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Therapeutic Apheresis and Dialysis 2014; 18(1):31–36 doi: 10.1111/1744-9987.12053 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Is Parenteral Phosphate Replacement in the Intensive Care Unit Safe? Banwari Agarwal,1 Agnieszka Walecka,1 Steve Shaw,1 and Andrew Davenport2 1
Intensive Care Unit, 2Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK
Abstract: Hypophosphatemia is well recognized in the intensive care setting, associated with refeeding and continuous forms of renal replacement therapy (CCRT). However, it is unclear as to when and how to administer intravenous phosphate supplementation in the general intensive care setting. There have been recent concerns regarding phosphate administration and development of acute kidney injury. We therefore audited our practice of parenteral phosphate administration. We prospectively audited parenteral phosphate administration (20 mmol) in 58 adult patients in a general intensive care unit in a University tertiary referral center. Fifty-eight patients were audited; mean age 57.2 ⫾ 2.0 years, 70.7% male. The median duration of the infusion was 310 min (228–417), and 50% of the patients were on CRRT. 63.8% of patients were hypophosphatemic (1.45 mmol/L). There was no correlation between the change in serum phosphate and the pre-infusion phosphate. Although there were no significant changes in serum urea, creatinine or other electrolytes, arterial ionized calcium fell from 1.15 ⫾ 0.01 to 1.13 ⫾ 0.01 mmol/L, P < 0.01. Although infusion of 20 mmol phosphate did not appear to adversely affect renal function and corrected hypophosphatemia in 67.7% of cases, we found that around 33% of patients who were given parenteral phosphate were not hypophosphatemic, and that the fall in ionized calcium raises the possibility of the formation of calcium-phosphate complexes and potential for soft tissue calcium deposition. Key Words: Calcium, Continuous renal replacement therapy, Hyperphosphatemia, Hypophosphatemia, Intensive care unit, Phosphate.
Phosphate plays a vital role in sustaining life, due to its key role in regulating cellular metabolism, as it is essential in forming high energy adenosine triphosphates.As such, hypophosphatemia can be life threatening, predisposing patients to cardiac arrhythmias (1) and hypotension (2), and in the intensive care setting respiratory muscle weakness with delayed respiratory weaning from ventilators (3). Although hypophosphatemia predominantly occurs in association with malnutrition and vitamin D deficiency, it can also occur due to renal phosphate losses. Normally renal phosphate reabsorption is under the control of phosphatonins (4), but can also
be affected by proximal renal tubular disorders (Fanconi and acquired Fanconi syndromes). In addition, renal phosphate wasting can occur secondary to drugs, particularly tenofovir and other reverse transcriptase inhibitors, and also acute liver failure following paracetamol (acetaminophen) poisoning (5). Hypophosphatemia can also occur following refeeding (6) or correction of severe metabolic acidosis, due to the intracellular movement of phosphate. Although phosphate retention occurs in patients with both acute and chronic kidney failure, phosphate can be removed during renal replacement therapy, more with hemodiafiltration than hemodialysis (HD) (7), but as phosphate clearance is predominantly timedependent (8), then relatively greater phosphate losses occur with continuous renal replacement therapy (CRRT) and increasing intensity of renal replacement therapy (9). Therefore hypophosphatemia is commonly encountered in intensive care patients treated repeatedly by CRRT.
Received September 2012; revised January 2013. Address correspondence and reprint requests to Dr Andrew Davenport, Centre for Nephrology, Royal Free Hospital, University College London Medical School, London NW3 2QG, UK. Email: [email protected] Conflicts of interest: No author has any conflict of interest.
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Whereas there are guidelines as to when to replace phosphate in patients at risk of the refeeding syndrome, including anorexia nervosa, cancer and alcoholism, to maintain the serum phosphate >0.5 mmol/L (6), the situation is less clear for the acutely ill patient admitted to the intensive care unit, as such a number of different regimes have been reported (10,11). However there are reports of phosphate infusions causing acute kidney failure dating back to the early 1990s (12), and more recently phosphate absorption from phosphate enemas used for bowel preparation have also been recorded to cause acute kidney injury due to the precipitation of calcium and phosphate crystals within the kidney (13). We therefore prospectively audited our intensive care practice of parenteral phosphate administration to determine the threshold serum level when phosphate supplementation is considered and. whether there was any measurable change in renal function, or development of significant hyperphosphatemia or hypocalcemia.
PATIENTS AND METHODS Intravenous phosphate replacement (Phosphate Polyfusor; Fresenius Kabi, Basingstoke, UK) 200 mL containing 20 mol PO43-, 3.8 mmol potassium and 32.4 mmol sodium) was prescribed by the supervising intensive care clinicians. Serum was analyzed by standard multi-channel biochemical analyzer (Roche Integra, Roche diagnostics, Lewes, UK), using the bromcresol green method for albumin determination, and arterial blood gases by near patient testing (blood gas analyzer, Stat Profile Critical Care Xpress, Nova Biomedical, Deeside, UK) (14). Total serum calcium was corrected for serum albumin using the equation: adjusted calcium = total calcium +0.02 (40-albumin) (15). Fifty percent of patients were receiving continuous veno-venous hemofiltration with post-dilutional fluid replacement (16) using the Aquarius hemofiltration machine (Baxter Healthcare, Compton, Berkshire, UK), with a standard blood flow 150 mL/min, with a median cycle volume of 2 L/h (2.0–2.0), using lactate based replacement solutions (Monosol, Baxter Healthcare, Compton, Berkshire, UK; sodium 140 mmol/L, magnesium 0.75 mmol/L, calcium 1.75 mmol/L, chloride 115 mmol/L, lactate 30 mmol/L and glucose 5.55 mmol/L) (17). Ethical approval was granted by the local ethics committee as part of an audit and clinical service development.
Ther Apher Dial, Vol. 18, No. 1, 2014
Statistical analysis Student’s t-test and Mann–Whitney U-test were used to analyze parametric and nonparametric data, in addition analysis of variance (anova) with post hoc analysis, Tukey and Dunnets’ corrections as appropriate, and both c2 analyses with Yates’s correction and Pearson’s correlation analysis were also used (Prism 5.0, Graph Pad, San Diego, CA, USA). Data are presented as mean ⫾ standard error of the mean (SEM), or median (inter-quartile range) of percentage. Statistical significance was taken at 0.05 or less. RESULTS Fifty-eight adult patients were monitored before and after a single intravenous Phosphate Polyfusor infusion. The mean age was 57.2 ⫾ 2.0 years, 70.7% were male and 70.7% were Caucasoid. Thirty-eight percent of admissions were following surgery (19% intra-abdominal, 8.6% post-liver transplant and 7% neurosurgery), and 62% medical admissions, most commonly due to sepsis 38% (21% respiratory infections). Including the patients with liver transplantation, 19% of patients had liver disease, and 8.6% chronic kidney disease, including two renal transplant patients admitted with sepsis. Twenty-one percent had a history of diabetes mellitus, and if required, received an insulin infusion to maintain serum glucose levels 1.05 mmol/L), but only one patient had a low magnesium ( 0.05. The fall in ionized calcium did not differ between groups, residual renal function group by 0.03 ⫾ 0.016 mmol/L, and CRRT group by 0.018 ⫾ 0.007 mmol/L, P > 0.05. There were no differences in chloride, but glucose was higher post-phosphate infusion in the CRRT group. We compared serum urea and creatinine results from the day prior to the phosphate infusion to those
FIG. 1. There was no relationship between serum phosphate (mmol/L) prior to an infusion of 20 mmol phosphate and the postinfusion serum phosphate concentration. (r = 0.066, P = 0.63)
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FIG. 2. Relationship between serum phosphate (mmol/L) prior to 20 mmol phosphate infusion and change in serum phosphate (mmol/) post-infusion.
before and for 2 days after infusion and found no differences for the group with residual renal function (Table 3). There was no statistically significant difference in the serum phosphate pre-infusion between those eating hospital food compared to those supported with enteral or total parenteral nutrition (0.84 ⫾ 0.02 vs. 0.76 ⫾ 0.03 vs. 0.86 ⫾ 0.04 mmol/L respectively), or post-infusion (1.36 ⫾ 0.17 vs. 1.08 ⫾ 0.04 vs. 1.06 ⫾ 0.05 mmol/L respectively). DISCUSSION Although hypophosphatemia can be life threatening, different centers have different thresholds as to
when and how phosphate should be replaced. Hypophosphatemia has been associated with rhabdomyolysis, red cell hemolysis, leukocyte dysfunction, and respiratory muscle weakness. Our study was not designed to investigate the effect of hypophosphatemia but to determine whether there were any adverse effects of administering intravenous phosphate supplementation. In theory, 10 mmol of phosphate would be expected to increase the extracellular phosphate concentration by 1.0 mmol in a 70 kg person, assuming no losses and no intracellular phosphate translocation. Due to the recent reports of phosphate induced acute kidney injury (12) associated with calcium phosphate crystal formation (13) we audited our standard policy of administering 20 mmol of parenteral phosphate. We found that only 64% of patients given intravenous phosphate supplementation were actually hypophosphatemic at the time of phosphate administration. As expected serum phosphate increased, and there was a statistically significant correlation between increase in phosphate and the post-infusion serum phosphate, but there was no correlation between the pre- and post-infusion phosphate concentrations, and as such, serum phosphate does not appear to be predictive of the response to a phosphate infusion. Studies from dialysis patients suggest that phosphate kinetics are complex and changes in
TABLE 2. Comparison of Phosphate Polyfusor infusion administered to patients with residual renal function (RRF) and those treated by continuous renal replacement therapy (CRRT)
Serum phosphate Serum calcium Serum magnesium Art ionized calcium Art ionized magnesium Art chloride Art glucose
RRF
RRF
CRRT
CRRT
Pre
Post
Pre
Post
0.82 ⫾ 0.02 2.21 ⫾ 0.04 0.93 ⫾ 0.03 1.13 ⫾ 0.01+ 0.68 ⫾ 0.04
1.13 ⫾ 0.05*** 2.19 ⫾ 0.04 1.0 ⫾ 0.03 1.10 ⫾ 0.02*+ 0.66 ⫾ 0.02
0.77 ⫾ 0.03 2.37 ⫾ 0.04 0.98 ⫾ 0.03 1.18 ⫾ 0.02 0.67 ⫾ 0.02
1.0 ⫾ 0.5** 2.3 ⫾ 0.04* 0.99 ⫾ 0.1 1.16 ⫾ 0.02* 0.69 ⫾ 0.02
109.9 ⫾ 0.7 7.3 ⫾ 0.4
106.0 ⫾ 3.6 6.8 ⫾ 0.3+
109.2 ⫾ 0.6 7.6 ⫾ 0.5
109.0 ⫾ 0.6 8.1 ⫾ 0.4
*P < 0.05, **P < 0.01, *** P < 0.001 versus Pre. +P < 0.05, ++P < 0.01, +++P < 0.001 versus CRRT. Changes in serum electrolytes and arterial blood gases (Art) pre (Pre) and following (Post) an infusion of phosphate. Serum calcium corrected for serum albumin All values in mmol/L unless otherwise specified.
TABLE 3. Serum urea (mmol/L) and creatinine (umol/L) in the residual renal function group prior to and following Phosphate Polyfusor infusion Serum Urea Creatinine
24 h Pre-infusion
Pre-infusion
24 h later
48 h later
6.8 ⫾ 1.1 46 (37–75)
6.7 ⫾ 1.1 47 (42–67)
7.4 ⫾ 1.2 49 (42–72)
8.0 ⫾ 1.3 49 (43–77)
Values described as mean ⫾ standard error of the mean (SEM) or median (interquartile range [IQR]); no significant differences between values observed.
Ther Apher Dial, Vol. 18, No. 1, 2014
© 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Parenteral Phosphate Supplementation serum phosphate behave as if distributed in a multicompartmental model (18). The change in phosphate was similar for both those with native renal function and those treated by CRRT, and although there appeared to be a weak correlation between infusion time and change in serum phosphate, this only accounted for less than 10% of the variation in the change in serum phosphate. Ionized calcium concentrations fell following the phosphate infusion. Although the actual fall was small, it was statistically significant, suggesting an increase in calcium-phosphate and potentially the possibility of calcium-phosphate soft tissue deposition (19,20). However, in the group with residual renal function there was no overt change in serum urea or creatinine. Previous groups have reported no change in serum creatinine when giving 9 mmol over 12 h (10), or giving lower doses ranging between 0.16–0.64 mmol/kg according to the severity of hypophosphatemia (11), whereas we were administering 20 mmol phosphate over a median infusion time of 310 min. There is one observational study that reported no change in total serum calcium when 50 mmol phosphate was infused over 24 h (21). Although we also did not observe a difference in total serum calcium, correction of serum calcium in critically ill patients for albumin concentrations may be prone to error (22), and when we measured ionized calcium, the ionized calcium concentrations did fall significantly post-phosphate infusion. Half our patients were treated by CRRT using phosphate-free replacement fluids. This group, possibly due to phosphate losses associated with CRRT had slightly lower pre-infusion serum phosphates, but the increase in phosphate was not different whether patients received CRRT or not, although the infusion rate was slightly, but not statistically faster for the CRRT group. Prior to the phosphate infusion only one patient in the residual renal function group had an elevated ionized calcium compared to 5 (17.2%) in the CRRT group, and conversely 12 (41.4%) had low ionized calcium compared to seven (24.1%) in the CRRT group, due to relatively high calcium concentration of 1.75 mmol/L used in the CRRT replacement fluid. Following the phosphate infusion 17 patients (58.6%) in the residual renal function group had a low ionized calcium, whereas there was no change in the number of patients with low ionized calcium in CRRT group, (c2 = 5.76, P = 0.016). Our audit of clinical practice noted that around 33% of patients given parenteral phosphate were not hypophosphatemic at the time of starting the infusion, and this does question whether the concerns of © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
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preventing hypophosphatemia in the intensive care setting have superseded treatment of hypophosphatemia. Infusing 20 mmol of phosphate over a median time of just over 5 h corrected hypophosphatemia in the majority of patients, slightly more in the residual renal function group, 77.8% compared to 61.1% for the CRRT group. This is probably due to ongoing phosphate losses with CRRT. However, administering a standard 20 mmol phosphate infusion did not correct serum phosphate into the normal serum reference range in 12 patients. These patients tended to have a lower serum phosphate preinfusion, and probably had a greater phosphate deficit than those patients who normalized serum phosphate post-infusion.
CONCLUSION Although total corrected serum calcium did not change, ionized calcium fell, particularly in the residual renal function group, raising the possibility of calcium-phosphate deposition. As such, a more cautious approach to phosphate supplementation should be considered in the general intensive care setting, both in terms of when to prescribe parenteral phosphate, and also reducing the rate of phosphate administration. Acknowledgments: We wish to thank the Royal Free Intensive care nursing staff for their efforts. The data contained in this paper have not been previously published in part or whole or in abstract form.
REFERENCES 1. Venditti FJ, Marotta C, Panezai FR, Oldewurtel HA, Regan TJ. Hypophosphatemia and cardiac arrhythmias. Miner Electrolyte Metab 1987;13:19–25. 2. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphataemia on myocardial performance in man. N Engl J Med 1977;297:901–3. 3. Newman JH, Neff TA, Ziporin P. Acute respiratory failure associated with hypophosphataemia. N Engl J Med 1977;296:1101–3. 4. Hall AM, Edwards SG, Lapsley M et al. Subclinical tubular injury in HIV-infected individuals on antiretroviral therapy: a cross-sectional analysis. Am J Kidney Dis 2009;54:1034–42. 5. Davenport A, Will EJ. Hypophosphataemia in acute liver failure. Br Med J 1988;296:131. 6. Terlevich A, Hearing SD, Woltersdorf WW et al. Refeeding syndrome: effective and safe treatment with Phosphates Polyfusor. Aliment Pharmacol Ther 2003;17:1325–9. 7. Oates T, Pinney JH, Davenport A. Haemodiafiltration versus high-flux haemodialysis: effects on phosphate control and erythropoietin response. Am J Nephrol 2011;33:70–5. 8. Davenport A, Gardner C, Delaney M, Pan Thames Renal Audit Group. Do differences in dialysis prescription impact on KDOQI bone mineral targets? The Pan Thames Renal Audit. Blood Purif 2010;30:111–17.
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9. Davenport A. Magnesium and phosphorus. Lancet 1988;352: 9138. 10. Vannatta JB, Whang R, Papper S. Efficacy of intravenous phosphorus therapy in the severely hypophosphatemic patient. Arch Intern Med 1981;141:885–7. 11. Clark CL, Sacks GS, Dickerson RN, Kudsk KA, Brown RO. Treatment of hypophosphataemia in patients receiving specialized nutrition support using a graduated dosing scheme: results from a prospective clinical trial. Crit Care Med 1995;23:1504–11. 12. Young IS, Neely RDG, Lavery GG. Treatment of hypophosphataemia. Lancet 1993;341:374. 13. Markowitz GS, Perazella MA. Acute phosphate nephropathy. Kidney Int 2009;76:1027–34. 14. Sava L, Pillai S, More U, Sontakke A. Serum calcium measurement: total versus free (ionized) calcium. Indian J Clin Biochem 2005;20:158–61. 15. National Kidney Foundation. KDOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease. Am J Kidney Dis 2003;42(Suppl 3):S1–201. 16. Agarwal B, Shaw S, Hari MS, Burroughs AK, Davenport A. Continuous renal replacement therapy (CRRT) in patients
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17.
18. 19. 20. 21. 22.
with liver disease: is circuit life different? J Hepatol 2009;51: 504–9. Agarwal B, Kovari F, Saha R, Shaw S, Davenport A. Do bicarbonate-based solutions for continuous renal replacement therapy offer better control of metabolic acidosis than lactatecontaining fluids? Nephron Clin Pract 2011;118:c392–398. Spalding EM, Chamney PW, Farrington K. Phosphate kinetics during hemodialysis: evidence for biphasic regulation. Kidney Int 2002;61:655–67. Sandin K, Hegbrant J, Kloo L. A theoretical investigation of the supersaturation of basic calcium phosphate in serum of dialysis patients. J Appl Biomater Biomech 2006;4:80–6. Ketteler M, Rothe H, Krüger T, Biggar PH, Schlieper G. Mechanisms and treatment of extraosseous calcification in chronic kidney disease. Nat Rev Nephrol 2011;19:509–16. Perreault MM, Ostrop NJ, Tierney MG. Efficacy and safety of intravenous phosphate replacement in critically ill patients. Crit Care 1997;31:683–8. Sharp CR, Kerl ME, Mann FA. A comparison of total calcium, corrected calcium, and ionized calcium concentrations as indicators of calcium homeostasis among hypoalbuminaemic dogs requiring intensive care. J Vet Emerg Crit Care 2009;19:571–8.
© 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Therapeutic Apheresis and Dialysis 2014; 18(1):31–36 doi: 10.1111/1744-9987.12053 © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Is Parenteral Phosphate Replacement in the Intensive Care Unit Safe? Banwari Agarwal,1 Agnieszka Walecka,1 Steve Shaw,1 and Andrew Davenport2 1
Intensive Care Unit, 2Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK
Abstract: Hypophosphatemia is well recognized in the intensive care setting, associated with refeeding and continuous forms of renal replacement therapy (CCRT). However, it is unclear as to when and how to administer intravenous phosphate supplementation in the general intensive care setting. There have been recent concerns regarding phosphate administration and development of acute kidney injury. We therefore audited our practice of parenteral phosphate administration. We prospectively audited parenteral phosphate administration (20 mmol) in 58 adult patients in a general intensive care unit in a University tertiary referral center. Fifty-eight patients were audited; mean age 57.2 ⫾ 2.0 years, 70.7% male. The median duration of the infusion was 310 min (228–417), and 50% of the patients were on CRRT. 63.8% of patients were hypophosphatemic (1.45 mmol/L). There was no correlation between the change in serum phosphate and the pre-infusion phosphate. Although there were no significant changes in serum urea, creatinine or other electrolytes, arterial ionized calcium fell from 1.15 ⫾ 0.01 to 1.13 ⫾ 0.01 mmol/L, P < 0.01. Although infusion of 20 mmol phosphate did not appear to adversely affect renal function and corrected hypophosphatemia in 67.7% of cases, we found that around 33% of patients who were given parenteral phosphate were not hypophosphatemic, and that the fall in ionized calcium raises the possibility of the formation of calcium-phosphate complexes and potential for soft tissue calcium deposition. Key Words: Calcium, Continuous renal replacement therapy, Hyperphosphatemia, Hypophosphatemia, Intensive care unit, Phosphate.
Phosphate plays a vital role in sustaining life, due to its key role in regulating cellular metabolism, as it is essential in forming high energy adenosine triphosphates.As such, hypophosphatemia can be life threatening, predisposing patients to cardiac arrhythmias (1) and hypotension (2), and in the intensive care setting respiratory muscle weakness with delayed respiratory weaning from ventilators (3). Although hypophosphatemia predominantly occurs in association with malnutrition and vitamin D deficiency, it can also occur due to renal phosphate losses. Normally renal phosphate reabsorption is under the control of phosphatonins (4), but can also
be affected by proximal renal tubular disorders (Fanconi and acquired Fanconi syndromes). In addition, renal phosphate wasting can occur secondary to drugs, particularly tenofovir and other reverse transcriptase inhibitors, and also acute liver failure following paracetamol (acetaminophen) poisoning (5). Hypophosphatemia can also occur following refeeding (6) or correction of severe metabolic acidosis, due to the intracellular movement of phosphate. Although phosphate retention occurs in patients with both acute and chronic kidney failure, phosphate can be removed during renal replacement therapy, more with hemodiafiltration than hemodialysis (HD) (7), but as phosphate clearance is predominantly timedependent (8), then relatively greater phosphate losses occur with continuous renal replacement therapy (CRRT) and increasing intensity of renal replacement therapy (9). Therefore hypophosphatemia is commonly encountered in intensive care patients treated repeatedly by CRRT.
Received September 2012; revised January 2013. Address correspondence and reprint requests to Dr Andrew Davenport, Centre for Nephrology, Royal Free Hospital, University College London Medical School, London NW3 2QG, UK. Email: [email protected] Conflicts of interest: No author has any conflict of interest.
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Whereas there are guidelines as to when to replace phosphate in patients at risk of the refeeding syndrome, including anorexia nervosa, cancer and alcoholism, to maintain the serum phosphate >0.5 mmol/L (6), the situation is less clear for the acutely ill patient admitted to the intensive care unit, as such a number of different regimes have been reported (10,11). However there are reports of phosphate infusions causing acute kidney failure dating back to the early 1990s (12), and more recently phosphate absorption from phosphate enemas used for bowel preparation have also been recorded to cause acute kidney injury due to the precipitation of calcium and phosphate crystals within the kidney (13). We therefore prospectively audited our intensive care practice of parenteral phosphate administration to determine the threshold serum level when phosphate supplementation is considered and. whether there was any measurable change in renal function, or development of significant hyperphosphatemia or hypocalcemia.
PATIENTS AND METHODS Intravenous phosphate replacement (Phosphate Polyfusor; Fresenius Kabi, Basingstoke, UK) 200 mL containing 20 mol PO43-, 3.8 mmol potassium and 32.4 mmol sodium) was prescribed by the supervising intensive care clinicians. Serum was analyzed by standard multi-channel biochemical analyzer (Roche Integra, Roche diagnostics, Lewes, UK), using the bromcresol green method for albumin determination, and arterial blood gases by near patient testing (blood gas analyzer, Stat Profile Critical Care Xpress, Nova Biomedical, Deeside, UK) (14). Total serum calcium was corrected for serum albumin using the equation: adjusted calcium = total calcium +0.02 (40-albumin) (15). Fifty percent of patients were receiving continuous veno-venous hemofiltration with post-dilutional fluid replacement (16) using the Aquarius hemofiltration machine (Baxter Healthcare, Compton, Berkshire, UK), with a standard blood flow 150 mL/min, with a median cycle volume of 2 L/h (2.0–2.0), using lactate based replacement solutions (Monosol, Baxter Healthcare, Compton, Berkshire, UK; sodium 140 mmol/L, magnesium 0.75 mmol/L, calcium 1.75 mmol/L, chloride 115 mmol/L, lactate 30 mmol/L and glucose 5.55 mmol/L) (17). Ethical approval was granted by the local ethics committee as part of an audit and clinical service development.
Ther Apher Dial, Vol. 18, No. 1, 2014
Statistical analysis Student’s t-test and Mann–Whitney U-test were used to analyze parametric and nonparametric data, in addition analysis of variance (anova) with post hoc analysis, Tukey and Dunnets’ corrections as appropriate, and both c2 analyses with Yates’s correction and Pearson’s correlation analysis were also used (Prism 5.0, Graph Pad, San Diego, CA, USA). Data are presented as mean ⫾ standard error of the mean (SEM), or median (inter-quartile range) of percentage. Statistical significance was taken at 0.05 or less. RESULTS Fifty-eight adult patients were monitored before and after a single intravenous Phosphate Polyfusor infusion. The mean age was 57.2 ⫾ 2.0 years, 70.7% were male and 70.7% were Caucasoid. Thirty-eight percent of admissions were following surgery (19% intra-abdominal, 8.6% post-liver transplant and 7% neurosurgery), and 62% medical admissions, most commonly due to sepsis 38% (21% respiratory infections). Including the patients with liver transplantation, 19% of patients had liver disease, and 8.6% chronic kidney disease, including two renal transplant patients admitted with sepsis. Twenty-one percent had a history of diabetes mellitus, and if required, received an insulin infusion to maintain serum glucose levels 1.05 mmol/L), but only one patient had a low magnesium ( 0.05. The fall in ionized calcium did not differ between groups, residual renal function group by 0.03 ⫾ 0.016 mmol/L, and CRRT group by 0.018 ⫾ 0.007 mmol/L, P > 0.05. There were no differences in chloride, but glucose was higher post-phosphate infusion in the CRRT group. We compared serum urea and creatinine results from the day prior to the phosphate infusion to those
FIG. 1. There was no relationship between serum phosphate (mmol/L) prior to an infusion of 20 mmol phosphate and the postinfusion serum phosphate concentration. (r = 0.066, P = 0.63)
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FIG. 2. Relationship between serum phosphate (mmol/L) prior to 20 mmol phosphate infusion and change in serum phosphate (mmol/) post-infusion.
before and for 2 days after infusion and found no differences for the group with residual renal function (Table 3). There was no statistically significant difference in the serum phosphate pre-infusion between those eating hospital food compared to those supported with enteral or total parenteral nutrition (0.84 ⫾ 0.02 vs. 0.76 ⫾ 0.03 vs. 0.86 ⫾ 0.04 mmol/L respectively), or post-infusion (1.36 ⫾ 0.17 vs. 1.08 ⫾ 0.04 vs. 1.06 ⫾ 0.05 mmol/L respectively). DISCUSSION Although hypophosphatemia can be life threatening, different centers have different thresholds as to
when and how phosphate should be replaced. Hypophosphatemia has been associated with rhabdomyolysis, red cell hemolysis, leukocyte dysfunction, and respiratory muscle weakness. Our study was not designed to investigate the effect of hypophosphatemia but to determine whether there were any adverse effects of administering intravenous phosphate supplementation. In theory, 10 mmol of phosphate would be expected to increase the extracellular phosphate concentration by 1.0 mmol in a 70 kg person, assuming no losses and no intracellular phosphate translocation. Due to the recent reports of phosphate induced acute kidney injury (12) associated with calcium phosphate crystal formation (13) we audited our standard policy of administering 20 mmol of parenteral phosphate. We found that only 64% of patients given intravenous phosphate supplementation were actually hypophosphatemic at the time of phosphate administration. As expected serum phosphate increased, and there was a statistically significant correlation between increase in phosphate and the post-infusion serum phosphate, but there was no correlation between the pre- and post-infusion phosphate concentrations, and as such, serum phosphate does not appear to be predictive of the response to a phosphate infusion. Studies from dialysis patients suggest that phosphate kinetics are complex and changes in
TABLE 2. Comparison of Phosphate Polyfusor infusion administered to patients with residual renal function (RRF) and those treated by continuous renal replacement therapy (CRRT)
Serum phosphate Serum calcium Serum magnesium Art ionized calcium Art ionized magnesium Art chloride Art glucose
RRF
RRF
CRRT
CRRT
Pre
Post
Pre
Post
0.82 ⫾ 0.02 2.21 ⫾ 0.04 0.93 ⫾ 0.03 1.13 ⫾ 0.01+ 0.68 ⫾ 0.04
1.13 ⫾ 0.05*** 2.19 ⫾ 0.04 1.0 ⫾ 0.03 1.10 ⫾ 0.02*+ 0.66 ⫾ 0.02
0.77 ⫾ 0.03 2.37 ⫾ 0.04 0.98 ⫾ 0.03 1.18 ⫾ 0.02 0.67 ⫾ 0.02
1.0 ⫾ 0.5** 2.3 ⫾ 0.04* 0.99 ⫾ 0.1 1.16 ⫾ 0.02* 0.69 ⫾ 0.02
109.9 ⫾ 0.7 7.3 ⫾ 0.4
106.0 ⫾ 3.6 6.8 ⫾ 0.3+
109.2 ⫾ 0.6 7.6 ⫾ 0.5
109.0 ⫾ 0.6 8.1 ⫾ 0.4
*P < 0.05, **P < 0.01, *** P < 0.001 versus Pre. +P < 0.05, ++P < 0.01, +++P < 0.001 versus CRRT. Changes in serum electrolytes and arterial blood gases (Art) pre (Pre) and following (Post) an infusion of phosphate. Serum calcium corrected for serum albumin All values in mmol/L unless otherwise specified.
TABLE 3. Serum urea (mmol/L) and creatinine (umol/L) in the residual renal function group prior to and following Phosphate Polyfusor infusion Serum Urea Creatinine
24 h Pre-infusion
Pre-infusion
24 h later
48 h later
6.8 ⫾ 1.1 46 (37–75)
6.7 ⫾ 1.1 47 (42–67)
7.4 ⫾ 1.2 49 (42–72)
8.0 ⫾ 1.3 49 (43–77)
Values described as mean ⫾ standard error of the mean (SEM) or median (interquartile range [IQR]); no significant differences between values observed.
Ther Apher Dial, Vol. 18, No. 1, 2014
© 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
Parenteral Phosphate Supplementation serum phosphate behave as if distributed in a multicompartmental model (18). The change in phosphate was similar for both those with native renal function and those treated by CRRT, and although there appeared to be a weak correlation between infusion time and change in serum phosphate, this only accounted for less than 10% of the variation in the change in serum phosphate. Ionized calcium concentrations fell following the phosphate infusion. Although the actual fall was small, it was statistically significant, suggesting an increase in calcium-phosphate and potentially the possibility of calcium-phosphate soft tissue deposition (19,20). However, in the group with residual renal function there was no overt change in serum urea or creatinine. Previous groups have reported no change in serum creatinine when giving 9 mmol over 12 h (10), or giving lower doses ranging between 0.16–0.64 mmol/kg according to the severity of hypophosphatemia (11), whereas we were administering 20 mmol phosphate over a median infusion time of 310 min. There is one observational study that reported no change in total serum calcium when 50 mmol phosphate was infused over 24 h (21). Although we also did not observe a difference in total serum calcium, correction of serum calcium in critically ill patients for albumin concentrations may be prone to error (22), and when we measured ionized calcium, the ionized calcium concentrations did fall significantly post-phosphate infusion. Half our patients were treated by CRRT using phosphate-free replacement fluids. This group, possibly due to phosphate losses associated with CRRT had slightly lower pre-infusion serum phosphates, but the increase in phosphate was not different whether patients received CRRT or not, although the infusion rate was slightly, but not statistically faster for the CRRT group. Prior to the phosphate infusion only one patient in the residual renal function group had an elevated ionized calcium compared to 5 (17.2%) in the CRRT group, and conversely 12 (41.4%) had low ionized calcium compared to seven (24.1%) in the CRRT group, due to relatively high calcium concentration of 1.75 mmol/L used in the CRRT replacement fluid. Following the phosphate infusion 17 patients (58.6%) in the residual renal function group had a low ionized calcium, whereas there was no change in the number of patients with low ionized calcium in CRRT group, (c2 = 5.76, P = 0.016). Our audit of clinical practice noted that around 33% of patients given parenteral phosphate were not hypophosphatemic at the time of starting the infusion, and this does question whether the concerns of © 2013 The Authors Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis
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preventing hypophosphatemia in the intensive care setting have superseded treatment of hypophosphatemia. Infusing 20 mmol of phosphate over a median time of just over 5 h corrected hypophosphatemia in the majority of patients, slightly more in the residual renal function group, 77.8% compared to 61.1% for the CRRT group. This is probably due to ongoing phosphate losses with CRRT. However, administering a standard 20 mmol phosphate infusion did not correct serum phosphate into the normal serum reference range in 12 patients. These patients tended to have a lower serum phosphate preinfusion, and probably had a greater phosphate deficit than those patients who normalized serum phosphate post-infusion.
CONCLUSION Although total corrected serum calcium did not change, ionized calcium fell, particularly in the residual renal function group, raising the possibility of calcium-phosphate deposition. As such, a more cautious approach to phosphate supplementation should be considered in the general intensive care setting, both in terms of when to prescribe parenteral phosphate, and also reducing the rate of phosphate administration. Acknowledgments: We wish to thank the Royal Free Intensive care nursing staff for their efforts. The data contained in this paper have not been previously published in part or whole or in abstract form.
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