloraemia due to the co-infusion of arginine-HCl. Finally, because of
`the structural similarity of benzoate and phenylacetate to salicylates, they have the
`potential to cause central hyperventilation and respiratory alkalosis.
`Previous reports have implicated benzyl alcohol (which is converted to benzoic
`acid) as a cause of the (cid:147)gasping syndromeˇ and death in premature infants (Brown
`1982; Gershanik et al 1982). While benzoic acid undoubtedly causes an increased
`anion gap metabolic acidosis, it also has been shown to interfere with various meta-
`bolic pathways (Tremblay and Qureshi 1993). High-dose benzoate sequesters
`coenzyme A, leading to a de—ciency of acetyl-CoA. This results in inhibition of
`carbamoylphosphate synthetase and pyruvate carboxylase, thus a(cid:134)ecting the urea
`cycle and gluconeogenesis (Cyr and Tremblay 1989; Cyr et al 1991). Carnitine de—-
`ciency through urinary loss of benzoylcarnitine further reduces acetyl-CoA and inhi-
`bits fatty acid oxidation (Baynen and Geelen 1982; Kalbag and Palekar 1988;
`Ohtani et al 1988; Van Hove et al 1995). There are two reports of adverse reactions
`to the use of phenylacetate in humans including emesis and neurotoxicity (Thibault
`et al 1994, 1995). The latter may be accounted for by the fact that phenylacetate has
`been shown to inhibit several neuronal-associated enzymes including choline acetyl-
`
`J. Inherit. Metab. Dis. 23 (2000)
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`transferase, dopa decarboxylase, 5-hydroxytryptophan decarboxylase and glutamic
`acid decarboxylase (Davidson and Sandler 1959; Fellman 1956; Hartman et al
`1955; Petempska et al 1984). The formation of phenylacetyl-CoA decreases the
`availability of acetyl-CoA and inhibits fatty acid and sterol synthesis.
`Intoxication with sodium benzoate and sodium phenylacetate should always be
`considered in patients receiving these intravenous medications. In the event of
`suspected overdose, the drugs should be discontinued and the patient should be
`carefully monitored for clinical and biochemical deterioration, with special attention
`to the anion gap. Haemodialysis is the treatment of choice. Supplementation with
`glycine and/or carnitine should also be considered as additional therapy. Clear and
`unambiguous orders and con—rmation of dosages by physicians, nurses and phar-
`macists should be carefully observed.
`
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