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Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?
e-SPEN Journal xxx (2014) e1ee5
Contents lists available at ScienceDirect
e-SPEN Journal journal homepage: http://www.elsevier.com/locate/clnu
Original article
Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help? N.D. Appleton a, W.D. Neithercut b, C. Edwards c, M. Duncan c, C.J. Walsh a, * a
Department of Surgery, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK Department of Clinical Biochemistry, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK c Nutrition Support Team, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK b
a r t i c l e i n f o
s u m m a r y
Article history: Received 20 November 2013 Accepted 8 April 2014
Background and aims: Patients with high output stomas and enterocutaneous fistulae are prone to fluid and electrolyte abnormalities, particularly dehydration, hyponatraemia and hypomagnesaemia. As well as medication to prolong transit time and aid absorption, proton pump inhibitors (PPIs) have been advocated to reduce gastrointestinal losses. Recent, reports in other clinical areas have linked long-term PPI use to hypomagnesaemia. We wondered whether PPIs used to reduce stoma losses may paradoxically be aggravating hypomagnesaemia in these patients? Our aim was to audit the effect of stopping PPIs, used solely for reduction of gastrointestinal losses, in a cohort of patients with high stoma losses. Methods: Nine patients (8 high output stomas: 1 enterocutaneous fistula) were regularly attending a dedicated clinic for supervision and management of fluid and electrolytes during October 2012. Stoma outputs, blood and urine results were recorded before and after stopping their PPI. Results: There was a significant reduction in average daily stoma outputs when the PPI was stopped. Before PPI cessation, mean daily stoma volume was 1550 mls (SE:147.67) compared to mean of 1344 mls after (SE:130.29, t(8) ¼ 2.11, p < 0.05). Additionally, there was a significant increase in both urinary sodium (mean on PPI ¼ 32.6 mmol/L, SE:22.7, off PPI ¼ 63.8, SE:6.65, t(8) ¼ 4.22, p ¼ 0.003) and urinary potassium (mean on PPI ¼ 61.9 mmol/L, SE:7.21, off PPI ¼ 77.8 mmol/L, t(8) ¼ 2.33, p ¼ 0.05). Mean plasma magnesium across the group was not significantly affected by stopping the PPI, yet some individuals had marked improvements (mean before ¼ 0.59 mmol/L, SE:0.40 compared to mean after ¼ 0.64 mmol/L, SE:0.40, t(8) ¼ 1.42, p ¼ 0.226). Conclusion: Our findings do not support current thinking with regard to PPIs reducing enteric losses in patients with high stoma losses. The PPI effect on hypomagnesaemia in this cohort is uncertain but cessation should be considered in resistant hypomagnesaemia. Ó 2014 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Hypomagnesaemia Proton pump inhibitors High output stoma Enterocutaneous fistula
1. Introduction Optimal fluid and electrolyte balance in surgical patients continues to be challenging [1,2], and this is particularly the case for patients with high output stomas or enterocutaneous fistulae. Successful management of such patients involves meticulous attention to fluid balance. Stoma output can usually be controlled by manipulating oral intake, including the restricted intake of hypotonic fluids, and by the use of pharmacological ‘stoppers’ e
* Corresponding author. E-mail address: [email protected] (C.J. Walsh).
loperamide and codeine, as first line drugs. Less commonly, a somatostatin analogue such as octreotide can be used. Proton pump inhibitors (PPIs) have previously been advocated for use in patients with high output stomas or enterocutaneous fistulas to reduce output [3e5] and as a result are commonly used for this purpose in these patients. As well as losing water and sodium, these patients are particularly prone to hypomagnesaemia due to rapid losses of magnesium rich fluid from their proximal small bowel. Magnesium replacement is very commonly required in this patient cohort. Usually this can be achieved with oral supplements of magnesium oxide, gluconate or aspartate preparations, but not infrequently additional intravenous magnesium replacement is needed.
http://dx.doi.org/10.1016/j.clnme.2014.04.002 2212-8263/Ó 2014 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
e2
N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5
Over the past 5 years, there have been an increasing number of reports in the literature in other clinical settings that link the long term use of PPIs to hypomagnesaemia [6e8]. In view of this, we questioned whether PPIs used to reduce stoma losses may paradoxically be aggravating hypomagnesaemia in these patients? We present an internal audit on the effect of PPI cessation, in a group of patients with high output stomas and enterocutaneous fistulas taking PPIs solely as part of their fluid balance regime. Already at risk of hypomagnesaemia from gastrointestinal losses, their PPI therapy was temporarily withdrawn to observe differences including whether it was having a contributory effect on plasma magnesium levels. 2. Materials and methods At our hospital, patients with high output stomas or enterocutaneous fistulas who are surgically stable, sepsis free and meeting their nutritional needs enterally, are managed on an outpatient basis. They are asked to attend a dedicated weekly clinic which is led by the Nutrition Support Team composed of nutrition nurse specialists, a pharmacist, a dietician, a consultant clinical biochemist, and a consultant colorectal surgeon. Access to stoma care and tissue viability is available if required. All individual cases are discussed as part of a weekly nutrition multi-disciplinary team meeting. The primary aim of the clinic is to prevent complications associated with high output stomas or enterocutaneous fistulae, particularly acute renal injury and fluid and electrolyte abnormalities. The patients are monitored with regular assessment of fluid balance, blood and urine electrolytes, medication review and anthropometric measurements. There are day-case facilities provided for intravenous fluid and electrolyte administration as required. As part of an internal audit, during October 2012, patients were asked to prospectively record their daily stoma or fistula output volumes (forthwith termed “stoma output”) for one week. Additionally, they were asked to provide a 24 h urinary sample for urinary sodium, potassium and 24 h urinary magnesium analysis. On arrival at the clinic their routine blood tests were taken (urea and electrolytes, calcium, magnesium, phosphate, parathyroid hormone level, vitamin D level and glucose). Patients were questioned on the dose and duration of their PPI, whether they were on a PPI for another reason (for example, peptic ulcer disease), whether they were on hypotonic oral fluid restriction and/or taking electrolyte replacement solution, their use of other pharmacological ‘stoppers’ (loperamide, codeine or octreotide) and finally, whether they were taking diuretic medication, salt tablets or potassium, magnesium, calcium or vitamin D supplements. Patients were informed not to alter their normal ad libitum instructions with regard to table salt. These baseline measurements were recorded prospectively and the patients were then asked to stop their PPI. Two weeks later, on
Table 2 Comparison of stoma outputs and plasma magnesium levels pre- and post-PPI cessation. (Stoma output ¼ mean daily output over one week). Patient
1 2 3 4 5 6 7 8 9
On PPI
Off PPI
Plasma Mg (mmol/L)
Stoma output (mls)
Plasma Mg (mmol/L)
Stoma output (mls)
0.38 0.67 0.48 0.48 0.66 0.63 0.75 0.62 0.66
1650 2100 2300 1100 1500 1600 1500 1300 900
0.64 0.69 0.46 0.72 0.72 0.56 0.83 0.57 0.65
1800 1300 2000 1100 1000 1500 1500 1100 800
returning to the clinic, individuals again provided a record of the previous weeks daily stoma output volumes and had the same routine investigations. Written consent was obtained from each individual prior to inclusion of their data in this clinical audit. Data were analysed and a paired-samples t-test was used to perform statistical analysis (SPSSÒ version 18.0, Chicago, IL, US.) with a p-value of <0.05 deemed statistically significant. 3. Results During the month of October 2012, nine patients were attending the clinic. (4 male: 5 female, median age 65 years old, range 37e83.) Eight had high output stomas, and one had an enterocutaneous fistula. They had all been taking omeprazole 40 mg twice daily for a median of twelve months (range 4e84 month) solely to reduce stoma output volumes. Every patient was restricting their daily oral intake to 1.5 L which included one litre of electrolyte replacement drink. Furthermore, all patients were taking loperamide and six were taking codeine to reduce stoma output. None of the patients were on somatostatin analogues. Five were regularly taking oral magnesium supplements, two were taking calcium supplements and two were taking vitamin D supplements. No patients were on diuretic medication, a known cause of hypomagnesaemia (See Table 1). There was a significant reduction in average daily stoma outputs from being on a PPI (mean ¼ 1550 mls, SE: 147.67) compared to being taken off the PPI (mean ¼ 1344 mls, SE: 130.29, t(8) ¼ 2.11, p < 0.05). (See Table 2, Graph 1.) Additionally, there was a significant increase in both urinary sodium (mean on PPI ¼ 32.6 mmol/L, SE:22.7, off PPI ¼ 63.8, SE:6.65, t(8) ¼ -4.22, p ¼ 0.003) and urinary potassium (mean on PPI ¼ 61.9 mmol/L, SE:7.21, off PPI ¼ 77.8 mmol/L, t(8) ¼ 2.33, p ¼ 0.05) (See Table 3). No significant changes were demonstrated in mean plasma sodium (p ¼ 0.250), potassium (p ¼ 0.707), urea (p ¼ 0.479),
Table 1 Lop (loperamide), Cod (codeine), Mag (magnesium), ca (calcium). Patient
Age (years)
Sex
Oral fluid restriction (mls)
Electrolyte replacement solution
Stoppers
Oral supplements
Diuretics
1 2 3 4 5 6 7 8 9
71 65 68 37 53 68 56 83 59
M F F M M F F M F
1500 1500 1500 1500 1500 1500 1500 1500 1500
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Lop/Cod Lop/Cod Lop Lop/Cod Lop/Cod Lop/Cod Lop Lop Lop/Cod
Mag Mag Mag/Ca Mag/Ca None Mag Vit D None Vit D
No No No No No No No No No
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5
e3
Graph 2. Plasma magnesium levels pre and post PPI cessation.
Graph 1. Stoma outputs pre and post PPI cessation.
4. Discussion Table 3 24 h urinary electrolytes Mg (Magnesium), Na (Sodium), K (Potassium). Patient
1 2 3 4 5 6 7 8 9
Urinary Mg (plasma Mg) mmol/L
Urinary Na mmol/L
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
<0.28 0.32 0.29 <0.28 <0.28 0.72 1.03 1.14 0.83
0.55 0.42 1.09 0.48 1.09 0.62 2.26 4.15 0.93
20 3 35 63 37 6 <16 58 55
80 46 78 76 80 52 34 86 42
73 50 96 31 38 76 60 83 50
74 >67 >95 81 >79 >76 94 84 50
(0.38) (0.67) (0.48) (0.48) (0.66) (0.63) (0.75) (0.62 (0.66)
(0.64) (0.69) (0.46) (0.72) (0.72) (0.56) (0.83) (0.57) (0.65)
Urinary K mmol/L
creatinine (p ¼ 0.623), glucose (p ¼ 0.319), calcium (p ¼ 0.924), phosphate (p ¼ 0.804), parathyroid hormone (p ¼ 0.850) or vitamin D levels (p ¼ 0.363) (See Table 4). Whilst the mean plasma magnesium increased when the PPI was stopped there was no statistically significant change in plasma magnesium levels when on a PPI (mean ¼ 0.59 mmol/L, SE:0.40) compared to having stopped the PPI (mean ¼ 0.64 mmol/L, SE:0.40, t(8) ¼ -1.42, p ¼ 0.226). (See Table 2, Graph 2). Furthermore, no significantly demonstrable change was seen in patients’ mean 24 h urinary magnesium (p ¼ 0.06) (See Table 3). When taking the five patients receiving magnesium supplementation in isolation, although there was a trend towards a rise in plasma magnesium on stopping the PPI, this did not reach statistical significance (p ¼ 0.28).
Articles on the management of intestinal failure and short bowel syndrome [3e5] site three index papers from the 1990’s [9e11] advocating the use of PPI in such patients. Nightingale et al. [9], demonstrated in seven out of ten patients with high output stomas, a significant mean daily reduction in stoma output by 0.66 kg/ 24 h having administered omeprazole for five days. Furthermore, 11 patients with short bowel syndrome were analysed by Jeppesen et al. [10], and shown to have increased median weight absorption after five days of omeprazole compared to patients on no treatment and ranitidine. The earlier work from Nightingale et al. [11], appears to show the effect of octreotide, ranitidine and omeprazole in reducing intestinal output in two of fifteen patients with short bowel syndrome on three successive study days. Our case series, of similar sample size appears to challenge this earlier work. Interestingly in our study, stoma outputs significantly reduced on withdrawal of the PPI in this very select group with problematic high stoma losses and resistant electrolyte problems. Additionally, we have seen following cessation of the PPI therapy, a significant increase in mean urinary sodium and potassium, probably consequent to the reduction in stoma output. Patients with high output stomas or enterocutaneous fistulae are particularly vulnerable due to malabsorption and consequent rapid losses of magnesium from their remaining gastrointestinal tract, indeed, eight of our nine patients had a serum magnesium of <0.70 mmol/L when initially recorded (normal range 0.70e 0.95 mmol/L) despite five of them being on regular magnesium supplements. Magnesium is an important cofactor involved in many metabolic pathways, regulating calcium and potassium channels and stabilising neuronal excitability. It also plays a vital
Table 4 Plasma electrolytes: Na (Sodium), K (Potassium), Creat (Creatinine), Glu (Glucose), Ca (Calcium), Phos (Phosphate), PTH (Parathyroid Hormone), Vit D (Vitamin D).
1 2 3 4 5 6 7 8 9
Plasma Na mmol/L
Plasma K mmol/L
On PPI
Off PPI
On PPI
141 140 140 145 143 138 139 139 138
142 142 140 143 141 141 141 138 142
3.7 4.7 3.6 4 4.4 4.9 4.2 5.4 4.8
Plasma Urea mmol/L
Plasma Creat mmol/L
Plasma Glu mmol/L
Plasma Ca mmol/L
Plasma Phos mmol/L
Plasma PTH pmol/L
Plasma Vit D nmol/L
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
4.1 3.8 4.1 5.4 4.5 4.3 4.5 4.4 4.1
4.7 9.5 10.8 4.7 6.2 6.5 7.7 8.1 5.6
7.3 13.4 5.2 6 6 6.2 9.1 6 7.3
95 120 138 87 114 56 81 91 108
106 154 89 112 50 81 90 67 106
6.7 8.7 5.2 4.2 7.3 5.2 6.2 4.4 4.4
6.9 6.7 4.5 5.6 5.7 5.3 4.5 4.4 6.9
2.03 2.36 2.3 2.48 2.27 2.52 2.41 2.5 2.17
2.26 2.43 2.66 2.37 2.57 2.49 2.46 2.07 2.26
0.71 0.91 0.89 0.77 0.61 1.04 1.29 0.96 1.39
0.89 0.93 0.93 0.92 0.98 1.48 0.98 1.41 0.89
8.4 11.2 14.1 7 13.2 4.6 3.2 2.4 7.4
15.8 17.7 4.5 16.3 5.4 5 2.1 9.9 15.8
36 34 31 35 29 11 10 13 20
36 e 30 28 16 12 31 20 36
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
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N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5
role in protein synthesis and oxidative phosphorylation. Consequently, symptoms and signs of hypomagnesaemia can affect the neuromuscular (weakness, tremors, paraesthesia and seizures), cardiovascular (arrhythmias) and metabolic systems (hypokalaemia, hypocalcaemia, low levels of PTH) [12]. Biochemical hypomagnesaemia is thought to be common in the general population, having an estimated prevalence of 2.5e15% [13], however the true prevalence of sub-clinical hypomagnesaemia remains unknown. Since 2006, there have been increasing reports of the association of long term PPI use and hypomagnesaemia. Mackay et al. [6], published their experience with ten patients on PPIs for gastrooesophageal reflux disease for a mean duration of 8.3 years. They noted biochemical resolution and symptom control within two weeks of stopping the PPI. In 2011, Cundy et al. [7], on reviewing the literature, found 28 reported cases and concluded that, although a rare side effect of PPIs, hypomagnesaemia was a true class effect of the drug however, the mechanism of this action was unknown. This effect was seen after long term use (at least 5 years) and would rapidly resolve within 1e2 weeks of stopping the PPI. More recently, Hess et al. [8], in their systematic review, found 36 cases and confirmed it to be a class effect seen after a median of 5.5 years (range 2 weekse13 years) of use. They noted that discontinuation of the PPI resulted in recovery from hypomagnesaemia in 4 days and on re-introduction, hypomagnesaemia reoccurred just four days later. Our group of patients with a pre-existing risk of hypomagnesaemia were using PPI therapy solely to reduce their stoma outputs. They were all on the same PPI (omeprazole) at the same dose (40 mg twice daily), restricting their fluid intake to 1.5 L/day and using loperamide to reduce their stoma outputs. Additionally, they were all taking the same electrolyte replacement drink and using table salt ad libitum. As is often the case in patients with high gastrointestinal losses, none were on a diuretic to confound interpretation. Having been on their PPI for a median duration of 12 months, we were unable to show a significant increase in plasma magnesium levels on withdrawing their PPI therapy for two weeks. From Table 3, it can be seen that the lowest serum magnesium levels are associated with the lowest urinary magnesium levels suggesting evidence of magnesium depletion. Furthermore, all patients had an intact renal response indicated by each having urinary magnesium levels of <12 mg on every sample. The low urinary sodium levels suggest sodium retention, probably due to stoma output. All patients vitamin D levels revealed vitamin D insufficiency and so despite normal serum calcium levels, it is not surprising that parathyroid hormone levels were raised in all but two patients. Despite their hypomagnesaemia, none of our patients had hypokalaemia. We do recognise the limitations of our report. In particular we appreciate the sample size is small but we would point out that current practice is based on studies of a similar size [9e11]. Additionally, there is no simple or reliable test which directly measures magnesium losses from the intestine, and secondly, serum magnesium gives limited information about total magnesium balance. It is possible that although we failed to demonstrate a significant increase in serum magnesium in this current cohort, a greater effect may be seen in these individuals should they go on to have >5 years of PPI therapy. Moreover individual responses were such that cessation of a PPI should be trialled if a patient has resistant hypomagnesaemia. It is also noteworthy that all of our patients were vitamin D deficient. This unexpected outcome requires further investigation and highlights the significant metabolic stress these patients are under.
In conclusion, there are increasing numbers of reports linking PPIs with hypomagnesaemia. Patients with high output stomas and enterocutaneous fistulae, who are already at an increased risk of hypomagnesaemia due to rapid fluid and electrolyte losses, tend to be on PPI therapy. We recommend that in the absence of a contraindication such as peptic ulcer disease, consideration be given to stopping PPIs in high output stoma or enterocutaneous fistulae patients with refractory hypomagnesaemia. Our finding of a reduction in mean daily stoma output and a significantly increased urinary sodium concentration on withdrawal of PPI therapy challenges current thinking on the use of PPIs in fluid balance management for such patients. Sources of funding No funding was sort or received by any contributing author. Statement of authorship Specific author contributions are as follows: NDA carried out design of audit, analysis and interpretation of data and wrote the paper. WDN carried out processing and interpretation of data and critically revised the paper. CE carried out data collection. MD carried out data collection and critically revised the paper. CJW carried out design of audit, interpretation of data and critically revised the paper. All authors have approved the final version of the manuscript, including the authorship list. Conflict of interests All authors have no personal interests to declare. Acknowledgements This paper won the Roger Croton Medal following oral presentation at the Roger Croton Regional Surgical Meeting, Liverpool, UK in July 2013 and was presented as an oral poster presentation at the BAPEN Annual Conference, Harrogate, November 2013. No writing assistance was sought in the preparation of this manuscript. References [1] Walsh SR, Walsh CJ. Intravenous fluid associated morbidity in postoperative patients. Ann R Coll Surg Engl 2005;87:126e30. [2] Powell-Tuck J, Gosling P, Lobo DN, Allison SP, Carlson GL, Gore M, et al. British consensus guidelines on intravenous fluid therapy for adult surgical patients GIFTASUP BAPEN medical; 2010. [3] Carlson G, Gardiner K, McKee R, MacFie J, Vaizey C. The surgical management of patients with acute intestinal failure. Surgical Intestinal Failure Working Party on behalf of the Association of Surgeons of Great Britain and Ireland; September 2010. [4] Nightingale JMD. The medical management of intestinal failure: methods to reduce the severity. Proc Nutr Soc 2003;62:703e10. [5] Baker ML, Williams RN, Nightingale JMD. Causes and management of high output stomas. Colorectal Dis 2011;13:191e7. [6] Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 2010;103:387e95. [7] Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol 2011;27:180e5. [8] Hess MW, Hoenderoop JGJ, Bindels RJM, Drenth JPH. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther 2012;36:405e13.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5 [9] Nightingale JMD, Walder ER, Farthing MJG, Lennard-Jones JE. Effect of omeprazole on intestinal output in the short bowel syndrome. Aliment Pharmacol Ther 1991;5:405e12. [10] Jeppesen PB, Staun M, Tjellesen L, Mortensen PB. Effect of intravenous ranitidine and omeprazole on intestinal absorption of water, sodium and macronutrients in patients with intestinal resection. Gut 1998;43:763e9.
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[11] Nightingale JM, Lennard-Jones JE, Walker ER, Farthing MJG. Jejunal efflus in short bowel syndrome. Lancet 1990;336:765e8. [12] Ayuk J, Gittoes NJL. How should hypomagnesaemia be investigated and treated? Clin Endocrinol 2011;73:743e6. [13] Mouw DR, Latessa RA, Hickner J. Clinical enquiries. What are the causes of hypomagnesemia? J Fam Pract 2005;54:174e6.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
Contents lists available at ScienceDirect
e-SPEN Journal journal homepage: http://www.elsevier.com/locate/clnu
Original article
Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help? N.D. Appleton a, W.D. Neithercut b, C. Edwards c, M. Duncan c, C.J. Walsh a, * a
Department of Surgery, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK Department of Clinical Biochemistry, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK c Nutrition Support Team, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Wirral CH49 5PE, UK b
a r t i c l e i n f o
s u m m a r y
Article history: Received 20 November 2013 Accepted 8 April 2014
Background and aims: Patients with high output stomas and enterocutaneous fistulae are prone to fluid and electrolyte abnormalities, particularly dehydration, hyponatraemia and hypomagnesaemia. As well as medication to prolong transit time and aid absorption, proton pump inhibitors (PPIs) have been advocated to reduce gastrointestinal losses. Recent, reports in other clinical areas have linked long-term PPI use to hypomagnesaemia. We wondered whether PPIs used to reduce stoma losses may paradoxically be aggravating hypomagnesaemia in these patients? Our aim was to audit the effect of stopping PPIs, used solely for reduction of gastrointestinal losses, in a cohort of patients with high stoma losses. Methods: Nine patients (8 high output stomas: 1 enterocutaneous fistula) were regularly attending a dedicated clinic for supervision and management of fluid and electrolytes during October 2012. Stoma outputs, blood and urine results were recorded before and after stopping their PPI. Results: There was a significant reduction in average daily stoma outputs when the PPI was stopped. Before PPI cessation, mean daily stoma volume was 1550 mls (SE:147.67) compared to mean of 1344 mls after (SE:130.29, t(8) ¼ 2.11, p < 0.05). Additionally, there was a significant increase in both urinary sodium (mean on PPI ¼ 32.6 mmol/L, SE:22.7, off PPI ¼ 63.8, SE:6.65, t(8) ¼ 4.22, p ¼ 0.003) and urinary potassium (mean on PPI ¼ 61.9 mmol/L, SE:7.21, off PPI ¼ 77.8 mmol/L, t(8) ¼ 2.33, p ¼ 0.05). Mean plasma magnesium across the group was not significantly affected by stopping the PPI, yet some individuals had marked improvements (mean before ¼ 0.59 mmol/L, SE:0.40 compared to mean after ¼ 0.64 mmol/L, SE:0.40, t(8) ¼ 1.42, p ¼ 0.226). Conclusion: Our findings do not support current thinking with regard to PPIs reducing enteric losses in patients with high stoma losses. The PPI effect on hypomagnesaemia in this cohort is uncertain but cessation should be considered in resistant hypomagnesaemia. Ó 2014 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Hypomagnesaemia Proton pump inhibitors High output stoma Enterocutaneous fistula
1. Introduction Optimal fluid and electrolyte balance in surgical patients continues to be challenging [1,2], and this is particularly the case for patients with high output stomas or enterocutaneous fistulae. Successful management of such patients involves meticulous attention to fluid balance. Stoma output can usually be controlled by manipulating oral intake, including the restricted intake of hypotonic fluids, and by the use of pharmacological ‘stoppers’ e
* Corresponding author. E-mail address: [email protected] (C.J. Walsh).
loperamide and codeine, as first line drugs. Less commonly, a somatostatin analogue such as octreotide can be used. Proton pump inhibitors (PPIs) have previously been advocated for use in patients with high output stomas or enterocutaneous fistulas to reduce output [3e5] and as a result are commonly used for this purpose in these patients. As well as losing water and sodium, these patients are particularly prone to hypomagnesaemia due to rapid losses of magnesium rich fluid from their proximal small bowel. Magnesium replacement is very commonly required in this patient cohort. Usually this can be achieved with oral supplements of magnesium oxide, gluconate or aspartate preparations, but not infrequently additional intravenous magnesium replacement is needed.
http://dx.doi.org/10.1016/j.clnme.2014.04.002 2212-8263/Ó 2014 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
e2
N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5
Over the past 5 years, there have been an increasing number of reports in the literature in other clinical settings that link the long term use of PPIs to hypomagnesaemia [6e8]. In view of this, we questioned whether PPIs used to reduce stoma losses may paradoxically be aggravating hypomagnesaemia in these patients? We present an internal audit on the effect of PPI cessation, in a group of patients with high output stomas and enterocutaneous fistulas taking PPIs solely as part of their fluid balance regime. Already at risk of hypomagnesaemia from gastrointestinal losses, their PPI therapy was temporarily withdrawn to observe differences including whether it was having a contributory effect on plasma magnesium levels. 2. Materials and methods At our hospital, patients with high output stomas or enterocutaneous fistulas who are surgically stable, sepsis free and meeting their nutritional needs enterally, are managed on an outpatient basis. They are asked to attend a dedicated weekly clinic which is led by the Nutrition Support Team composed of nutrition nurse specialists, a pharmacist, a dietician, a consultant clinical biochemist, and a consultant colorectal surgeon. Access to stoma care and tissue viability is available if required. All individual cases are discussed as part of a weekly nutrition multi-disciplinary team meeting. The primary aim of the clinic is to prevent complications associated with high output stomas or enterocutaneous fistulae, particularly acute renal injury and fluid and electrolyte abnormalities. The patients are monitored with regular assessment of fluid balance, blood and urine electrolytes, medication review and anthropometric measurements. There are day-case facilities provided for intravenous fluid and electrolyte administration as required. As part of an internal audit, during October 2012, patients were asked to prospectively record their daily stoma or fistula output volumes (forthwith termed “stoma output”) for one week. Additionally, they were asked to provide a 24 h urinary sample for urinary sodium, potassium and 24 h urinary magnesium analysis. On arrival at the clinic their routine blood tests were taken (urea and electrolytes, calcium, magnesium, phosphate, parathyroid hormone level, vitamin D level and glucose). Patients were questioned on the dose and duration of their PPI, whether they were on a PPI for another reason (for example, peptic ulcer disease), whether they were on hypotonic oral fluid restriction and/or taking electrolyte replacement solution, their use of other pharmacological ‘stoppers’ (loperamide, codeine or octreotide) and finally, whether they were taking diuretic medication, salt tablets or potassium, magnesium, calcium or vitamin D supplements. Patients were informed not to alter their normal ad libitum instructions with regard to table salt. These baseline measurements were recorded prospectively and the patients were then asked to stop their PPI. Two weeks later, on
Table 2 Comparison of stoma outputs and plasma magnesium levels pre- and post-PPI cessation. (Stoma output ¼ mean daily output over one week). Patient
1 2 3 4 5 6 7 8 9
On PPI
Off PPI
Plasma Mg (mmol/L)
Stoma output (mls)
Plasma Mg (mmol/L)
Stoma output (mls)
0.38 0.67 0.48 0.48 0.66 0.63 0.75 0.62 0.66
1650 2100 2300 1100 1500 1600 1500 1300 900
0.64 0.69 0.46 0.72 0.72 0.56 0.83 0.57 0.65
1800 1300 2000 1100 1000 1500 1500 1100 800
returning to the clinic, individuals again provided a record of the previous weeks daily stoma output volumes and had the same routine investigations. Written consent was obtained from each individual prior to inclusion of their data in this clinical audit. Data were analysed and a paired-samples t-test was used to perform statistical analysis (SPSSÒ version 18.0, Chicago, IL, US.) with a p-value of <0.05 deemed statistically significant. 3. Results During the month of October 2012, nine patients were attending the clinic. (4 male: 5 female, median age 65 years old, range 37e83.) Eight had high output stomas, and one had an enterocutaneous fistula. They had all been taking omeprazole 40 mg twice daily for a median of twelve months (range 4e84 month) solely to reduce stoma output volumes. Every patient was restricting their daily oral intake to 1.5 L which included one litre of electrolyte replacement drink. Furthermore, all patients were taking loperamide and six were taking codeine to reduce stoma output. None of the patients were on somatostatin analogues. Five were regularly taking oral magnesium supplements, two were taking calcium supplements and two were taking vitamin D supplements. No patients were on diuretic medication, a known cause of hypomagnesaemia (See Table 1). There was a significant reduction in average daily stoma outputs from being on a PPI (mean ¼ 1550 mls, SE: 147.67) compared to being taken off the PPI (mean ¼ 1344 mls, SE: 130.29, t(8) ¼ 2.11, p < 0.05). (See Table 2, Graph 1.) Additionally, there was a significant increase in both urinary sodium (mean on PPI ¼ 32.6 mmol/L, SE:22.7, off PPI ¼ 63.8, SE:6.65, t(8) ¼ -4.22, p ¼ 0.003) and urinary potassium (mean on PPI ¼ 61.9 mmol/L, SE:7.21, off PPI ¼ 77.8 mmol/L, t(8) ¼ 2.33, p ¼ 0.05) (See Table 3). No significant changes were demonstrated in mean plasma sodium (p ¼ 0.250), potassium (p ¼ 0.707), urea (p ¼ 0.479),
Table 1 Lop (loperamide), Cod (codeine), Mag (magnesium), ca (calcium). Patient
Age (years)
Sex
Oral fluid restriction (mls)
Electrolyte replacement solution
Stoppers
Oral supplements
Diuretics
1 2 3 4 5 6 7 8 9
71 65 68 37 53 68 56 83 59
M F F M M F F M F
1500 1500 1500 1500 1500 1500 1500 1500 1500
Yes Yes Yes Yes Yes Yes Yes Yes Yes
Lop/Cod Lop/Cod Lop Lop/Cod Lop/Cod Lop/Cod Lop Lop Lop/Cod
Mag Mag Mag/Ca Mag/Ca None Mag Vit D None Vit D
No No No No No No No No No
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N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5
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Graph 2. Plasma magnesium levels pre and post PPI cessation.
Graph 1. Stoma outputs pre and post PPI cessation.
4. Discussion Table 3 24 h urinary electrolytes Mg (Magnesium), Na (Sodium), K (Potassium). Patient
1 2 3 4 5 6 7 8 9
Urinary Mg (plasma Mg) mmol/L
Urinary Na mmol/L
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
<0.28 0.32 0.29 <0.28 <0.28 0.72 1.03 1.14 0.83
0.55 0.42 1.09 0.48 1.09 0.62 2.26 4.15 0.93
20 3 35 63 37 6 <16 58 55
80 46 78 76 80 52 34 86 42
73 50 96 31 38 76 60 83 50
74 >67 >95 81 >79 >76 94 84 50
(0.38) (0.67) (0.48) (0.48) (0.66) (0.63) (0.75) (0.62 (0.66)
(0.64) (0.69) (0.46) (0.72) (0.72) (0.56) (0.83) (0.57) (0.65)
Urinary K mmol/L
creatinine (p ¼ 0.623), glucose (p ¼ 0.319), calcium (p ¼ 0.924), phosphate (p ¼ 0.804), parathyroid hormone (p ¼ 0.850) or vitamin D levels (p ¼ 0.363) (See Table 4). Whilst the mean plasma magnesium increased when the PPI was stopped there was no statistically significant change in plasma magnesium levels when on a PPI (mean ¼ 0.59 mmol/L, SE:0.40) compared to having stopped the PPI (mean ¼ 0.64 mmol/L, SE:0.40, t(8) ¼ -1.42, p ¼ 0.226). (See Table 2, Graph 2). Furthermore, no significantly demonstrable change was seen in patients’ mean 24 h urinary magnesium (p ¼ 0.06) (See Table 3). When taking the five patients receiving magnesium supplementation in isolation, although there was a trend towards a rise in plasma magnesium on stopping the PPI, this did not reach statistical significance (p ¼ 0.28).
Articles on the management of intestinal failure and short bowel syndrome [3e5] site three index papers from the 1990’s [9e11] advocating the use of PPI in such patients. Nightingale et al. [9], demonstrated in seven out of ten patients with high output stomas, a significant mean daily reduction in stoma output by 0.66 kg/ 24 h having administered omeprazole for five days. Furthermore, 11 patients with short bowel syndrome were analysed by Jeppesen et al. [10], and shown to have increased median weight absorption after five days of omeprazole compared to patients on no treatment and ranitidine. The earlier work from Nightingale et al. [11], appears to show the effect of octreotide, ranitidine and omeprazole in reducing intestinal output in two of fifteen patients with short bowel syndrome on three successive study days. Our case series, of similar sample size appears to challenge this earlier work. Interestingly in our study, stoma outputs significantly reduced on withdrawal of the PPI in this very select group with problematic high stoma losses and resistant electrolyte problems. Additionally, we have seen following cessation of the PPI therapy, a significant increase in mean urinary sodium and potassium, probably consequent to the reduction in stoma output. Patients with high output stomas or enterocutaneous fistulae are particularly vulnerable due to malabsorption and consequent rapid losses of magnesium from their remaining gastrointestinal tract, indeed, eight of our nine patients had a serum magnesium of <0.70 mmol/L when initially recorded (normal range 0.70e 0.95 mmol/L) despite five of them being on regular magnesium supplements. Magnesium is an important cofactor involved in many metabolic pathways, regulating calcium and potassium channels and stabilising neuronal excitability. It also plays a vital
Table 4 Plasma electrolytes: Na (Sodium), K (Potassium), Creat (Creatinine), Glu (Glucose), Ca (Calcium), Phos (Phosphate), PTH (Parathyroid Hormone), Vit D (Vitamin D).
1 2 3 4 5 6 7 8 9
Plasma Na mmol/L
Plasma K mmol/L
On PPI
Off PPI
On PPI
141 140 140 145 143 138 139 139 138
142 142 140 143 141 141 141 138 142
3.7 4.7 3.6 4 4.4 4.9 4.2 5.4 4.8
Plasma Urea mmol/L
Plasma Creat mmol/L
Plasma Glu mmol/L
Plasma Ca mmol/L
Plasma Phos mmol/L
Plasma PTH pmol/L
Plasma Vit D nmol/L
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
On PPI
Off PPI
4.1 3.8 4.1 5.4 4.5 4.3 4.5 4.4 4.1
4.7 9.5 10.8 4.7 6.2 6.5 7.7 8.1 5.6
7.3 13.4 5.2 6 6 6.2 9.1 6 7.3
95 120 138 87 114 56 81 91 108
106 154 89 112 50 81 90 67 106
6.7 8.7 5.2 4.2 7.3 5.2 6.2 4.4 4.4
6.9 6.7 4.5 5.6 5.7 5.3 4.5 4.4 6.9
2.03 2.36 2.3 2.48 2.27 2.52 2.41 2.5 2.17
2.26 2.43 2.66 2.37 2.57 2.49 2.46 2.07 2.26
0.71 0.91 0.89 0.77 0.61 1.04 1.29 0.96 1.39
0.89 0.93 0.93 0.92 0.98 1.48 0.98 1.41 0.89
8.4 11.2 14.1 7 13.2 4.6 3.2 2.4 7.4
15.8 17.7 4.5 16.3 5.4 5 2.1 9.9 15.8
36 34 31 35 29 11 10 13 20
36 e 30 28 16 12 31 20 36
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role in protein synthesis and oxidative phosphorylation. Consequently, symptoms and signs of hypomagnesaemia can affect the neuromuscular (weakness, tremors, paraesthesia and seizures), cardiovascular (arrhythmias) and metabolic systems (hypokalaemia, hypocalcaemia, low levels of PTH) [12]. Biochemical hypomagnesaemia is thought to be common in the general population, having an estimated prevalence of 2.5e15% [13], however the true prevalence of sub-clinical hypomagnesaemia remains unknown. Since 2006, there have been increasing reports of the association of long term PPI use and hypomagnesaemia. Mackay et al. [6], published their experience with ten patients on PPIs for gastrooesophageal reflux disease for a mean duration of 8.3 years. They noted biochemical resolution and symptom control within two weeks of stopping the PPI. In 2011, Cundy et al. [7], on reviewing the literature, found 28 reported cases and concluded that, although a rare side effect of PPIs, hypomagnesaemia was a true class effect of the drug however, the mechanism of this action was unknown. This effect was seen after long term use (at least 5 years) and would rapidly resolve within 1e2 weeks of stopping the PPI. More recently, Hess et al. [8], in their systematic review, found 36 cases and confirmed it to be a class effect seen after a median of 5.5 years (range 2 weekse13 years) of use. They noted that discontinuation of the PPI resulted in recovery from hypomagnesaemia in 4 days and on re-introduction, hypomagnesaemia reoccurred just four days later. Our group of patients with a pre-existing risk of hypomagnesaemia were using PPI therapy solely to reduce their stoma outputs. They were all on the same PPI (omeprazole) at the same dose (40 mg twice daily), restricting their fluid intake to 1.5 L/day and using loperamide to reduce their stoma outputs. Additionally, they were all taking the same electrolyte replacement drink and using table salt ad libitum. As is often the case in patients with high gastrointestinal losses, none were on a diuretic to confound interpretation. Having been on their PPI for a median duration of 12 months, we were unable to show a significant increase in plasma magnesium levels on withdrawing their PPI therapy for two weeks. From Table 3, it can be seen that the lowest serum magnesium levels are associated with the lowest urinary magnesium levels suggesting evidence of magnesium depletion. Furthermore, all patients had an intact renal response indicated by each having urinary magnesium levels of <12 mg on every sample. The low urinary sodium levels suggest sodium retention, probably due to stoma output. All patients vitamin D levels revealed vitamin D insufficiency and so despite normal serum calcium levels, it is not surprising that parathyroid hormone levels were raised in all but two patients. Despite their hypomagnesaemia, none of our patients had hypokalaemia. We do recognise the limitations of our report. In particular we appreciate the sample size is small but we would point out that current practice is based on studies of a similar size [9e11]. Additionally, there is no simple or reliable test which directly measures magnesium losses from the intestine, and secondly, serum magnesium gives limited information about total magnesium balance. It is possible that although we failed to demonstrate a significant increase in serum magnesium in this current cohort, a greater effect may be seen in these individuals should they go on to have >5 years of PPI therapy. Moreover individual responses were such that cessation of a PPI should be trialled if a patient has resistant hypomagnesaemia. It is also noteworthy that all of our patients were vitamin D deficient. This unexpected outcome requires further investigation and highlights the significant metabolic stress these patients are under.
In conclusion, there are increasing numbers of reports linking PPIs with hypomagnesaemia. Patients with high output stomas and enterocutaneous fistulae, who are already at an increased risk of hypomagnesaemia due to rapid fluid and electrolyte losses, tend to be on PPI therapy. We recommend that in the absence of a contraindication such as peptic ulcer disease, consideration be given to stopping PPIs in high output stoma or enterocutaneous fistulae patients with refractory hypomagnesaemia. Our finding of a reduction in mean daily stoma output and a significantly increased urinary sodium concentration on withdrawal of PPI therapy challenges current thinking on the use of PPIs in fluid balance management for such patients. Sources of funding No funding was sort or received by any contributing author. Statement of authorship Specific author contributions are as follows: NDA carried out design of audit, analysis and interpretation of data and wrote the paper. WDN carried out processing and interpretation of data and critically revised the paper. CE carried out data collection. MD carried out data collection and critically revised the paper. CJW carried out design of audit, interpretation of data and critically revised the paper. All authors have approved the final version of the manuscript, including the authorship list. Conflict of interests All authors have no personal interests to declare. Acknowledgements This paper won the Roger Croton Medal following oral presentation at the Roger Croton Regional Surgical Meeting, Liverpool, UK in July 2013 and was presented as an oral poster presentation at the BAPEN Annual Conference, Harrogate, November 2013. No writing assistance was sought in the preparation of this manuscript. References [1] Walsh SR, Walsh CJ. Intravenous fluid associated morbidity in postoperative patients. Ann R Coll Surg Engl 2005;87:126e30. [2] Powell-Tuck J, Gosling P, Lobo DN, Allison SP, Carlson GL, Gore M, et al. British consensus guidelines on intravenous fluid therapy for adult surgical patients GIFTASUP BAPEN medical; 2010. [3] Carlson G, Gardiner K, McKee R, MacFie J, Vaizey C. The surgical management of patients with acute intestinal failure. Surgical Intestinal Failure Working Party on behalf of the Association of Surgeons of Great Britain and Ireland; September 2010. [4] Nightingale JMD. The medical management of intestinal failure: methods to reduce the severity. Proc Nutr Soc 2003;62:703e10. [5] Baker ML, Williams RN, Nightingale JMD. Causes and management of high output stomas. Colorectal Dis 2011;13:191e7. [6] Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 2010;103:387e95. [7] Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol 2011;27:180e5. [8] Hess MW, Hoenderoop JGJ, Bindels RJM, Drenth JPH. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther 2012;36:405e13.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002
N.D. Appleton et al. / e-SPEN Journal xxx (2014) e1ee5 [9] Nightingale JMD, Walder ER, Farthing MJG, Lennard-Jones JE. Effect of omeprazole on intestinal output in the short bowel syndrome. Aliment Pharmacol Ther 1991;5:405e12. [10] Jeppesen PB, Staun M, Tjellesen L, Mortensen PB. Effect of intravenous ranitidine and omeprazole on intestinal absorption of water, sodium and macronutrients in patients with intestinal resection. Gut 1998;43:763e9.
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[11] Nightingale JM, Lennard-Jones JE, Walker ER, Farthing MJG. Jejunal efflus in short bowel syndrome. Lancet 1990;336:765e8. [12] Ayuk J, Gittoes NJL. How should hypomagnesaemia be investigated and treated? Clin Endocrinol 2011;73:743e6. [13] Mouw DR, Latessa RA, Hickner J. Clinical enquiries. What are the causes of hypomagnesemia? J Fam Pract 2005;54:174e6.
Please cite this article in press as: Appleton ND, et al., Management of patients with high output stomas and enterocutaneous fistulae: Do proton pump inhibitors really help?, e-SPEN Journal (2014), http://dx.doi.org/10.1016/j.clnme.2014.04.002