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The Acidosis of Exogenous Phosphate Intoxication

The Acidosis of Exogenous Phosphate Intoxication BackgroundSevere hyperphosphatemia resulting from the use of laxatives and enemas with high levels of phosphate has been the subject of many case reports. These have generally focused on the hypernatremia and hypocalcemia that develop and become life-threatening. Less attention has been paid to the metabolic acidosis of phosphate intoxication.MethodsIn-depth analysis of a case of severe hyperphosphatemia and review of the literature for cases with sufficient data to permit correlation between the phosphate concentration, acidosis, and anion gap.ResultsMarked metabolic acidosis with a large increase in the anion gap was present in our patient. The correlation between these parameters and the plasma phosphate concentration was highly significant. Despite a paucity of data in most case reports, we did uncover other cases of anion gap–positive metabolic acidosis in patients with hyperphosphatemia.ConclusionsAmong high-risk patients, including the elderly and debilitated, the presence of metabolic acidosis, hypernatremia, an increased anion gap, and low plasma calcium levels or a prolonged QT interval on the electrocardiogram should raise suspicion of phosphate intoxication.RECENT FIGURES from the C. B. Fleet Company Inc, Lynchburg, Va, show 1-year sales of 769523 kg of sodium phosphate salts used for orally and rectally administered products to cleanse the intestines (Scott Crosby, oral communication, May 1997, C.B. Fleet Company Inc). This represents 5.62×109mmol of Na+and 8.73×109mEq of negative charge (at pH 7.4) contributed by H2PO4−and HPO42−. Sales of phosphate salts have increased greatly in recent years commensurate with their use as intestinal cleansing agents prior to endoscopy.Reports of phosphate intoxication severe enough to cause perceptible increases in the anion gap are uncommon but not rare,though typically not much attention is paid to the effect on the anion gap. The greatest emphasis is placed on hypocalcemia resulting from hyperphosphatemia and on the hyperosmolar state induced by hypernatremia.Data on the acid-base consequences of hyperphosphatemia are generally absent or are obtained only after the patient has had cardiac arrest or convulsions or other medical or surgical complication, at which time it is impossible to separate the effects of phosphate from those of lactate and other anions produced in excess.The case of phosphate intoxication presented herein features one of the highest phosphate levels and anion gaps ever reported in this situation. Strong correlation between the anion gap and plasma phosphate concentration was demonstrated. These data, combined with a review of the medical literature, permit construction of a clinical presentation that is highly suggestive of severe phosphate overdose even when a history of phosphate exposure is not available.METHODSAll the chemical tests were performed in the clinical laboratories at the Medical College of Virginia Hospital, Richmond. Data were analyzed by linear regression using P≤.05 as significant. Statistical analysis and graphing of data were performed using software (Quattro Pro, Corel, Ottawa, Ontario). The net cationic equivalency of albumin was calculated using the following formula:([−8.7×7.4]+43)×Albumin/69,where the albumin is expressed in grams per liter.Phosphate concentration was converted from milligrams per deciliter to milliequivalents per liter using a published formula.Estimated pH was calculated as7.5+[tCO2]/100,where tCO2represents the total carbon dioxide concentration.REPORT OF A CASEThe patient was a 74-year-old woman with known diabetes mellitus and resected colon cancer whose plasma creatinine and electrolyte levels 1 month prior to her acute illness were within normal limits. She was brought to the emergency department in an obtunded state after mistakenly ingesting the contents of 1 adult-sized Fleet enema. Representative initial and subsequent laboratory data are included in Table 1. Of note were the phosphate level of 20.2 mmol/L (62.5 mg/dL), osmolality of 350 mOsm/kg, and anion gap of 56 mEq/L, with a total carbon dioxide concentration of 6 mmol/L. The total calcium level was 1.07 mmol/L (4.29 mg/dL). She received the contents of half an ampule of sodium bicarbonate and 1 g of calcium gluconate, and was transferred to the intensive care unit where she underwent hemodialysis for several hours with partial correction of her electrolyte level disturbances. She required supplemental calcium and magnesium replacement. After dialysis her mental status improved, and she was successfully extubated and transferred to a medical ward. Subsequently, she developed signs of pancreatitis and a pancreatic pseudocyst was drained. Her recovery was otherwise uneventful.Table 1. Representative Laboratory Values for Reported Case*See table graphicAt the time when her arterial pH was 7.14 and anion gap was 56 mEq/L, the phosphate and albumin contributions to the gap were 34 and 14.9 mEq/L, respectively, and accounted for 89% of the total gap. There was tight correlation between the decreases in the plasma phosphate level and anion gap (R2=0.89) (Figure 1).Figure 1.Top, Correlation between the anion gap and plasma phosphate concentration using the data from the case reported. The regression equation was: y=1.32x+15.5 (R2=0.89). Bottom, Correlation between the anion gap and plasma phosphate concentration using the data from Wason et al.The regression equation was: y=0.945x+12.7 (R2= 0.89), with x representing the independent variable and y the dependent variable.Since the formula for converting phosphate concentration from milligrams per deciliter to milliequivalents per literrequires a value for blood pH, which generally is not available, we examined the quantitative contribution of pH to the calculation. As shown in Table 2, the effect of pH changes within clinically pertinent limits is actually rather small compared with that of the phosphate concentration. Use of a pH of 7.4 when the actual pH is unknown does not introduce an unacceptably large error. We also used a formula to estimate pHthat depends on the total carbon dioxide concentration. Even though estimated and measured pH values did show a significant degree of correlation, the formula failed to account for the contribution of respiratory alkalosis and gave lower values for pH in the alkalotic range compared with measured values (Figure 2). A comparison of the calculated anionic charge of phosphate using estimated vs measured pH showed almost complete identity.Table 2. Conversion of Phosphate*See table graphicFigure 2.Correlation between the measured pH and the pH calculated from the formula: pH=7.15+(total carbon dioxide concentration/100) using the data from the reported case. Line of identity is shown. The regression equation was: y=0.375x+4.5 (R2=0.81) with x representing the independent variable and y the dependent variable.LITERATURE REVIEWWe reviewed a total of 36 articles published over 30 years and found 2 that had enough data for a statistical analysis of phosphate concentrations and anion gap. Wason et aldescribed a 5-month-old infant who was treated with an adult-sized Fleet enema. The patient was unresponsive on admission. Initial laboratory data showed an anion gap of 36.5 mEq/L and phosphate level of 14.3 mmol/L (44.3 mg/dL), which converted to 25 mEq/L at a pH of 7.28. The coefficient of determination (R2) of the anion gap vs plasma phosphate concentration was 0.89. Of interest, the y-intercept of the linear regression plot (Figure 1) was 12.7, which corresponds precisely to the value expected for a normal albumin concentration of 40 g/L. (No albumin values were reported in the article.)The case reported by Thatte et alis most instructive. It featured a 42-year-old man with recurrent pancreatitis and renal insufficiency who was admitted because of weakness and vomiting. Admission laboratory studies revealed an anion gap of 50.5 mEq/L with a total carbon dioxide concentration of 25 mmol/L and a chloride level of 68 mmol/L. The phosphate level was elevated at 7.72 mmol/L (23.9 mg/dL), which converted to 13.9 mEq/L at a pH of 7.41. Hyperphosphatemia accounted for only 30% of the total anion gap. With hydration, both the anion gap and hyperphosphatemia declined (R2=0.91), forcing the conclusion that there must have been one or more additional anions that remained unidentified and were cleared in proportion to the clearance of phosphate. The patient subsequently developed lactic acidosis and died.A case reported in 1975concerned a patient with pancreatitis and dehydration whose plasma levels of Na+, K+, Cl−, total carbon dioxide concentration, and anion gap on admission were 170, 5.3, 70, and 38 mmol/L and 67 mEq/L, respectively, with a phosphate level of 10 mmol/L (31 mg/dL) and an albumin level of 53 g/L. The equivalent anionic charges for phosphate and albumin were 18 and 16.4 mEq/L. Together, they accounted for only 51% of the gap. On day 2, the gap had decreased to 33.7 mEq/L and the phosphate level to 3.2 mmol/L (9.91 mg/dL; 5.7 mEq/L at pH 7.41). This patient had a complex acid-base disturbance, and the severe hyperphosphatemia failed to account for the extraordinarily large anion gap.The infant described by Smith et alhad a phosphate level of 13.4 mmol/L (41.5 mg/dL; 24 mEq/L at pH 7.4) and a total anion gap of 43 mEq/L. No plasma albumin concentration was provided, but hyperalbuminemia secondary to hemoconcentration might readily have accounted for most of the outstanding 19 mEq/L. A fatal case was reported by Fass et al.Their patient's presenting plasma Na+concentration was 177 mmol/L and the total carbon dioxide concentration was 18 mmol/L. No chloride value was provided. The phosphate level was 19.2 mmol/L (59.5 mg/dL; 32.2 mEq/L at the measured pH of 7.12). Another fatal case reported by Martin et alinvolved a child whose admission electrolyte levels were as follows: Na+, 183 mmol/L; K+, 7 mmol/L; Cl−, 98 mmol/L; and total carbon dioxide concentration, 6.7 mmol/L, providing an anion gap of 85 mEq/L. The phosphate concentration was greatly elevated at 20.4 mmol/L (63.2 mg/dL; 35.2 mEq/L at the estimated pH of 7.22 and 28.5 mEq/L at the measured pH of 6.6). In the case reported by Escalante et al,the anion gap was 23.9 mEq/L. This increased gap was fully explained by a phosphate level of 6.17 mmol/L (19.1 mg/dL), which converted to 10.8 mEq/L at the measured pH of 7.27.Levitt et aldescribed an infant with a plasma phosphate level of 4.52 mmol/L (14 mg/dL; 8.1 mEq/L at pH 7.4) and normal electrolyte levels but an anion gap of only 11.5 mEq/L. The patient described by Filho and Lassmanhad an anion gap of 21.5 mEq/L but a phosphate level of 10.3 mmol/L (31.9 mg/dL), equivalent to 18.5 mEq/L at a pH of 7.4. Since the plasma albumin level was normal and was expected to contribute approximately 12 mEq/L to the anion gap, there clearly was an excess of anionic charge, which raises speculation about the presence of some unmeasured cation.For the 2 patients described by Fine and Patterson,the plasma phosphate levels of 11.3 and 7.43 mmol/L (35.0 and 23.0 mg/dL, respectively) matched closely the reported increases in the anion gap. Similarly, the patient of Sutters et alhad an arterial pH of 7.28, an anion gap of 44.5 mEq/L, and a plasma phosphate level of 14.5 mmol/L (44.90 mg/dL), which contributed 25.3 mEq/L and accounted for most of the increase in the anion gap.COMMENTThe well-hydrated adult patient with normal kidney function has a potent defense against the development of hyperphosphatemic acidosis.Young children with small kidneys and correspondingly little capacity to clear phosphate are at high risk when confronted with the massive phosphate load present in adult-sized oral and enema intestinal cleansing formulations. Used appropriately as preparations for endoscopy, effective doses of Phospho-Soda (C.B. Fleet Company Inc) or phosphate enemas carry minimal risk of toxic effects, although the plasma phosphate concentration may transiently increase above normal.These preparations enjoy better acceptance by patients compared with solutions of polyethylene glycol with electrolytes and are likely to see wider usage.Metabolic acidosis is a consistent feature of severe phosphate intoxication even in the absence of secondary events, such as seizures or cardiac arrest. At a pH of 7.4, the molar ratio of HPO42−to H2PO4−is 4:1, calculated using a pKaof 6.8. A 25-mL dose of Fleet Phospho-Soda contains 104 mmol of phosphate, with a HPO42−/H2PO4−ratio of 0.19. One adult-sized enema contains 164 mmol of phosphate with the same molar ratio of 0.19. Exogenously provided phosphate eventually leaves the body dissolved in urine predominantly as H2PO4−since urine pH is customarily below 6.0. Hence, the net effect of normal quantities of dietary phosphate on acid-base balance is either neutral or acid buffering. But, in the case of phosphate intoxication, rate of absorption exceeds rate of excretion. Each 5 molecules of NaH2PO4added to the extracellular compartment at a pH of 7.4 will dissociate to 5 Na+, 4 H+, H2PO4−, and 4 HPO42−. This addition of H+requires neutralization by buffers such as HCO3−, leading to a metabolic acidosis with an enlarged anion gap. The severity of the acidosis depends on how much and how quickly NaH2PO4is absorbed, quantitative aspects of the renal phosphaturic response, and the preexisting buffering capacity of the individual. Once renal excretion of H2PO4−exceeds absorption, the acidosis and increased anion gap should begin to resolve. As an aside, the acidosis may assist in maintaining a safe level of ionized calcium in the face of low total calcium levels, so that correction of the acidosis with intravenous sodium bicarbonate should not be aggressively pursued and should be guided by measurements of ionized calcium in the blood.Risk factors for intoxication in adults include fluid restriction and an individual's inability to satisfy his or her need for fluids, perhaps due to confinement, extreme debility, or gastrointestinal disease. Aging also constitutes a risk factor. The more sedentary lifestyle, altered gut motility patterns, and low-fiber diets of the elderly contribute to the problem of constipation and, secondarily, to increased dependence on laxatives and enemas. There is also the age-related decline in renal function, which is frequently overlooked because the plasma creatinine level may remain within the range of normal despite a 50% or greater decrease in the glomerular filtration rate compared with that in younger individuals of the same sex. Moreover, mental obtundation often attends metabolic disorders in the elderly so that important historical information may be lacking when the patient first presents. Among these categories of patients, phosphate intoxication should be strongly considered in the presence of dehydration, altered mental status, and neuromuscular irritability when accompanied by hypernatremia, an increased anion gap, metabolic acidosis, and a prolonged QT interval on the electrocardiogram. This clinical picture shares many features with ethylene glycol intoxication. Hyperphosphatemia, if documented, should be quantitatively analyzed to determine how much of the anion gap it explains so that other processes are not overlooked. As with other disturbances of acid-base regulation, knowing the concentration of plasma albumin and its net cationic equivalency will enhance the differential diagnostic value of the anion gap.LThatteJROsterISingerJBourgoignieLMFishmanBARoosReview of the literature: severe hyperphosphatemia.Am J Med Sci.1995;310:167-174.SWasonTTillerCCunhaSevere hyperphosphatemia, hypocalcemia, acidosis, and shock in a 5-month-old child following the administration of an adult Fleet enema.Ann Emerg Med.1989;18:696-700.EDEhrenpreisJMWielandJCabralVEstevezDZaitmanKSecrestSymptomatic hypocalcemia, hypomagnesemia, and hyperphosphatemia secondary to Fleet's Phospho-Soda colonoscopy preparation in a patient with a jejunoileal bypass.Dig Dis Sci.1997;42:858-860.PKMoseleyWESegarFluid and serum electrolyte disturbances as a complication of enemas in Hirschsprung's disease.AJDC.1968;115:714-718.PLoughnanGCMullinsBrain damage following a hypertonic phosphate enema.AJDC.1977;131:1032.GCYuDBLeeClinical disorders of phosphate metabolism.West J Med.1987;147:569-576.MLevittCGessertLFinbergInorganic phosphate (laxative) poisoning resulting in tetany in an infant.J Pediatr.1973;82:479-481.MSSmithKWFeldmanCTFurukawaComa in an infant due to hypertonic sodium phosphate medication.J Pediatr.1973;82:481-482.AJFilhoMNLassmanSevere hyperphosphatemia induced by a phosphate containing laxative.Ann Pharmacother.1996;30:141-142.MSuttersCLGabouryWMBennettSevere hyperphosphatemia and hypocalcemia: a dilemma in patient management.J Am Soc Nephrol.1996;7:2056-2061.AFineJPattersonSevere hyperphosphatemia following phosphate administration for bowel preparation in patients with renal failure: two cases and a review of the literature.Am J Kidney Dis.1997;29:103-105.BKirschbaumRMCulpepperThe pK1of the carbonic acid-bicarbonate buffer system in hemodialyzed patients.Am J Med Sci.1989;298:237-242.RGutierrezJROsterFBSchlessingerGOPerezDGFedermanCAVaamondeSerum sulfate concentration and the anion gap in hemodialysis patients.ASAIO Trans.1991;37:92-96.RDZisperMDBischelDEAbramsHypocalcemic tetany due to sodium phosphate ingestion in acute renal failure.Nephron.1975;14:378-381.RFassSDoLJHixsonFatal hyperphosphatemia following Fleet Phospho-Soda in a patient with colonic ileus.Am J Gastroenterol.1993;88:929-932.RRMartinGRLisehoraMBraxtonPJBarciaFatal poisoning from a sodium phosphate enema.JAMA.1987;257:2190-2192.CPEscalanteMAWeiserKFinkelHyperphosphatemia associated with phosphorous containing laxatives in a patient with chronic renal insufficiency.South Med J.1997;90:240-242.JADiPalmaSEBuckleyBAWarnerRMCulpepperBiochemical effects of oral sodium phosphate.Dig Dis Sci.1996;41:749-753.CFCohanSCKadakiaASKadakiaSerum electrolyte, mineral, and pH changes after phosphate enema, water enema, and electrolyte lavage solution enema for flexible sigmoidoscopy.Gastrointest Endosc.1992;38:575-578.SMCohenSDWexnerSRBinderowProspective, randomized endoscopic-blinded trial comparing precolonoscopy bowel cleansing methods.Dis Colon Rectum.1994;37:689-696.THuynhSVannerWPattersonSafety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia.Am J Gastroenterol.1995;90:104-107.Accepted for publication September 2, 1997.Reprints: Barry Kirschbaum, MD, Medical College of Virginia, Box 980160, Richmond, VA 23298. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

The Acidosis of Exogenous Phosphate Intoxication

JAMA Internal Medicine , Volume 158 (4) – Feb 23, 1998

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Abstract

BackgroundSevere hyperphosphatemia resulting from the use of laxatives and enemas with high levels of phosphate has been the subject of many case reports. These have generally focused on the hypernatremia and hypocalcemia that develop and become life-threatening. Less attention has been paid to the metabolic acidosis of phosphate intoxication.MethodsIn-depth analysis of a case of severe hyperphosphatemia and review of the literature for cases with sufficient data to permit correlation between the phosphate concentration, acidosis, and anion gap.ResultsMarked metabolic acidosis with a large increase in the anion gap was present in our patient. The correlation between these parameters and the plasma phosphate concentration was highly significant. Despite a paucity of data in most case reports, we did uncover other cases of anion gap–positive metabolic acidosis in patients with hyperphosphatemia.ConclusionsAmong high-risk patients, including the elderly and debilitated, the presence of metabolic acidosis, hypernatremia, an increased anion gap, and low plasma calcium levels or a prolonged QT interval on the electrocardiogram should raise suspicion of phosphate intoxication.RECENT FIGURES from the C. B. Fleet Company Inc, Lynchburg, Va, show 1-year sales of 769523 kg of sodium phosphate salts used for orally and rectally administered products to cleanse the intestines (Scott Crosby, oral communication, May 1997, C.B. Fleet Company Inc). This represents 5.62×109mmol of Na+and 8.73×109mEq of negative charge (at pH 7.4) contributed by H2PO4−and HPO42−. Sales of phosphate salts have increased greatly in recent years commensurate with their use as intestinal cleansing agents prior to endoscopy.Reports of phosphate intoxication severe enough to cause perceptible increases in the anion gap are uncommon but not rare,though typically not much attention is paid to the effect on the anion gap. The greatest emphasis is placed on hypocalcemia resulting from hyperphosphatemia and on the hyperosmolar state induced by hypernatremia.Data on the acid-base consequences of hyperphosphatemia are generally absent or are obtained only after the patient has had cardiac arrest or convulsions or other medical or surgical complication, at which time it is impossible to separate the effects of phosphate from those of lactate and other anions produced in excess.The case of phosphate intoxication presented herein features one of the highest phosphate levels and anion gaps ever reported in this situation. Strong correlation between the anion gap and plasma phosphate concentration was demonstrated. These data, combined with a review of the medical literature, permit construction of a clinical presentation that is highly suggestive of severe phosphate overdose even when a history of phosphate exposure is not available.METHODSAll the chemical tests were performed in the clinical laboratories at the Medical College of Virginia Hospital, Richmond. Data were analyzed by linear regression using P≤.05 as significant. Statistical analysis and graphing of data were performed using software (Quattro Pro, Corel, Ottawa, Ontario). The net cationic equivalency of albumin was calculated using the following formula:([−8.7×7.4]+43)×Albumin/69,where the albumin is expressed in grams per liter.Phosphate concentration was converted from milligrams per deciliter to milliequivalents per liter using a published formula.Estimated pH was calculated as7.5+[tCO2]/100,where tCO2represents the total carbon dioxide concentration.REPORT OF A CASEThe patient was a 74-year-old woman with known diabetes mellitus and resected colon cancer whose plasma creatinine and electrolyte levels 1 month prior to her acute illness were within normal limits. She was brought to the emergency department in an obtunded state after mistakenly ingesting the contents of 1 adult-sized Fleet enema. Representative initial and subsequent laboratory data are included in Table 1. Of note were the phosphate level of 20.2 mmol/L (62.5 mg/dL), osmolality of 350 mOsm/kg, and anion gap of 56 mEq/L, with a total carbon dioxide concentration of 6 mmol/L. The total calcium level was 1.07 mmol/L (4.29 mg/dL). She received the contents of half an ampule of sodium bicarbonate and 1 g of calcium gluconate, and was transferred to the intensive care unit where she underwent hemodialysis for several hours with partial correction of her electrolyte level disturbances. She required supplemental calcium and magnesium replacement. After dialysis her mental status improved, and she was successfully extubated and transferred to a medical ward. Subsequently, she developed signs of pancreatitis and a pancreatic pseudocyst was drained. Her recovery was otherwise uneventful.Table 1. Representative Laboratory Values for Reported Case*See table graphicAt the time when her arterial pH was 7.14 and anion gap was 56 mEq/L, the phosphate and albumin contributions to the gap were 34 and 14.9 mEq/L, respectively, and accounted for 89% of the total gap. There was tight correlation between the decreases in the plasma phosphate level and anion gap (R2=0.89) (Figure 1).Figure 1.Top, Correlation between the anion gap and plasma phosphate concentration using the data from the case reported. The regression equation was: y=1.32x+15.5 (R2=0.89). Bottom, Correlation between the anion gap and plasma phosphate concentration using the data from Wason et al.The regression equation was: y=0.945x+12.7 (R2= 0.89), with x representing the independent variable and y the dependent variable.Since the formula for converting phosphate concentration from milligrams per deciliter to milliequivalents per literrequires a value for blood pH, which generally is not available, we examined the quantitative contribution of pH to the calculation. As shown in Table 2, the effect of pH changes within clinically pertinent limits is actually rather small compared with that of the phosphate concentration. Use of a pH of 7.4 when the actual pH is unknown does not introduce an unacceptably large error. We also used a formula to estimate pHthat depends on the total carbon dioxide concentration. Even though estimated and measured pH values did show a significant degree of correlation, the formula failed to account for the contribution of respiratory alkalosis and gave lower values for pH in the alkalotic range compared with measured values (Figure 2). A comparison of the calculated anionic charge of phosphate using estimated vs measured pH showed almost complete identity.Table 2. Conversion of Phosphate*See table graphicFigure 2.Correlation between the measured pH and the pH calculated from the formula: pH=7.15+(total carbon dioxide concentration/100) using the data from the reported case. Line of identity is shown. The regression equation was: y=0.375x+4.5 (R2=0.81) with x representing the independent variable and y the dependent variable.LITERATURE REVIEWWe reviewed a total of 36 articles published over 30 years and found 2 that had enough data for a statistical analysis of phosphate concentrations and anion gap. Wason et aldescribed a 5-month-old infant who was treated with an adult-sized Fleet enema. The patient was unresponsive on admission. Initial laboratory data showed an anion gap of 36.5 mEq/L and phosphate level of 14.3 mmol/L (44.3 mg/dL), which converted to 25 mEq/L at a pH of 7.28. The coefficient of determination (R2) of the anion gap vs plasma phosphate concentration was 0.89. Of interest, the y-intercept of the linear regression plot (Figure 1) was 12.7, which corresponds precisely to the value expected for a normal albumin concentration of 40 g/L. (No albumin values were reported in the article.)The case reported by Thatte et alis most instructive. It featured a 42-year-old man with recurrent pancreatitis and renal insufficiency who was admitted because of weakness and vomiting. Admission laboratory studies revealed an anion gap of 50.5 mEq/L with a total carbon dioxide concentration of 25 mmol/L and a chloride level of 68 mmol/L. The phosphate level was elevated at 7.72 mmol/L (23.9 mg/dL), which converted to 13.9 mEq/L at a pH of 7.41. Hyperphosphatemia accounted for only 30% of the total anion gap. With hydration, both the anion gap and hyperphosphatemia declined (R2=0.91), forcing the conclusion that there must have been one or more additional anions that remained unidentified and were cleared in proportion to the clearance of phosphate. The patient subsequently developed lactic acidosis and died.A case reported in 1975concerned a patient with pancreatitis and dehydration whose plasma levels of Na+, K+, Cl−, total carbon dioxide concentration, and anion gap on admission were 170, 5.3, 70, and 38 mmol/L and 67 mEq/L, respectively, with a phosphate level of 10 mmol/L (31 mg/dL) and an albumin level of 53 g/L. The equivalent anionic charges for phosphate and albumin were 18 and 16.4 mEq/L. Together, they accounted for only 51% of the gap. On day 2, the gap had decreased to 33.7 mEq/L and the phosphate level to 3.2 mmol/L (9.91 mg/dL; 5.7 mEq/L at pH 7.41). This patient had a complex acid-base disturbance, and the severe hyperphosphatemia failed to account for the extraordinarily large anion gap.The infant described by Smith et alhad a phosphate level of 13.4 mmol/L (41.5 mg/dL; 24 mEq/L at pH 7.4) and a total anion gap of 43 mEq/L. No plasma albumin concentration was provided, but hyperalbuminemia secondary to hemoconcentration might readily have accounted for most of the outstanding 19 mEq/L. A fatal case was reported by Fass et al.Their patient's presenting plasma Na+concentration was 177 mmol/L and the total carbon dioxide concentration was 18 mmol/L. No chloride value was provided. The phosphate level was 19.2 mmol/L (59.5 mg/dL; 32.2 mEq/L at the measured pH of 7.12). Another fatal case reported by Martin et alinvolved a child whose admission electrolyte levels were as follows: Na+, 183 mmol/L; K+, 7 mmol/L; Cl−, 98 mmol/L; and total carbon dioxide concentration, 6.7 mmol/L, providing an anion gap of 85 mEq/L. The phosphate concentration was greatly elevated at 20.4 mmol/L (63.2 mg/dL; 35.2 mEq/L at the estimated pH of 7.22 and 28.5 mEq/L at the measured pH of 6.6). In the case reported by Escalante et al,the anion gap was 23.9 mEq/L. This increased gap was fully explained by a phosphate level of 6.17 mmol/L (19.1 mg/dL), which converted to 10.8 mEq/L at the measured pH of 7.27.Levitt et aldescribed an infant with a plasma phosphate level of 4.52 mmol/L (14 mg/dL; 8.1 mEq/L at pH 7.4) and normal electrolyte levels but an anion gap of only 11.5 mEq/L. The patient described by Filho and Lassmanhad an anion gap of 21.5 mEq/L but a phosphate level of 10.3 mmol/L (31.9 mg/dL), equivalent to 18.5 mEq/L at a pH of 7.4. Since the plasma albumin level was normal and was expected to contribute approximately 12 mEq/L to the anion gap, there clearly was an excess of anionic charge, which raises speculation about the presence of some unmeasured cation.For the 2 patients described by Fine and Patterson,the plasma phosphate levels of 11.3 and 7.43 mmol/L (35.0 and 23.0 mg/dL, respectively) matched closely the reported increases in the anion gap. Similarly, the patient of Sutters et alhad an arterial pH of 7.28, an anion gap of 44.5 mEq/L, and a plasma phosphate level of 14.5 mmol/L (44.90 mg/dL), which contributed 25.3 mEq/L and accounted for most of the increase in the anion gap.COMMENTThe well-hydrated adult patient with normal kidney function has a potent defense against the development of hyperphosphatemic acidosis.Young children with small kidneys and correspondingly little capacity to clear phosphate are at high risk when confronted with the massive phosphate load present in adult-sized oral and enema intestinal cleansing formulations. Used appropriately as preparations for endoscopy, effective doses of Phospho-Soda (C.B. Fleet Company Inc) or phosphate enemas carry minimal risk of toxic effects, although the plasma phosphate concentration may transiently increase above normal.These preparations enjoy better acceptance by patients compared with solutions of polyethylene glycol with electrolytes and are likely to see wider usage.Metabolic acidosis is a consistent feature of severe phosphate intoxication even in the absence of secondary events, such as seizures or cardiac arrest. At a pH of 7.4, the molar ratio of HPO42−to H2PO4−is 4:1, calculated using a pKaof 6.8. A 25-mL dose of Fleet Phospho-Soda contains 104 mmol of phosphate, with a HPO42−/H2PO4−ratio of 0.19. One adult-sized enema contains 164 mmol of phosphate with the same molar ratio of 0.19. Exogenously provided phosphate eventually leaves the body dissolved in urine predominantly as H2PO4−since urine pH is customarily below 6.0. Hence, the net effect of normal quantities of dietary phosphate on acid-base balance is either neutral or acid buffering. But, in the case of phosphate intoxication, rate of absorption exceeds rate of excretion. Each 5 molecules of NaH2PO4added to the extracellular compartment at a pH of 7.4 will dissociate to 5 Na+, 4 H+, H2PO4−, and 4 HPO42−. This addition of H+requires neutralization by buffers such as HCO3−, leading to a metabolic acidosis with an enlarged anion gap. The severity of the acidosis depends on how much and how quickly NaH2PO4is absorbed, quantitative aspects of the renal phosphaturic response, and the preexisting buffering capacity of the individual. Once renal excretion of H2PO4−exceeds absorption, the acidosis and increased anion gap should begin to resolve. As an aside, the acidosis may assist in maintaining a safe level of ionized calcium in the face of low total calcium levels, so that correction of the acidosis with intravenous sodium bicarbonate should not be aggressively pursued and should be guided by measurements of ionized calcium in the blood.Risk factors for intoxication in adults include fluid restriction and an individual's inability to satisfy his or her need for fluids, perhaps due to confinement, extreme debility, or gastrointestinal disease. Aging also constitutes a risk factor. The more sedentary lifestyle, altered gut motility patterns, and low-fiber diets of the elderly contribute to the problem of constipation and, secondarily, to increased dependence on laxatives and enemas. There is also the age-related decline in renal function, which is frequently overlooked because the plasma creatinine level may remain within the range of normal despite a 50% or greater decrease in the glomerular filtration rate compared with that in younger individuals of the same sex. Moreover, mental obtundation often attends metabolic disorders in the elderly so that important historical information may be lacking when the patient first presents. Among these categories of patients, phosphate intoxication should be strongly considered in the presence of dehydration, altered mental status, and neuromuscular irritability when accompanied by hypernatremia, an increased anion gap, metabolic acidosis, and a prolonged QT interval on the electrocardiogram. This clinical picture shares many features with ethylene glycol intoxication. Hyperphosphatemia, if documented, should be quantitatively analyzed to determine how much of the anion gap it explains so that other processes are not overlooked. As with other disturbances of acid-base regulation, knowing the concentration of plasma albumin and its net cationic equivalency will enhance the differential diagnostic value of the anion gap.LThatteJROsterISingerJBourgoignieLMFishmanBARoosReview of the literature: severe hyperphosphatemia.Am J Med Sci.1995;310:167-174.SWasonTTillerCCunhaSevere hyperphosphatemia, hypocalcemia, acidosis, and shock in a 5-month-old child following the administration of an adult Fleet enema.Ann Emerg Med.1989;18:696-700.EDEhrenpreisJMWielandJCabralVEstevezDZaitmanKSecrestSymptomatic hypocalcemia, hypomagnesemia, and hyperphosphatemia secondary to Fleet's Phospho-Soda colonoscopy preparation in a patient with a jejunoileal bypass.Dig Dis Sci.1997;42:858-860.PKMoseleyWESegarFluid and serum electrolyte disturbances as a complication of enemas in Hirschsprung's disease.AJDC.1968;115:714-718.PLoughnanGCMullinsBrain damage following a hypertonic phosphate enema.AJDC.1977;131:1032.GCYuDBLeeClinical disorders of phosphate metabolism.West J Med.1987;147:569-576.MLevittCGessertLFinbergInorganic phosphate (laxative) poisoning resulting in tetany in an infant.J Pediatr.1973;82:479-481.MSSmithKWFeldmanCTFurukawaComa in an infant due to hypertonic sodium phosphate medication.J Pediatr.1973;82:481-482.AJFilhoMNLassmanSevere hyperphosphatemia induced by a phosphate containing laxative.Ann Pharmacother.1996;30:141-142.MSuttersCLGabouryWMBennettSevere hyperphosphatemia and hypocalcemia: a dilemma in patient management.J Am Soc Nephrol.1996;7:2056-2061.AFineJPattersonSevere hyperphosphatemia following phosphate administration for bowel preparation in patients with renal failure: two cases and a review of the literature.Am J Kidney Dis.1997;29:103-105.BKirschbaumRMCulpepperThe pK1of the carbonic acid-bicarbonate buffer system in hemodialyzed patients.Am J Med Sci.1989;298:237-242.RGutierrezJROsterFBSchlessingerGOPerezDGFedermanCAVaamondeSerum sulfate concentration and the anion gap in hemodialysis patients.ASAIO Trans.1991;37:92-96.RDZisperMDBischelDEAbramsHypocalcemic tetany due to sodium phosphate ingestion in acute renal failure.Nephron.1975;14:378-381.RFassSDoLJHixsonFatal hyperphosphatemia following Fleet Phospho-Soda in a patient with colonic ileus.Am J Gastroenterol.1993;88:929-932.RRMartinGRLisehoraMBraxtonPJBarciaFatal poisoning from a sodium phosphate enema.JAMA.1987;257:2190-2192.CPEscalanteMAWeiserKFinkelHyperphosphatemia associated with phosphorous containing laxatives in a patient with chronic renal insufficiency.South Med J.1997;90:240-242.JADiPalmaSEBuckleyBAWarnerRMCulpepperBiochemical effects of oral sodium phosphate.Dig Dis Sci.1996;41:749-753.CFCohanSCKadakiaASKadakiaSerum electrolyte, mineral, and pH changes after phosphate enema, water enema, and electrolyte lavage solution enema for flexible sigmoidoscopy.Gastrointest Endosc.1992;38:575-578.SMCohenSDWexnerSRBinderowProspective, randomized endoscopic-blinded trial comparing precolonoscopy bowel cleansing methods.Dis Colon Rectum.1994;37:689-696.THuynhSVannerWPattersonSafety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia.Am J Gastroenterol.1995;90:104-107.Accepted for publication September 2, 1997.Reprints: Barry Kirschbaum, MD, Medical College of Virginia, Box 980160, Richmond, VA 23298.

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 23, 1998

References