Safety first: the case against oral sodium phosphate
28 May 2014 (online)
Adequate bowel preparation is necessary for the successful completion of a high-quality colonoscopy. Good bowel preparation is associated with increased efficacy, decreased procedure times, increased adenoma detection rates, and fewer complications . Despite the importance of bowel cleanliness in the performance of colonoscopy, bowel preparation is poor in up to 24 % of examinations .
Several different bowel purgative regimens are available, with each regimen striving to optimize efficacy, patient tolerability, and safety. These include polyethylene glycol (PEG) electrolyte solutions (4 L), sulfate-free PEG, low-volume PEG (2 L), magnesium citrate with a stimulant laxative, and oral sodium phosphate (OSP).
PEG solutions are safe because they are iso-osmotic and pass through the bowel without any net absorption or secretion   ; however, the main drawbacks are unpalatability and immediate side effects (i. e. abdominal fullness, nausea, and bloating), which can affect patient tolerance . Sulfate-free and low-volume PEG formulations have demonstrated equal efficacy and improved patient tolerance compared with large-volume PEG . Currently, a split-dose regimen of 4 L PEG is the most widely recommended preparation for routine colonoscopy.
Both aqueous and tablet forms of OSP are as effective as PEG and better tolerated, resulting in improved patient compliance. In fact, five head-to-head meta-analyses concluded that OSP was superior to PEG. However, safety concerns have limited its widespread use . As a hyperosmotic substance, OSP draws intravascular water into the bowel lumen to cleanse the colon, thereby causing electrolyte shifts and potential serum electrolyte disturbances. OSP has also been associated with acute phosphate nephropathy leading to chronic kidney disease; all older patients, those with underlying renal insufficiency or active colitis or who take diuretics appear to be at increased risk . OSP can also induce hyperphosphatemia, hypocalcemia, hypermagnesemia, and in rare cases, hypernatremia, especially if it is not accompanied by adequate water intake . Because of the potential side effects of OSP, laboratory values should be monitored in high-risk patients, adding further to the inconvenience and cost of colonoscopy. In 2008, the United States Food and Drug Administration recommended against the use of the over-the-counter formulations of OSP for bowel preparation and also required that a warning be added to the product labels . As a result, the manufacturer of OSP, Salix (Raleigh, North Carolina, USA) voluntarily withdrew the product from the US market.
In this issue of Endoscopy, Choi et al. present the results of a retrospective study designed to evaluate whether there is an association between OSP preparation and acute renal failure (ARF) in patients taking it prior to colonoscopy . The study was conducted using the Korean Health Insurance Review and Assessment Service (HIRA), a national database with all claims, medications, and procedures for the entire population of 50 million people in South Korea. The authors used a case-crossover design, an infrequently used study design that helps to determine whether short-lived exposures (i. e. OSP) are associated with an outcome of interest (i. e. hospitalization for ARF). In the study, Choi et al. studied 1105 patients who developed ARF after colonoscopy, and who had a previous OSP prescription. For each patient, there was one hazard period immediately before the hospitalization for ARF and four control periods, which were matched according to time windows (1-, 2-, 4-, 8-, and 12-week windows). The authors found that there was a significant association between OSP use and hospitalization for ARF, as there was an increased risk of ARF in all time windows. The risk was greatest in the 1-week period (adjusted odds ratio [OR] 3.7). The risk decreased with longer time windows, with an adjusted OR of 2.0 in the 12-week time window. It can be concluded that with a smaller time window, there is a greater OSP effect and this further supports the association.
The authors should be commended for studying this important association between OSP and potential renal dysfunction. They found a fourfold increase in use of OSP in the hazard period compared with the control periods, suggesting that OSP when used before colonoscopy increases the risk of ARF. Using a case-crossover study design is useful after transient exposures and permits each case to serve as its own control, allowing for self-matching and thus eliminating the need to control for nontime-varying covariates. Furthermore, risk exposure can be calculated using many control windows for every one case window, and indeed the authors studied four control windows and performed sensitivity analyses varying the duration of the time windows. Another strength of this study is that HIRA includes data for the entire South Korean population and as such adds to the generalizability of the study. Finally, the authors had access to all prescription medication lists and could adjust for potential confounders affecting the development of ARF, such as the use of diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.
One weakness of the study is that the HIRA dataset was missing certain clinically relevant information, such as laboratory values, and as such, neither confirmation of the validity of the claims data nor grading of the severity of ARF could be performed. The authors relied on International Classification of Diseases 10th revision (ICD-10) claims codes to select patients with a hospitalization with a primary or secondary diagnosis of ARF; some patients could have been missed because the code for ARF may have been lower down on their problem list, raising the possibility of both selection and misclassification bias. Laboratory studies such as creatinine levels and other electrolytes would have increased the robustness of the study by helping to define the severity of ARF and the extent of any metabolic derangements. Interestingly, the study sample was older and fairly sick, with 59.5 % of the sample having three or more co-morbidities including hypertension (71.6 %), diabetes (40.9 %), and cancer (35.9 %). Of note, 13.3 % of the patients had chronic renal failure. Clearly, this was not representative of a healthy screening population. The study would have been strengthened by including the indication for colonoscopy and then performing a stratified analysis by indication (e. g. screening vs. diagnostic).
Despite these limitations, this study offers further evidence that despite being an effective and well-tolerated bowel preparation, OSP is likely to engender some risk for ARF. Taken into a broader clinical context, it seems that the use of OSP for bowel preparation would subject often asymptomatic patients presenting for routine colorectal cancer screening to unnecessary risk.
As increasing evidence mounts regarding the safety of OSP, more authoritative guidelines are excluding OSP from their recommendations for routine colonoscopy bowel preparation. Guidelines from societies such as the American Society for Gastrointestinal Endoscopy have already recommended against the routine use of OSP in the USA, where this medication has had a boxed warning since 2008 . In 2013, the European Society of Gastrointestinal Endoscopy similarly recommended against the use of OSP, except in cases of extreme circumstances when patients cannot tolerate alternative therapies .
Perhaps the setting in which this study stands to make the greatest impact then is in those countries where the use of OSP remains routine. For endoscopy units in these countries, a switch from OSP to a safer PEG-based regimen should be strongly considered. Patient safety during colonoscopy should be a top priority and this begins with the choice of the bowel purgative regimen.
- 1 Burke C, Church J. Enhancing the quality of colonoscopy: the importance of bowel purgatives. Gastrointest Endosc 2007; 66: 565-573
- 2 Lebwohl B, Kastrinos F, Glick M et al. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc 2011; 73: 1207-1214
- 3 Mamula P, Adler DG, Conway JD et al. Colonoscopy preparation: an ASGE technology status evaluation report. Gastrointest Endosc 2009; 69: 1201-1209
- 4 Connor A, Tolan D, Hughes S et al. Consensus guidelines for the safe prescription and administration of oral bowel cleansing agents. Gut 2012; 61: 1525-1532
- 5 A consensus document on bowel preparation before colonoscopy: prepared by a Task Force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006; 64: 154
- 6 Hassan C, Bretthauer M, Kaminski MF et al. Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2013; 45: 142-150
- 7 Cohen L, Tennyson C. Bowel preparation for colonoscopy: maximizing efficacy, minimizing risk. Gastroenterology and Endoscopy News 2011; 1-8
- 8 Schoenfeld PS, Burke CA, Cohen LB et al. Recent advances in optimal bowel preparation: Proceedings from a live roundtable at the 2011 DDW annual conference. Gastroenterol Hepatol 2011; 1-15
- 9 Choi NK, Lee J, Chang Y et al. Acute renal failure following oral sodium phosphate bowel preparation: a nationwide case-crossover study. Endoscopy 2014; 46: 465-470