A Common Complication of NSAIDS; Indomethacin Induced Hyperkalaemia
Y Aggarwal, SpR Renal Medicine
A 68 year old male was reviewed by the medical registrar on-call, as requested by the orthopaedic team for ongoing concerns regarding a persistent isolated hyperkalaemia of mean range 6.8-7.8mmol/l.
The patient was 3 weeks post removal of a total hip prosthesis due to recurrent local infections. The longer term plan was for a prosthesis replacement following a 6 week course of systemic antibiotics to eradicate any residual infection and associated seeding.
After an initial stormy course, where the patient had required intra- and immediate post-operative blood products (9 units of packed red cells and clotting products), the patient had started to rehabilitate well and infection markers/cultures were low/negative.
Blood tests week 1 post operatively had shown normal renal function with a potassium level of 4mmol/l. However during the last 5 days the serum potassium had gradually elevated to >6.5mmol/l and was resistant to correction with insulin and dextrose (‘potassium rescues’).
The medical registrar also had the following information about the patient:
- Past medical history - Osteoarthritis & gastro-oesophageal reflux disease (GORD).
- Pre-hospital medications - Citalopram (? patient-specific indication), omeprazole and regular paracetamol all of which he had ‘been on for years’.
- On examination the following clinical features were noted:
Normal blood glucose
Relative hypotension - BP 100-110 /70mmHg (pre-op BP 135-145/80)
Resting heart rate 90bpm
Left peripherally inserted cannula (PIC) at the antecubital fossa ending mid upper arm – no thrombophlebitis
Mild to moderate hypovolaemia – dry mucous membranes, low BP, reduced capillary refill, cool peripheries
Remainder of the systems examination was normal.
- Bedside observation
Fluid balance: 4L negative balance for the last 3 days. Reduced urine output in the last 18 hours with an average of 5-10mls/hour over the last 6 hours.
Urine dip: Clear
Blood test were as follows (SI Units):
|Day 3-20 post op||Day 22 post op|
|Hb||10||12 – last blood transfusion 3 weeks ago|
No urinary electrolytes were available at the time of the review.
Venous blood gas - Normal pH, lactate, chloride level, bicarbonate and base excess
ECG - Normal sinus rhythm with global tall tented T waves.
The patient was now on the following medications and advice as to whether they cause hyperkalaemia has also been added as a footnote:
- Tazocin  and teicoplanin  changed to ertapenem  and teicoplanin 3 days previous as their dosage timings facilitate outpatient administration
- Enoxaparin  prophylactic dosage started 2 weeks ago
- Omeprazole  since admission
- Paracetamol since his operation
- Indomethacin started 7 days ago
- Morphine sulphate tablets  - last required 7 days earlier
- Sodium docusate - last used several days previously
- Movicol- last used several days previously
Impression: Indomethacin/NSAID induced hyperkalaemia, hyponatraemia and stage 1 AKI 
The patient had mild AKI secondary to moderate hypovolaemia and medications: pertinently the indomethacin as the prescription coincided with the hyperkalaemia AND hyponatraemia. The heparin and omeprazole may have had an additive effect.
The patient had acute management of the hyperkalaemia to achieve levels of < 5.5mmol/l. The management strategy was as follows:
1 - Removal of the causative aetiology
The indomethacin was immediately stopped
2 - Cardiac stabilisation - necessary as the patient had hyperkalaemia related ECG changes
Continuous ECG monitoring
10ml 10% calcium gluconate to stabilise the cardiac action potential - as per local protocols
3 - Potassium removal
Intracellular shifts (a temporary bridging measure to more definitive methods)
Insulin and dextrose infusions
**IV sodium bicarbonate
Definitive potassium reduction methods
IV hydration and correction of GFR – increase renal losses
**Use of cation-exchange resins such as calcium resonium – increase GI losses
**Diuretics such as loops – increase renal losses **Considered but not used in this patient
4 - Repeat potassium testing at 1, 2 4 hour intervals depending on the potassium level
5 - Other medications were rationalised where possible
The omeprazole was stopped but prophylactic dose heparin was continued.
Antibiotics were unchanged due to the ease of outpatient administration.
6 - Dietary potassium was restricted i.e. low potassium diet.
7 - Alternative non-NSAID analgesia was used.
Indomethacin was re-introduced (accidentally) at a later date and resulted in a hyperkalaemia within 48 hours of the first dose.
8 – Side effects from NSAIDS were recorded in the patient's notes. The patient's GP and the patient were also informed to avoid future adverse events.
Patient progress: The renal function normalised and was unchanged with the re-introduction of omeprazole. The patient remained under on-going orthopaedic care.
Discussion: NSAIDs reduce the production of renal prostaglandins. Renal prostaglandins are essential in the regulation of normal renal perfusion. They cause afferent arteriole dilatation to oppose the afferent and efferent arteriolar vasoconstriction brought about by angiotensin II to maintain renal perfusion pressures and the glomerular filtration rate (GFR).
Renal prostaglandins also promote the secretion of renin, impair sodium reabsorption in the loop of Henle and cortical collecting tubule, and partially antagonise the effect of antidiuretic hormone (ADH) to increase water reabsorption in the collecting tubules. These routes of action are important in understanding how electrolyte imbalances occur with NSAID administration.
The kidney produces prostaglandins (PGE2, PGF2, PGD2, prostacyclin (PGI2) and thromboxane A2 (TXA2)). Their relative production varies at different sites within the kidney. The major product of cortical synthesis is PGI2, whereas in the medulla PGE2 is the main prostaglandin . Prostaglandins act locally to where they are synthesised.
The renal prostaglandins are synthesised from phospholipids which are converted to arachidonic acid by Phospholipase A2. Phospholipase A2 is activated by kinins, antidiuretic hormone (ADH), angiotensin II, and extracellular hyper-osmolality. Arachidonic acid is converted to prostaglandin endoperoxides by cyclo-oxygenase (COX). The endoperoxides are converted to prostaglandins by specific prostaglandin synthetases.
Hyperkalaemia: NSAIDs block prostaglandin production by inhibiting the cyclooxygenases (COX-1 and COX-2). Reduction in the renal prostaglandins result in a reduction in GFR by no longer opposing vasoconstriction effects of angiotensin II. A fall in GFR causes negative feedback and reduced renin secretion, leading to reduced angiotensin II formation, reduced aldosterone release and subsequently reduced potassium excretion. The net effect is a rise in the plasma potassium concentration which is even more prominent when a patient has a contracted volume status .
Hyponatremia: Renal prostaglandins also inhibit ADH activity, and thus their diminished production results in reduced free water excretion, net water retention and subsequent hyponatremia especially if the ADH level is high, for example, due to a contracted volume state and or SIADH.
Indomethacin is a potent NSAID and causes hyporeninaemic hypoaldosteronism resulting in hyperkalaemia and hyponatraemia.
Indomethacin may not be as familiar as other NSAIDS but it is frequently used. Always check the British National Formulary (BNF) for medications you may not be familiar with.
Always update the patient’s drug history records and inform the GP and patient to avoid a repeat of the drug intolerance and associated adverse event.
Brief note on Hyperkalaemia:
Hyperkalaemia is defined as a serum potassium concentration greater than 5.5mmol/L in adults.
A useful way to approach the aetiology of hyperkalaemia is in terms of a) increased potassium ingestions, b) decreased potassium losses and/or c) shifts of potassium from the intracellular to the extracellular space.
The most common causes involve decreased excretion.
Further reading regarding the clinical presentations, management, and aetiology can be found in chapter 2 of Oxford Desk Reference: Nephrology by Jonathan Barratt, Kevin Harris, and Peter Topham (Oxford Desk Reference Series | Hardback | 27 November 2008) and other renal textbooks.
Notes and References:
 Tazoci/Tazobactam can result in mild renal dysfunction and typically hypokalaemia – see the following:
- "Product Information. Zosyn (piperacillin-tazobactam)." Lederle Laboratories, Wayne, NJ.
- Lau WK, Mercer D, Itani KM, et al. "A Randomized, Open-Label, Comparative Study of Piperacillin/Tazobactam Administered by Continuous Infusion vs. Intermittent Infusion for the Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection." Antimicrob Agents Chemother (2006):
- Bow EJ, Rotstein C, Noskin GA, et al. "A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies." Clin Infect Dis 43 (2006): 447-59
- Abate G, Godbole K, Springston C "Piperacillin / tazobactam-induced petechial rash." Ann Pharmacother 44 (2010): 1345-6
 Teicoplanin usually results in hypokalaemia – see the following:
- Ramírez E, Rossignoli T, Campos AJ, et al. Drug-induced life-threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals. Eur J Clin Pharmacol. 2013 Jan;69(1):97-110.
 Ertapenem can result in a small rise in serum creatinine and usually decreased serum potassium levels – see the following:
- "Product Information. Invanz (ertapenem)." Merck & Company Inc, West Point, PA.
- Itani KM, Wilson SE, Awad SS, Jensen EH, Finn TS, Abramson MA "Ertapenem versus cefotetan prophylaxis in elective colorectal surgery." N Engl J Med 355 (2006): 2640-51
 LMWH can result in mild and significant hyperkalaemia when given as either a prophylactic or therapeutic dose – see the following:
- Koren-Michowitz M, Avni B, Michowitz Y, et al. Early onset of hyperkalaemia in patients treated with low molecular weight heparin: a prospective study. Pharmacoepidemiol Drug Saf. 2004 May;13(5):299-302.
- Ogundipe. Low Molecular Weight Heparins Can Lead To Hyperkalaemia. The Internet Journal of Geriatrics and Gerontology. 2004 Volume 2 Number 2.
- Gheno G, Cinetto L, et al. Variations of serum potassium level and risk of hyperkalaemia in inpatients receiving low-molecular-weight heparin. Eur J Clin Pharmacol. 2003 Sept; 59 (5-6): 373-7.
- Rippin JD, Hado HSH, Green N, Elhadd TA. Serious hyperkalaemia after short use of low molecular weight heparin in a diabetic patient. Clinical Medicine Jan/Feb 2003.Vol 3 No 1
 Anecdotal reporting of hyperkalaemia following the use of omeprazole. See Tashiro M, Yoshikawa I, Kume K et al. Acute hyperkalaemia associated with intravenous omeprazole therapy. The American Journal of Gastroenterology (2003) 98, 1209–1210 and "Product Information. Zegerid (omeprazole-sodium bicarbonate)." Santarus Inc, San Diego, CA.
 A NSAID well known to cause hyperkalaemia. See Goldszer R, Coodley E, Rosner M et al. Hyperkalaemia associated with indomethacin. Arch Intern Med. 1981 May;141(6):802-4.
- Tan SY, Shapiro R, Franco R et l. Indomethacin-induced prostaglandin inhibition with hyperkalaemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med. 1979 May;90(5):783-5.
- Lafrance JP1, Miller DR. Dispensed selective and nonselective nonsteroidal anti-inflammatory drugs and the risk of moderate to severe hyperkalaemia: a nested case-control study. Am J Kidney Dis. 2012 Jul;60(1):82-9. doi: 10.1053/j.ajkd.2012.02.328. Epub 2012 Apr 12.
 Morphine sulphate is not known to cause any serum potassium abnormalities however it is important to point out that its active metabolites accumulate in advance renal impairment resulting in respiratory and neuro- toxicity and thus its use when the GFR ≤ 30ml/min/m3 is limited and often avoided. See:
 Increase in serum creatinine by 1.5-2 from baseline, KDIGO guidance
 Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-70S AND Whelton A. Renal and related cardiovascular effects of conventional and COX-2- specific NSAIDs and non-NSAID analgesics. Am J Ther. 2000;7:63-74.
 Oliw E. (1979). Prostaglandins and kidney function. An experimental study in the rabbit. Acta physiologica scandinavica Suppl. 461.
Weber PC, Scherer B, Siess W et al. (1980). Possible significance of renal prostaglandins for renin release and blood pressure control. In Advances in Prostaglandin and Thromboxone Research, vol.7, eds. SAMUELSSON, B., RAMWELL, P. W. & PAOLETTI, R., pp. 1067-1077. New York: Raven.