ABC of Intravenous Fluids, Electrolyte Disorders and AKI Management in Adults

Home , Electrolyte imbalance, Hypotonic hyponatremia

Mohamed Ahmed Eltoum

MBBS (Khartoum), MSc – Neph/Educ (Brighton), MRCP (Ireland), MRCP (UK), CCT – Dual Accreditation (UK) Consultant Physician and Nephrologist (UK)

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can be ordered from WASD:

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ISBN: 978-1-907106-88-0

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No responsibility for the views expressed in this book is assumed by the Editors or WASD.

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Humbly, to my late parents, who loved, cared, gave everything and sacriﬁ ced for us. I also dedicate it to my brothers and sisters; and to my wife and daughter for their encouragement, endurance, and patience during many long hours of work.

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My profound appreciation and deep regards are due to my teachers, and mentors for their exemplary guidance and constant encouragement throughout my life; particularly Dr Juan Mason and Dr G Venkat-Raman, at Queen Alexandra Hospital, Portsmouth, UK.

I am extremely grateful to many colleagues for their comments on the earlier versions of the manuscript, although any errors are my own. A special gratitude is to Stephanie Wadham, Clinical Pharmacist at Yeovil District Hospital, UK.

I would also like to acknowledge the contribution of Professor Allam Ahmed, of the World Association of Sustainable Development, Dr Adil Dafa’Alla, and Mr Mouiz Ahmed in lifting the booklet to the publication platform.

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Dedication i

Acknowledgement ii

Table of Contens iii

Chapter 1: Introduction 1

Chapter 2: Intravenous Fluid Therapy in Adults 3

Chapter 3: Management of Hyponatraemia 13

Chapter 4: Management of Hypernatraemia 23

Chapter 5: Management of Hypokalaemia 31

Chapter 6: Management of Hyperkalaemia 39

Chapter 7: Management of Hypocalcaemia 45

Chapter 8: Management of Hypercalcaemia 51

Chapter 9: Management of Hypomagnesaemia 57

Chapter 10: Management of Hypophosphataemia 63

Chapter 11: Management of Acute Kidney Injury 69

Appendices: A. Observation Chart and the NEWS Concept 77 B. A Simpliﬁ ed Fluid Prescription Chart 81 C. Check list for Fluid Prescription 83

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INTRODUCTION

The ABC notes’ objective is to promote quality in patients’ care, particularly in the ‘developing’ part of the world where access to resources is limited. The notes are meant to provide information to aid trainees and general clinicians caring for adult patients. It is not proposed that they are used to set up a standard of care or an exclusive management plan; it is the responsibility of the clinician to inter- pret and apply the information they contain. Practice will understandably not be uni- form, depending on the available resources; health-care professionals should treat every case on its own merits. Contact a senior colleague or an expert if in doubt. The stepwise structure given in the clinical management ﬂ owcharts is to ensure sim- pliﬁ cation and consistency in clinical decision-making. Introductory General Principles about Electrolyte disorders: 1. Laboratory personnel are to telephone abnormal results to the treating team or the ward. Always compare with previous results, when available; 2. The symptoms and signs (S/S) are usually proportionate to the degree and speed at which the electrolyte imbalance (increase/decrease) develops. The S/S are prominent when the imbalance in s[electrolyte] occurs rapidly or is large;

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3. A thorough history and physical examination usually discloses the cause and guides management – causes are typically evident from the history; 4. Management depends on a comprehensive history, thorough physical examination, and selective investigations. Apply the ABCDE approach in very ill patients; 5. Secure proper intravenous (IV) access for IV replacement: large veins, or CV line if access poor for K, Ca, PO4, and Mg replacement infusions. Use an infusion pump to prevent overly rapid administration when replacing all fi ve electrolytes; 6. Prevention of electrolytes imbalance: A. Proper assessment of body fl uid balance status. Use IV fl uids only if oral or enteral route is not possible. Apply the fi ve Rs, intravenous fl uid chapter. B. Ill patients need closer monitoring to avoid electrolytes imbalance; C. Remove, and treat any precipitating factor(s); D. Fluid balance charts should be designed to include: a. Input prescription – type, route, and rate of administration. Guidance for fl uid selection. Methods for calculating infusion fl uid requirements; b. Output monitoring – UOP, fl uid losses from gastrointestinal or skin, daily weighing; c. Monitoring of serum electrolyte levels. The ABC notes are written for the non-specialist. The chapter on management of AKI is written principally to inform the non-specialist, including when to involve the intensivist and the nephrologist. The practical exercises are basic, discussing important clinical themes. They will hopefully consolidate the information given. Consultation of the local guidelines, and of the local formulary, if available, is advised for prescription purposes. More elaboration on the booklet subjects will soon be provided in PowerPoint for- mat, on the web, to provide more insight and to aid teaching. Finally, comments and suggestions to improve the booklet are sincerely invited. Kindly communicate through the e-mail: [email protected] Confl ict of interest disclosure: None

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INTRAVENOUS FLUID THERAPY IN ADULTS

Intravenous Fluids and Electrolyte (IVF) administration is an important, common therapeutic intervention; water constitutes 60% of total body weight in men and 55% in women[1]. It is crucial to prescribe the correct fl uid type, volume, and administration rate[1]. Adequate IVF prescribing necessitates a meticulous assessment of fl uid balance and a proper understanding of the physiology and pathophysiology of the distribution of water and electrolytes in addition to the properties of common IVF[1, 2]. Intravenous fl uids should be administered only if a patient’s requirements cannot be fulfi lled through the oral or enteral route; they should be stopped as soon as possible[1]. Intravenous fl uids should be administered under stringent monitoring of the patient’s response through frequent recording of vital signs, at least daily fl uid balance charts/weight, and measurement of renal function; appropriate actions should be taken when necessary[1, 2]. Prescription of intravenous fl uid is usually carried by the most junior doctors[1, 3]. Uninitiated prescribing is a result of insuffi cient knowledge and training and could induce serious complications. Excessive or inappropriate fl uids may precipitate pulmonary oedema or severe hyponatraemia, whereas under-resuscitation can result in Acute Kidney Injury (AKI)[2, 4].

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Normal distribution of water in the body: a man of 70kg total body weight:

Total Body Water (TBW) volume542L, 60% body weight (Mainly in muscles, less in fat) ICF volume528L, ECF volume514L, 40% body weight (2/3 TBW) 20% body weight (1/3 TBW) Interstitial ﬂ uid Plasma volume511L, volume53L, 80% of ECF 20% ECF

Abbreviations: ICF5Intracellular Fluid; ECF5Extracellular Fluid

Daily ﬂ uid balance under normal conditions: a man of 70 kg total body weight:

Input Output Source Volume (ml) Site of loss Volume (ml) Water 1000 Urine 1000 Food 650 Skin (insensible) 500 Oxidation (insensible) 350 Lungs (insensible) 400 Faeces 100 Total 2000 Total 2000 Adapted from[5]. Daily (24 hour) ﬂ uid requirements of a healthy adult are 25–35ml/kg.

Daily electrolytes requirements:

Daily requirements (mmol/kg) For 70kg Adult Sodium 1 –2 70 –140 Potassium 0.5 –1 35 –70 Calcium 0.2 –0.3 1.4 –2.1 Magnesium 0.35 –0.45 24.5 –31.5 Chloride Equal to Na Equal to Na - Bicarbonate/Acetate Use with Cl to balance cations Use with Cl to balance cations and help PH and help PH Daily glucose requirements are 50–1Y00g

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Fluid balance in disease and injury It is worth remembering that the physiological diffi culty in excreting an excess sodium and water load becomes more pronounced in disease and injury. This is driven by the non-specifi c metabolic responses to stress and infl ammation[5, 6]: 1. The stress response to injury or surgery stimulates secretion of ADH, catecholamines and activates Rennin-Angiotensin-Aldosterone System (RAAS). It results in Water and Salt Retention (anti-diuresis and oliguria), even in the presence of volume overload. 2. Increased systemic capillary permeability causes extravasation of albumin and fl uid into the interstitial space. It results in intravascular hypovolaemia, inducing further sodium and water retention by activation of the RAAS and secretion of ADH.

The multiple haemodynamic and non-haemodynamic stimuli for ADH secretion place acutely ill in-patients at risk of developing hyponatraemia[2, 7], and the simultaneous activation of the RAAS is probably protective.

3. RAAS activity and cellular loss of potassium secondary to protein catabolism causes potassium depletion that reduces the ability to excrete a sodium load[5, 6]. In addition[5, 6]: 4. Saline infusion causes Cl/Na overload. Hyperchloraemia induces renal vasoconstriction and the reduced GFR compromises the ability of the kidney to excrete sodium and water, see resuscitation below; 5. External pressure kidney (Abdominal Compartment Syndrome) plus increased intra-capsular pressure due to oedematous renal tissue can precipitate AKI.

NB. It is crucial, post-surgery, to diﬀ erentiate the harmless oliguria caused by the stress response from that caused by AKI.

Further, normal ﬂ uid and electrolyte balance can also be signiﬁ cantly altered in malnutrition, medical treatment (e.g., Diuretics, NSAIDs), and organ dysfunction (e.g., Oedema in Heart Failure, Renal Failure, Liver Failure i.e. re-distribution)[5, 6].

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IV Fluid, Crystalloids and Colloids: constituents, properties and indications:

Na/Cl K Other Osmolarity PH/ Max Duration Indication MWT dose (ml/ of ECV (kDa) Kg/24h) expansion, hour NSa 154/154 0 0 308 5 –5.5/0 None 1–4 Res (Fluid of (isotonic) choice)

Hartmann’sa 131/111 5 Lactate 279 6.5/0 None 1–4 Res (HM) (~ RL) (HCO3)/Ca: Rep (Fluid 29/2 of choice) D5Wa 0/0 0 50g D/1L 280 4.5/0 Avoid NA RM–use D/S (hypotonic) over usage Gelatinb 4% 154/120 0 Succinylated, 274 7.4/30 None 3 –4 Consider for (Gelofusine) Cross-linked Res 5% Albumenb 130–160/ 0 Protein 12.5g 310 7.4/69 None 12 –24 Consider for 130–160 Res a5Crystalloid; b5Colloid Abbreviations: MWT5Molecular Weight, kDa5Kilodalton, NS50.9% Normal Saline, Res5Resuscitation, HM5Hartmenn’s, RL5Ringer’s Lactate, Rep5Replacement, D5%W55% Dextrose in Water, RM5Routine Maintenance, D/S5Dextrose/Saline *D5%W infusion: has no eﬀ ect on tonicity; dextrose is rapidly taken up by the cells and metabolised[2]. Thus, the steady state eﬀ ect is that of adding water, which dilutes plasma. An isotonic solution is that with a sodium concentration [Na] approximately equal to serum [Na][2].

The Colloid Osmotic Pressure, [Oncotic Pressure], (mmHg) for: Plasma is 25; Gelofusin is 26–29; 5% Albumen is 20; and 0 for Crystalloids.

Colloids vs Crystalloids for ﬂ uid resuscitation: Crystalloids Colloids MWT/IV persistence Low/short High/(retained IV) Replacement volume required Large Less (increase BP more rapidly) Interstitial oedema 111 1 Cost Low High IV5Intravenous, Y5Yes, N5No

Despite their theoretical superiority over crystalloids, colloids’ eff ect is less than expected due to capillary leak in acute illness[5]. Gelatins have a low MWT as higher MWT solutions tend to gel[8], and is rapidly excreted through the kidneys; hence short-term volume expansion. Moreover, the substantially higher cost of colloids, their adverse side eff ects’ profi le and the lack of clinical superiority over crystalloids deter their use in resuscitation[8–11].

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ASSESSMENT OF VOLUME STATUS

Assess and manage patients’ ﬂ uid and electrolyte needs as part of at least every day ward review. Extra-vascular volume deﬁ cits do not become clinically apparent until they reach 10% of body weight.

The pre- (rarely available) and post-fl uid loss body weight is the most accurate parameter for assessing total fl uid defi cit. There is no formula available for an accurate estimation of total fl uid defi cit[12]. Hence, assessing hypovolaemia and IVF requirement is a summation of: a. History: fl uid losses, e.g. diarrhoea and vomiting; co-morbidities; current medications etc.; b. Clinical examination: current status and trends in:

Clinical indicators of moderate/severe volume depletion:

ECF volume: Moderate deﬁ cit Severe deﬁ cit General Decreased skin turgor Atonic muscles Sunken eyes National Early Warning Score (NEWS)$5[1,13,14] CVS Postural hypotension Hypotension (SBP,90) Tachycardia (HR.90 bpm) Absent peripheral pulses Collapsed veins CNS/autonomic responses Fatigue/lethargy Cold extremities/Pallor (the commonest symptoms) Stupor/coma RR.20/minute[1]. GIT Anorexia Nausea and Vomiting Anorexia Ileus Fluid balance charts UOP,30 ml/h suggest the need for IVF

c. Laboratory investigations – current status and trends:

Serum biochemistry Disproportionately high serum urea compared to creatinine High serum lactate indicates tissue hypoperfusion High Hct/Albumen (if not caused by bleeding) Hypokalaemia indicates the need for potassium supplementation Urine biochemistry u[Na] reﬂ ects renal perfusion, and a low value ( , 20 mmol/L) indicates renal hypoperfusion.

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Proper assessment is a collective integration of history, physical signs and laboratory ﬁ ndings – FBC and UEs[1], followed by clinical monitoring of current status and the pattern of change in NEWS, ﬂ uid balance charts, and weight[1]. The use of the conventional CVP/PWP and sophisticated haemodynamic parameters has limitations.

If the assessment indicates the need for parenteral fl uid: Remember the fi ve R's on prescribing intravenous fl uids:

The 5 Rs. Indication Fluid of choice Volume

1. Resuscitation# Severe intravascular Isotonic crystalloids: A bolus of 500ml over (to restore the depletion NS or , 15 minutes intravascular volume HM[1, 2, 8, 15] Re-assess: give up to and tissue perfusion) 2L of NS as rapidly as possible–Senior advice if no response

2. Routine maintenance Euvolaemic but, unable (5% D‡10.45% saline120 ~2L or (RM)* to take PO or enterally KCl) – monitor for HoN/ Previous 24hr UOP1 (to maintain the ECV (e.g. NPO pre/post-op- HrN[12] insensible losses and normal erative; on ventilator) electrolyte balance) (switch to PO or enteral asap)

3. Replacement 1Ongoing losses: D/V; HM[1] Adjust the IV RM: post-AKI polyurea,/ (“increase”) to ac- excessive sweating, count for the losses high OP stoma, etc. Correct electrolyte deﬁ cits (or excesses)

4. Re-distribution Abnormal ﬂ uid distribu- “Decrease”[1] Adjust the IV RM: tion from the circulation (“decrease”) to account to the tissues: for the 3rd spacing e.g. Gross oedema Correct electrolyte deﬁ cits (or excesses)

5. Re-assess and continuously monitor the clinical fl uid status/response to therapy (at least daily): a. History – fl uid losses, co-morbidities, current medications etc. b. Clinical examination – ABCDE (trends and context): BP/PR: the most important parameters to guide the volume of fl uid replacement required; Body weight (base line and daily): the best measure for assessing and monitoring volume balance– defi cit/gain; Fluid balance charts. c. Laboratory investigations: Laboratory values (UEs); u[Na] may be helpful in patients with high volume GI losses: Reduced u[Na] excretion (,30 mmol/L)5total body Na depletion u[Na]: if,155persistent volume depletion and the need for more fl uids NB. u[Na] values may be misleading in the presence of renal impairment or diuretic therapy

Adapted from[1]. Abbreviations: NS5Normal Saline, HM5Hartmann’s Solution

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Resuscitation#: balanced crystalloids, such as Hartmann’s or Ringers lactate/ acetate, are favoured over normal saline as the fi rst choice[6, 8] because comparative human studies revealed that normal saline is associated with higher s[Cl] and metabolic acidosis[16–18] as well as reduced renal blood fl ow[19]. In animal models, hyperchloraemia was long known to produce renal vasoconstriction and reduced glomerular fi ltration rate[20]. The data in relation to the eff ect on serum potassium is confl icting. Compared to balanced crystalloids, normal saline was associated with a comparable incidence of hyperkalaemia[21] in the most recent publication; higher serum potassium[22], and hyperkalaemia[23] in peri-renal transplant patients. However, this ‘physiological̕ superiority of balanced crystaloids is not yet borne out in the available limited, small, ‘clinical’ trials. A Cochrane systematic review revealed that the choice of non-buff ered salt-based (e.g. normal saline) or buff ered (modifi ed with adding bicarbonate or bicarbonate precursors – balanced crystaloids) intravenous fl uids in the peri-operative period has no infl uence on mortality, renal function and blood loss; both are safe and eff ective[24]. The use of a buff ered crystalloid compared with normal saline, in intensive care units (mostly post-operative), did not reduce the rate of AKI or renal replacement therapy[25]. Studies in kidney transplant patients revealed no diff erence in the transplant outcome between patients receiving peri- transplant normal saline or those receiving balanced solutions[18, 21–23]. There was a tendency towards increased thrombotic propensity in the balanced solutions arm; two patients lost their graft to transplant renal artery thrombosis[22].

Resuscitation: normal saline is preferred in patients with hyponatraemia, alkalosis, cerebrovascular disease or brain injury[26].

Routine Maintenance*: the National Institute for Health and Care Excellence (NICE) recommendation for starting routine maintenance fl uids, by giving 25–35ml/ day of hypotonic crystaloids ([4% D/1/5 NS/27 mmol KCl]/L) under close monitoring to provide 1mmol/kg of Na, Cl and K[1], has since been disapproved in a recent North American publication[2]. Isotonic Fluids are recommended as the fi rst choice, because hypotonic (Na,130) IVF was the main ‘reported’ cause of hospital-acquired hyponatraemia[2]. The ‘evidence-base’ for favouring isotonic fl uids over hypotonic fl uids was from comparative prospective studies in a diff erent population, children, the majority of whom were surgical and critical care patients rather than acute admission units or general wards[2]. Of the isotonic fl uids ‘balanced’ crystalloids are probably superior to normal saline[6, 8]. However, the disparity would confi rm that close clinical and biochemical monitoring is as important as the choice of intravenous fl uid type.

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Give less volume, ~20ml/Kg/day, for elderly and those with renal and heart failure[1].

4–5% D‡5is given to prevent excess catabolism and limit starvation ketosis, 50–100g of glucose/day[1, 2]. It prevents hypoglyacaemia, but does not provide complete nutritional support[1, 2]. Involve the dietician to address nutritional needs[1].

Methods of parenteral ﬂ uid administration: IV, SC, IO (intraosseous–a rescue technique in paediatrics mainly, safe, eﬀ ective, reliable and relatively simple).

Fluid choice was historically guided mainly by a theoretical, physiological rationale, and pre-clinical studies[1, 8]. The sparse evidence and the controversy about the ideal IVF composition in diﬀ erent clinical settings[1,2,5–8] necessitates conducting well-structured, large, randomised, controlled trials. Currently, in either choice; judicious administration of IVF under meticulous clinical and biochemical monitoring is mandatory, and every case ought to be managed on its own merits. International guidelines were a success in disciplines such as renal medicine, and a call for guidelines in this ﬁ eld is pertinent.

DO NOT PRESCRIBE IVF FOR.24 HOURS

CONCLUSION

Prescribing IVF should be part of the core medical pre- and post-graduate training. Hospitals need to appoint a senior medical staﬀ members, doctors and nurses, as intravenous ﬂ uid management champions, and arrange for periodical tutorials and workshops on the subject. Monitor and Audit.

REFERENCES

[1] National Institute for Health and Care Excellence (NICE 2013): Intravenous ﬂ uid therapy for adults in hospital. (Clinical Guideline 174). www.nice.org.uk/CG174. [2] Moritz, M.L. and Ayus, J.C. Maintenance Intravenous Fluids in Acutely Ill Patients. The New England Journal of Medicine (2015), Vol. 373, pp. 1350–60. DOI: 10.1056/NEJMra1412877. [3] Lobo, D.N., Dube, M.G. and Neal, K.R. Problems with solutions: drowning in the brine of an inadequate knowledge base. Clinical Nutrition (2001), Vol. 20, No. 2, pp. 125–130.

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[4] National Confi dential Enquiry into Perioperative Deaths. Extremes of age: the 1999 report of the National Confi dential Enquiry into Perioperative Deaths (1999). www.Ncepod.org.uk/ pdf/1999 /99full.pdf. [5] Frost, P. Intravenous fl uid therapy in adult inpatients. British Medical Journal (2015), pp. 350. doi: http://dx.doi.org/10.1136/bmj.g7620 [6] Powell-Tuck, J., Gosling, P. and Lobo, D.N. (2011). British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients. http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup .pdf (viewed in 05.2015). [7] Steele, A., Gowrishankar, M. and Abrahamson, S. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Annals of Internal Medicine (1997), Vol. 126, pp. 20–5. [8] Severs, D., Hoorn, E.J. and Rookmaaker, M.B. A Critical Appraisal of Intravenous Fluids: from the physiological basis to clinical evidence. Nephrol Dial Transplant (2014), Vol. 30, pp. 178–187. doi: 10.1093/ndt/gfu005. [9] Gosling, P., Rittoo, D. and Manji, M., Hydroxyethylstarch as a risk factor for acute renal failure in severe sepsis. Lancet (2001), Vol. 358, p. 581. [10] Roberts I. Colloids versus crystalloids for fl uid resuscitation in critically ill patients. The Cochrane Database of Systematic Reviews 2004. CD000567. [11] Perel, P., Roberts, I. and Ker, K. Colloids versus crystalloids for fl uid resuscitation in critically ill patients. Cochrane Database Systematic Reviews (2013), p. 2. CD000567. [12] Uptodate. Maintenance and replacement fl uid therapy in adults (accessed 12.12.2015) [13] Royal College of Physicians. National Early Warning Score (NEWS): standardising the assessment of acute-illness severity in the NHS. RCP, 2012. [14] National Institute for Health and Care Excellence (NICE): Acutely ill patients in hospital: recognition of and response to acute illness in adults in hospital. [15] KDIGO Clinical Practice Guideline for AKI. KI Supplements (2012), Vol. 2, No. 1. http://www. kidney- international.org [16] McFarlane, C. and Lee, A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fl uid replacement. Anaesthesia (1994), Vol. 49, pp. 779–781. [17] Williams, E.L., Hildebrand, K.L., McCormick, S.A. and Bedel, M.J. The eff ect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesthesia & Analgesia (1999), Vol. 88, pp. 999–1003 [18] Hadimioglu, N., Saadawy, I. and Saglam, T. The eff ect of diff erent crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesthesia & Analgesia (2008), Vol. 107, pp. 264–269. [19] Chowdhury, A.H., Cox, E.F., Francis, S.T. and Lobo, D.N. A randomized, controlled, double- blind crossover study on the eff ects of 2-L infusions of 0.9% saline and plasma-lyte (R) 148 on renal blood fl ow velocity and renal cortical tissue perfusion in healthy volunteers. Annals of Surgery (2012), Vol. 256, pp. 18–24. [20] Wilcox, C.S. Regulation of renal blood fl ow by plasma chloride. The Journal of Clinical Investigation (1983), Vol. 71, pp. 726–735. [21] Potura, E., Lindner, G., Biesenbach, P., et al. An acetate-buff ered balanced crystalloid versus 0.9% saline in patients with end-stage renal disease undergoing cadaveric renal transplantation: a prospective randomized controlled trial. Anesthesia & Analgesia (2015), Vol. 120, No. 1, pp. 123–9. doi: 10.1213/ANE.0000000000000419.

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[22] Khajavi, M.R., Etezadi, F. and Moharari, R.S. Eff ects of normal saline vs lactated Ringer’s during renal transplantation. Renal Failure (2008), Vol. 30, pp. 535–539. [23] O’Malley, C.M.N., Frumento, R.J. and Hardy, M.A. A Randomized, Double-Blind Comparison of Lactated Ringer’s Solution and 0.9% NaCl During Renal Transplantation. Anesthesia & Analgesia (2005), Vol. 100, No. 5, pp. 1518–1524. doi: 10.1213/01.ANE.0000150939.28904.81 [24] Burdett, E., Dushianthan, A. and Guerrero E. Perioperative buff ered versus non-buff ered fl uid administration for surgery in adults. Cochrane Database of Systematic Reviews (2012), p. 12. CD004089. [25] Young, P., Bailey, M. and Beasley, R. Eff ect of buff ered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. The Journal of the American Medical Association (JAMA), (2015), Vol. 314, No. 16, pp. 1701–10. doi: 10.1001/jama.2015.12334. [26] Lobo, D.N. and Awad, S. Should chloride-rich crystalloids remain the mainstay of fl uid resuscitation to prevent ‘Pre-Renal’ acute kidney injury? Kidney International (2014), Vol. 86, No. 6, pp. 1096–1105. doi: 10.1038/ki.2014.105.

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MANAGEMENT OF HYPONATRAEMIA

Hyponatraemia (HoN) is a serum sodium concentration (s[Na]),135mmol/l. It is due to an excess of body water in relation to existing Na stores. HoN is the commonest disorder of body fl uid and electrolyte balance and is usually an incidental fi nding on routine blood tests. It is often multifactorial. The classifi cation according to Extracellular Volume (ECV) status is most useful for its diagnostic and therapeutic value. Management of HoN depends on comprehensive history, thorough physical examination and selective investigations[1–8].

T YPES OF HYPONATRAEMIA[1–8] 1. Hypotonic (dilutional) HoN: is the commo nest type. It is the type associated with a hypotonic state (hypotonicity and IC oedema), responsible for the Symptoms and Signs (S/S). Its causes and management are discussed in the ﬂ ow charts below and the section ‘Treatment – further’.

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Low measured Serum Osmolality (sOsm): in most cases, see fl ow chart below. Normal measured sOsm: secondary to fl ushing with iso-osmotic solutions during Transurethral Resection of the Prostate (TURP) – using glycine or sorbitol; both are ineff ective (permeable) osmole. High measured sOsm: secondary to alcohols and advanced Chronic Kidney Disease (CKD). It is hypotonic despite the high sOsm as both alcohol and urea are ineff ective osmoles. 2. Non-hypotonic (measured sOsm normal or high) HoN: Isotonic: normal measured sOsm (pseudo-hyponatraemia) HoN: due to high protein or lipids. Hypertonic: high measured sOsm (translocational, re-distributive) HoN: due to hyperglycaemia or hypertonic mannitol – both are eff ective (impermeable) osmoles.

Non-hypotonic hyponatraemia is not associated with the hypotonic state; hence no S/S of HoN

Hypotonic HoN: Clinical Management Flow Chart[1–8]

Symptoms and Signs (S/S): Asymptomatic in most patients; often non-speciﬁ c; moderate: nausea, headache and S/S are prominent when confusion; severe: drowsiness, seizures and the decrease in s[Na] coma – death from * occurs rapidly or is large Brain herniation in acute cases. Unless s[Na] is falling rapidly, levels of 125–135mmol/l are usually asymptomatic O/E: assess ECV Mucous Membranes, Skin Turgor, Blood Pressure (BP), Pulse – aided by biochemical tests Investigations: Paired Serum & Urine (spot sample): U&E, (s[Na] in mmol/l) Osmolality; Glucose (serum) Degree of HoN, if s[Na]: mild: 130–135; Moderate: 125–129; Severe: ,125

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Hypotonic HoN: Clinical Management Flow(1–15)

ECV Hypovolaemic HoN Euvolaemic HoN Hypervolaemic Mechanism Relative depletion of salt to Excess of water to salt Retention of water water Exclude the error of 11(ADH), and salt sample taken from the 1 (RAAS ) drip arm

Expected uOsm$100a uOsm$100a uOsm$100a Results sUrea.7 (UA normal /high) sUrea,7 (UA low) sUrea variable sOsm,275 u[Na].30 u[Na].30 u[Na]#30 (if not on (mOsm/kg) diuretics)

Causea: 1. Renal losses: 1. SIAD, 1. Advanced Cardiac Rate of onset: Diuretics – especially HCZ, [Drugs – CMZ, TCA, failure Acute,48h renal tubular disease, SSRI, PPI, Pulmonary, 2. Advanced Hepatic Chronic$48h Addison’s, Cerebral salt Cerebral diseases, failure wasting syndrome Secondary adrenal 3. Nephrotic syndrome insuﬃ ciency, 4. Renal failure (NB. 2. Extra-renal losses: Hypothyroidism sOsm.295, u[Na] GI (diarrhoea/vomiting)/ (rare)] .30) Skin (sweat) (NB: u[Na]#30) 2. Psychogenic Polydipsia; low salt intake (rare) Excess iv ﬂ uids – 5%D (the commonest cause) (NB. uOsm,100)

Treatment [1–4, 8–13] Restore euvolaemia SIAD: 1. Restrict Na intake (the 5 Rs – see IVF therapy, Treat underlying cause ,100mmol/day and P --- ): e.g. 0.9% NS 1–2L in FR as in SIADH. b Fluid Res triction (FR) 3 hr then sodium chloride (to,UOP volume) 2. For renal and cardiac 0.45% 1–2L in 12hr. usually to ,800ml/d failure: furosemide Recheck U&E at 3 and (ﬁ rst line treatment) 80mg oral or 40mg IV. 3. For hepatic failure 12hrs, monitor UOP Osmotic solutes PO, stop all diuretics. See Urea (second line text treatment) or 4. If hypokalaemic or NaCl 1 Low dose HCO3.32mmol/l furosemide 20mg am/ correct K deﬁ cit, see MD P () Monitor the response Abbreviations: ADH5Anti-Diuretic Hormone; RAAS5Renin-Angiotensin-Aldosterone System; sOsm5Serum Osmolality; uOsm5Urine Osmolality; UA5Uric Acid; HCZ5Hydrochlorothiazide; SIAD5Syndrome of Inappropriate Anti-Diuresis; CMZ5Carbamazepine; TCA5Tricyclic Antidepressant; SSRI5Selective Serotonin Reuptake receptor Inhibitor; PPI5Proton Pump Inhibitors; D5Dextrose; UOP5Urine Output; PO5Orally; MD5Mid-Day *Brain Herniation is reported almost exclusively in acute hypotonic HoN (short time for brain adaptation): post-operative in women and children, massive water ingestion in psychosis and marathon runners; intracranial pathology e.g. SAH. auOsm$100 indicates an inappropriately concentrated urine, usually substantially higher: uOsm typically.sOsm.

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Treatment for all Patients (continuation) a. Swift determination and treatment of the underlying cause. Monitor s[Na] and UOP; b. Stop non-essential parenteral ﬂ uids and medications that can provoke hyponatraemia; c. Correct any concomitant hypokalaemia, this raises s[K] and s[Na] simultaneously; d. Rate of correction of HoN depends on the duration, symptoms and severity; e. Hypertonic saline, see footnote, should be used carefully with consultant approval; f. Failure to correct or recurrence of hyponatraemia merits referral to the appropriate team, e.g. renal, endocrine and psychiatric.

Treatment (further) 1. Prompt ﬂ uid resuscitation in volume-deplete patients to restore Euvolaemia: The type, strength, volume and rate of administration of the IV ﬂ uid should be clearly written and explained to the nurses. See chart above and note below.

bRestoring EC volume stops the non-osmotic stimulation of ADH release and promotes water diuresis that speeds correction – can cause overly rapid correction. Hence, sudden increase in UOP to (.100ml/h) suggests that a rapid correct of hyponatraemia is imminent and necessitates optimising the ﬂ uid type, e.g. ½ NS instead of NS and closer monitoring of s[Na] levels.

2. Emergency therapy, using 3% Hypertonic Saline Solution (HSS) (513mmol/l): Hyponatraemia with SEVERE symptoms such as seizures or coma, see footnote.

On achieving the s[Na] correction target – do not expect patients with symptoms to completely recover immediately

3. Non-emergency, in-patient therapy: a. Hyponatraemia with moderate symptoms, including self-induced water intoxication and post- operative cases, admit. Apply the steps in b. below as appropriate. Close monitoring. Consider HSS at a lower dose and slower infusion rate.

b. Severe Hyponatraemia with no or mild symptoms, admit: Fluid restriction (,800ml/d) to introduce negative ﬂ uid balance: in patients with oedema (HF/ Cirrhosis), advanced CKD, SIADH, and PP. Loop Diuretics (LD) in HF/SIADH. This also guards against volume overload if HSS is used.

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Osmotic solutes orally in SIADH with s[Na] .120: Urea (20–120g powder in, e.g. orange juice), it induces osmotic diuresis, increasing the excretion of electrolyte-free water. NaCl 1 LD are an alternative. Avoid Demeclocycline/Lithium because of their side eff ects profi le, the unpredictability of N DI, and the diffi culty of titrating the eff ect when it happens.

4. Community Treatment: Chronic Moderate Hyponatraemia: (SIAD, heart failure, or cirrhosis) is typically Asymptomatic. It can be associated with subclinical or subtle neurological symptoms, e.g. gait instability, falls and cognitive deﬁ cit. Thus selective treatment, in the community, as outlined in 3/b above is worthwhile.

CONCLUSION Prevention of hyponatraemia is of paramoxunt importance since most initial therapies, such as ﬂ uid restriction, are relatively ineﬀ ective in correcting euvolemic and hypervolemic hyponatremia[16].

3% Hypertonic Saline Solution (HSS): Suggested 3% HSS boluses: 100ml bolus over 10–15 minutes; increases s[Na] by 2–3mmol/l; check s[Na] after 20 minutes. If severe neurologic symptoms persist, or if the s[Na] is not improving, a 100ml bolus of HSS can be repeated 1–2 more times at 10-minute intervals. Rapidly increase s[Na] by 4–6mmol/l over several hours; this alleviates symptoms and prevents Brain Herniation. If no symptomatic improvement, other possibilities should be explored. The increase in s[Na] should not exceed 8mmol/l in any given 24hr period to avoid the rare, serious Osmotic Demyelination Syndrome (ODS), in chronic hyponatraemia when s[Na] increases too rapidly. The risk of ODS through overly rapid correction is less of a concern in acute hyponatraemia because the brain has not had time to adapt to its hypotonic environment. However, this would make them more prone to develop brain herniation and necessitates prompt therapy[1–5,7,9,10–12]. Patients at highest risk of ODS are those with: s[Na]#105mmol/l; Hypokalaemia; Thiazide therapy; Alcoholism; Malnutrition; Liver disease. Close monitoring of treatment in ‘ICU’ to avoid s[Na] overcorrection and possible ODS: Beware: the correction can be much more than the expected or calculated. Apply conservative therapeutic goals for correction, 8mmol/l in 24hrs, 14mmol/l in 48hrs and 16mmol/l in 72hrs. Monitor s[Na] and UOP to prevent overcorrection, every 2hr in emergency cases. Reduced ADH secretion and Brisk Diuresis is the commonest cause of overcorrection. Sudden increase in UOP to (.100ml/h) suggests a rapid correction of hyponatraemia is imminent, and necessitates closer monitoring of s[Na] levels. If overcorrection occurs, stop HSS; consider Desmopressin 2mcg IV with 5%D 10ml/kg over 1hr to re-lower s[Na]. Hypokalaemia correction can contribute to s[Na] overcorrection[3,9–11,14]. HSS: the experience and evidence to guide its use is very limited. A global clinical trial or at least a prospective, standardized registry to collect data on its use is worthwhile. Chronic HoN: the administration of HSS will only be required in exceptional circumstances. HHS: prepare if not available, arrange with the pharmacist.

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Practical Exercises 1–4 All results are in mmol/L unless stated otherwise

Practical Exercise 1: A 60 year old healthy chronic smoker presented to his doctor with general malaise. He was euvolaemic, weight 70kg, early clubbing, systemic examination was unrevealing. Lab results: s[Na] 110, s[K] 4, urea 2, s[Cr] 54μmol/L, sOsm 226mOsm/ Kg, uOsm 618mOsm/Kg, u[Na] 46. Other biochemical tests and Full Blood Count (FBC) indices were within the normal range. Chest X-ray (CXR) revealed a suspicious shadow left mid-zone. He was admitted under the respiratory physicians for further investigations.

Q1. The cause of hyponatraemia is: a. SIADH b. Addison’s disease c. Psychogenic polydipsia d. Pseudo-hyponatraemia e. Central diabetes insipidus

A1. The cause is SIADH, statement (a), resulting in euvolaemic hypotonic hyponatraemia. The SIADH is likely due to bronchogenic carcinoma.

Q2. Treatment included: a. 0.9% Normal saline, 24hr infusion, at 100mL/h b. 750mL oral ﬂ uid restriction c. 3% HSS at 100ml infusion over 20 minutes d. Intravenous furosemide and sodium chloride e. Demeclocycline

A2. Treatment included ﬂ uid restriction, statement (b); oral furosemide and sodium chloride.

Practical Exercise 2: A 21 year old athlete developed a grand mal seizure after completing the marathon. Observations were unremarkable, weight was 62kg. He was in post-ictal state; Glasgow Coma Scale (GCS) was 6/15, needed intubation. Other systems examination was unrevealing. s[Na] 114, it was normal a week earlier at a routine medical,

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s[K] 4.2, urea 1, s[Cr] 46μmol/L, sOsm 232mOsm/Kg, uOsm 98mOsm/Kg, and u[Na] 32. Other complete biochemical screening, FBC, and C-Reactive Protein (CRP) tests were normal.

Q1. The cause of hyponatraemia is: a. Cerebral salt wasting syndrome b. Hypothyroisism c. Excessive water intake d. Diabetic ketoacidosis e. SIADH

A1. The cause is excessive water intake, statement (c), causing euvolaemic hypotonic hyponatraemia.

Q2. What is the immediate treatment? a. 0.9% Normal saline at 250mL/h b. 750mL oral ﬂ uid restriction c. Intravenous anti-convulsant infusion d. Tolvaptan e. 3% HSS at 100ml infusion over 20 minutes

A2. The immediate treatment is 3% HSS at 100ml infusion over 20 minutes, statement (e). Tolvaptan is contraindicated in hyponatraemic urgencies, hypovolaemia, and liver disease.

Practical Exercise 3: A 70 year old male was admitted with diarrhoea, vomiting for four days, lethargy, and inability to stand because of dizziness for two days. He continued to take Indapamide for essential hypertension. The skin turgor was reduced, weight 64kg, BP 90/50, pulse rate 108 per minute. Systemic examination was unrevealing. Serum urea 16.4, s[Cr] 125μmol/L, s[Na] 108, s[K] 2.7, serum bicarbonate 28, sOsm 236 mOsm/Kg water and uOsm 655 mOsm/Kg water, u[K] 28.

Q1. The cause of hyponatraemia/ hypokalaemia is: a. Gastrointestinal and renal loss b. Mainly gastrointestinal loss c. Pseudo-hyponatraemia

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d. SIADH e. Lab error

A1. The cause is gastrointestinal and renal loss, statements (a), resulting in hypovolaemic hypotonic hyponatremia and hypokalaemia.

Q2. Treatment included: a. Admission to High Dependency Unit (HDU). b. Prompt ﬂ uid resuscitation with 5% dextrose c. Increase Indapamide dose d. A trial of Demeclocycline e. Slow sodium tablets

A2. He needed High Dependency Unit (HDU) admission, statement (a), and prompt ﬂ uid resuscitation with 2 litres (L) of (0.9% normal saline 1 20mmol KCl/L) over four hours. Euvolaemia restored, BP 115/70 mmHg, no postural drop. Repeat s[Na] 112, K 3. Intravenous ﬂ uid switched to hypotonic 0.45% saline120mmol KCl/L, 1L over next eight hours. This is because volume repletion stops the non-osmotic stimulation of ADH release and promotes water diuresis that speeds correction, can cause overly rapid correction. Further, s[Na] was 114, s[K] 3.1. Next 12 hours, additional infusion of 1L of 0.45% saline120mmol KCl, plus increased oral intake to match the increasing hourly UOP, this is to guard against overly rapid correction rate. Repeat s[Na] 116, s[K] 3.4. Over the next 24 hours patient was encouraged to drink to match the high UOP and given oral KCl, s[Na] and s[K] monitored closely. Indapamide was discontinued on admission.

Practical Exercise 4: A 76 year old male, chronic smoker, known case of hypertension admitted with increasing ankle swelling and shortness of breath. He felt unwell two months prior with intermittent central chest pains that lasted for a week; sought no medical advice. BP was 125/75mmHg, pulse rate 108/minute irregular. Jugular Venous Pressure (JVP) was high, lower limb oedema to the thigh, weight 78kg – 66kg three weeks earlier. Bi-basal chest crackles, systemic examination was unremarkable otherwise. Investigations included ECG, CXR, Echocardiogram, s[Na] 121, s[K] 4.3, sOsm 244mOsm/Kg, uOsm 554mOsm/Kg. Other biochemical screening, FBC and CRP tests

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were normal. A diagnosis of heart failure secondary to Ischaemic cardiomyopathy was made.

Q1. The cause of hyponatraemia is: a. SIADH b. Psychogenic polydipsia c. Renal loss of sodium d. Pseudo-hyponatraemia e. Congestive heart failure

A1. The cause is congestive cardiac failure, statement (e), resulting in hypervolaemic hypotonic hyponatremia.

Q2. Treatment included all except: a. Avoidance of loop diuretics as they will worsen hyponatraemia b. Scrupulous monitoring of weight and renal function c. Restrict Na1 intake ,100mmol/day d. Fluid restriction to 750ml/day e. Gradual introduction of beta blockers and RAAS blockade

A2. Treatment included all except (a). Loop diuretics are essential for diuresis, and correction of hyponatraemia.

REFERENCES [1] Spasovski, G., Vanholder, R. and Allolio, B. Clinical practice guideline on diagnosis and treatment of hyponatraemia. European Journal of Endocrinology (2014), Vol. 170, pp. G1–G47 [2] Verbalis, J.G., Goldsmith, S.R. and Greenberg, A. Diagnosis, Evaluation and Treatment of Hyponatremia: Expert Panel Recommendations. The American Journal of Medicine (2013), Vol. 126, No 10A http://dx.doi.org/10.1016/j.amjmed.2013.07.006 [3] Overgaard-Steensen, C. and Ring, T. Clinical review: Practical approach to hyponatraemia and hypernatraemia in critically ill patients. Critical Care (2013), Vol. 17, pp. 206. http://www.ccforum.com/content/17/1/206 [4] Young, I., Crean, P. and Fitzpatrick, K. Hyponatraemia in adults (on or after 16th birthday). Guidelines and Audit Implementation Network 2010 (GAIN), Northern Ireland. http://www.gain-ni.org/images/Uploads/Guidelines/Hyponatraemia_guideline.pdf [5] National Institute for Health and Care Excellence (NICE). Hyponatraemia. Clinical Knowledge Summaries. http://cks.nice.org.uk/hyponatraemia#!goalsoutcomes (accessed 05.2015)

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[6] The BMJ Best Practice. Assessment of Hyponatraemia. 11.2014. http://bestpractice.bmj.com/ best-practice/monograph/57/diagnosis.html [7] Adrogué, H.J., Madias, N.E. and Hyponatremia. New England Journal of Medicine (2000), Vol. 342, pp. 1581–1589, 25 May. DOI: 10.1056/NEJM200005253422107 [8] Fenske, W., Maier, S.K and Blechschmidt, A. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. The American Journal of Medicine (2010), Vol. 123, pp. 652–657. [9] Uptodate. Overview of the treatment of hyponatraemia in adults [10] Moritz, M.L. and Ayus, J.C. 100 cc 3% Sodium Chloride Bolus: A novel treatment for hyponatremic encephalopathy. Metabolic Brain Disease (2010), Vol. 25, pp. 91–96. [11] Sterns, R.H., Nigwekar, S.U. and Hix, J.K. The treatment of hyponatremia. Seminars in Nephrology (2009), Vol. 29, pp. 282–299. [12] Hew-Butler, T., Almond, C. and Ayus, J.C. Consensus statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa. Clinical Journal of Sport Medicine (2005), Vol. 15, pp. 208–213. [13] Gross P. Management of severe Hyponatraemia. Kidney International (2001), Vol. 60, pp. 2417–2427; doi:10.1046/j.1523–1755.2001.00063. [email protected] +49 351 458 2645.) [14] Mohmand, H.K., Issa, D. and Ahmad, Z. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clinical Journal of the American Society of Nephrology (2007), Vol. 2, pp. 1110–1117. (doi:10.2215/CJN.00910207) [15] The National Patient Safety Agency. Risk of harm from CPM syndrome following rapid correction of sodium 2012. http://www.nrls.npsa.nhs.uk/resources/type/signals/?entryid45=132971. [16] Greenberg, A., Verbalis, J.G. and Amin, A.N. Current treatment practice and outcomes: report of the Hyponatremia Registry. Kidney International (2015), Vol. 88, pp. 167–77.

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MANAGEMENT OF HYPERNATRAEMIA

Hypernatraemia (HrN) is a serum sodium concentration (s[Na])>146mmol/L. Hyponatraemia develops in very young or very old patients; those with altered mental state and dependent elderly are at particularly high risk[1–8].

Mechanism HrN is due to deﬁ ciency of body water in relation to existing Na stores Symptoms and Signs Primarily neurologic. Thirst; Neurologic symptoms vary – lethargy, confusion, Prominent when ﬁ ts and coma in acute cases. the increase in s[Na] Hypernatraemia is chronic (i.e.$48hrs) in almost all occurs rapidly or is patients. large

Clinical assessment: For dehydration (dry mucus membranes, reduced skin turgor); and volume status, hypovolaemia (postural BP and tachycardia) Investigations Paired Serum/Urine (spot sample) for U&E, osmolality. Serum glucose

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Management of Hypernatraemia, ﬂ ow chart[1–8]

Extracellular Hypovolaemia Euvolaemia Oedema Volume (ECV) (Un-replaced water loss) (Un-replaced water loss) the commonest cause of HrN

Mechanism Relative depletion of Depletion of water, Relative increase of salt water to salt normal total body [Na] to water

Expected uOsm* [.600].sOsm uOsm1 [,300 ] ,sOsm uOsm [.600].sOsm results u[Na],20 u[Na].100

Causes: 1. Inability to drink; Renal ‘free’ water losses Excess salt (The failure of thirst – (rare) e.g. Diabetes Insipidus (DI) administration commonest in hypothalamic lesions 1. Nephrogenic – lithium Euvolaemia: blue) are usually 2. Renal free water ‘ ’ is the commonest cause Conn’s S evident from losses: Osmotic the history) 2. Pituitary Cushing’s S diuresis, (Rare) e.g. hyperglycaemia Rate of onset: (ADH administration will 3. Extra-renal water diﬀ erentiate between Acute,48hrs losses, e.g. sweat, GI central and nephrogenic Chronic$48hrs DI)

Immediate a. Prompt determination and treatment of the Acute (rare): treatment underlying cause Discontinue Na Only hypotonic b. Restore euvolaemia in hypovolaemic patients[4,5] Rapid reduction in ﬂ uids are c. Fluid replacement: enterally where possible, the s[Na] to 145 appropriate[4] safest route Monitor s[Na] every 1–2hrs

Asymptomatic: Hypovolaemic1 Normovolaemic symptomatic: 1Symptomatic:

Oral fl uids a. 0.9% NS for Correct HrN Monitor s[Na] stabilisation with hypotonic daily (1L in 2hrs). fl uids: using b. Correct HrN fl uids estimation with hypotonic equations, see fl uids: text below Monitor s[Na] 4–6 hourly. s[Na] must not fall by.10mmol/l in 24hrs Monitor UOP/Weight Further If the cause is not apparent at this stage, DI should be considered and management patient referred to endocrine team Abbreviations: uOsm5urine osmolality; sOsm5serum osmolality; GI5gastrointestinal; UOP5urine output; DI5diabetes insipidus; NS5normal saline; *HrN: normally induces (maximally) concentrated urine, uOsm.600; or 1‘inappropriately’ dilute urine if uOsm,300 in DI.

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Treatment of Hypernatraemia (continuation)[1–8]: 1. Prompt determination and treatment of the underlying cause: control GI losses, fever/sepsis, hyperglycaemia, hypercalcaemia, etc. 2. Fluid therapy to correct hypernatraemia: a. First, restore euvolaemia in hypovolaemic patients[4,5]. b. The type of fl uid depends on whether there is overall fl uid depletion or sodium excess. c. The rate of hypernataemia correction relies on its duration: Rapid if acute Slow over 2–3 days if chronic at a maximum reduction of 10mmol/24hrs – rapid correction is potentially dangerous d. Add the 24-hour obligatory fl uid losses and any further ongoing incidental fl uid losses. 3. Everything else: anticonvulsants for patients with seizures, involve ICU team.

Only hypotonic ﬂ uids are appropriate. In pure water loss (e.g. DI) use water or 5% D. In hypotonic sodium loss (e.g. GI) use 0.18% or 0.45% sodium chloride in mild to moderate ECV reduction states respectively. 0.9% NS is unsuitable for managing HrN except in cases of severe circulatory compromise where a limited volume can be given for stabilization before using hypotonic ﬂ uids[4].

Indications for urgent admission to hospital are: s[Na].155mmol/L s[Na] 146–155mmol/L with neurological disturbance or an inability to drink adequately

Conditions requiring urgent treatment of HrN using hypotonic ﬂ uids (e.g. 5%D, 1/5 or ½ NS)[3]: Hyperosmolar Hyperglycaemic State (HHS), HyperOsmolar Non-Ketotic (HONK): stabilise with 0.9%NS if severely haemo compromised followed by hypotonic ﬂ uids. DI (central or nephrogenic) if s[Na].170: needs urgent correction with IV 5% dextrose Exogenous sodium ingestion or infusion can result in marked HrN s[Na].190: infusion of IV 5% dextrose combined with a diuretic administration to remove excess sodium.

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A. Chronic Hypernatraemia (or unknown duration[4], almost all patients: The Total Water Defi cit (TWD) should be corrected over 2–3 days. A fraction (~50%) of the TWD is replaced in the fi rst day as per the equation below. It is replaced [preferably by oral/enteral water; IV 5% D if severe or oral/enteral not possible] to avoid the risk of rapid lowering of s[Na] and the grave Osmotic Demyelination Syndrome (ODS). Equations for estimating fl uid replacement to correct hypernatraemia are given below.

The response to correction should be guided by monitoring the clinical status and s[Na] levels.

Re-measure s[Na] after 4-6hrs and adjust infusion rate if the correction is either too fast or too slow. Monitor s[Na] levels every 4–6hrs in patients with ongoing ﬂ uid losses and ‘Replace’.

The goal is to slowly lower s[Na] by a maximum of 10mmol/l in a 24hr period (0.4mmol/h). Overly rapid correction of chronic Hypernatraemia may lead to cerebral oedema.

B. Acute Hypernatremia (#48) is rare[1–8]:

Treatment: The goal is to rapidly reduce sNa1 to normal in,24hrs using the equations for estimating ﬂ uid replacement to correct hypernatraemia given below.

The entire TWD is replaced [by iv 5% Dextrose] within 24hrs; (hourly infusion rate5TWD/24hr)

Monitor s[Na] and blood glucose every 1–2hrs until s[Na] is#145mmol/l. Once s[Na] has reached 145mmol/l, the rate of infusion is reduced and continued until normal level (140mmol/l) is restored. DI: give desmopressin – with consultant approval Rapid infusion of 5% D may induce hyperglycaemia (and osmotic diuresis); worsen hypertonicity: Slow infusion Use the 2.5% D; use insulin if persistent

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Untreated acute hypernatremia can lead to permanent neurologic injury from: ODS Cerebral haemorrhage – brain shrinkage can cause vascular rupture and IC haemorrhage

NB. Fluid Resuscitation/Replacement: many patients with hypernatraemia have concurrent ECF volume depletion (i.e. hypovolaemia) and/or hypokalaemia. Resuscitate; monitor ﬂ uids input and output and Replace any further ongoing water and electrolytes losses.

Estimating ﬂ uid replacement to correct hypernatraemia:

Using formula I and its derivative 2[4]: 1. Change in s[Na] (mmol/–L)5(infusate [Na]2s[Na]) / TBW11 Estimates the eﬀ ect of 1 litre of any infusate on s[Na] 2. Change in s[Na] (mmol/L)5{(infusate [Na]1infusate [K])2 s[Na]} / TBW11 Estimates the eﬀ ect of 1 litre of any infusate containing Na and K on s[Na]

The numerator in formula 1 is a simplifi cation of the expression (infusate [Na]– s[Na])31 litre, with the value yielded by the equation in mmol/L[4]. The estimated TBW (in litres) is calculated as a fraction of body weight. The fraction is 0.6 and 0.5 in young men and women, respectively and 0.5 and 0.45 in elderly men and women, respectively[4]. Formula 1 (and its derivative formula 2) estimates the change in the s[Na] caused by the retention of 1 litre of any infusate. The required volume of infusate and hence the infusion rate, is determined by dividing the change in the s[Na] targeted for a given treatment period by the value obtained from formula 1. The more hypotonic the infusate the less volume required[4]. Formula 1 (and its derivative formula 2) permits a quantitative and fl exible approach to the prescription of fl uids that can easily accommodate diff erent infusates and treatment periods[4].

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The conventional formula, given in the practical exercise below, provides an adequate estimate of the water deﬁ cit if hypernatremia is caused by pure water loss, but is not useful when sodium and potassium, in addition to water, must be prescribed[4].

CONCLUSION Prevention of hypernatraemia is very important. Ensure adequate intake in ill patients, pre-emptive management of possible causes, e.g. DM, Hypercalcaemia, DI, etc. Strict ﬂ uid balance charts and daily weighing, actioned appropriately.

PRACTICAL EXERCISE A 72-year-old male, a known case of bipolar disorder on Lithium for eight years, has a long-term urinary catheter, admitted with general malaise, confusion and impaired oral intake for few days. A diagnosis of severe urosepsis was made. Weight was 70kg, dry mucus membranes, febrile and tacchycardic, normal BP, no postural drop. His attentive daughter was prompting him to eat and drink. She measured the ﬂ uid input/output for the last 24 hours prior to admission at 2.1/4.5L respectively. s[Na] 166mmol/litre (L), s[K] 4.3mmol/L, and s[Cr] 115μmol/L, u[Na],10mmol/L.

Q1: What caused hypernatraemia? a. Fever b. Lithium c. Confusion d. All of the above e. None of the above

A1: This is a case of pre-renal acute kidney injury and chronic hypernatremia secondary mainly to pure water loss. Hypernatraemia is caused by the un- replaced free water loss secondary to fever and Lithium-induced nephrogenic diabetes insipidus, statement (d). He was unwell and confused, hence unable to compensate for the large urinary water loss, for few days prior to admission. Thus, the hypernatraemia correction should be over 2–3 days.

Q2: How would you replace the ﬂ uids? A2: The required ﬂ uid volume for replacement is estimated using Formula 1, or conventional equation.

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a. Estimating ﬂ uid replacement using Formula 1: the desired water replacement in the ﬁ rst 24 hours to reduce s[Na] by ~ 10mmol/L using 5% dextrose is: 1L of 5% dextrose will reduce s[Na] by - 4.6mmol/l, obtained from the equation (formula 1): 02166/3511. Therefore, the volume required to reduce s[Na] by 10mmol/l510/4.652.2L, Plus 1.5L to compensate for 24 hour obligatory water losses5total of 3.7L, given over 24 hours at 154ml/hour. Close monitoring of s[Na] and for hyperglycaemia. Introduce insulin if hyperglycaemia develops. Hyperglycaemia is deleterious; it will induce osmotic diuresis and worsen hypertonicity.

b. Estimating ﬂ uid replacement using the Conventional equation:

Estimating total water deﬁ cit (eTWD) equation to reduce s[Na] to 140 5%LBW x [(s[Na]/140) – 1] (The eTWD equations provide a simpliﬁ ed guide to initial therapy)

%LBW (lean body weight)5Total body water (TBW): %5Young men: 0.6; Young women: 0.5; Elderly men: 0.5; Elderly women: 0.45. This formula gives an estimation of the volume of additional ﬂ uid required to correct s[Na] to 140mmol/L.

Aim to replace 50% of this, eTWD, in 24hrs with water or IV 5% Dextrose.

The desired water replacement volume in the ﬁ rst 24 hours (to reduce sNa by 10mmol/L)5eTWD310mmol/l4(sNa2140); divide by 24hrs for hourly infusion rate.

Calculations: eTWD50.5 LBW3[(s[Na]/140)21]56.5L The desired water replacement in the ﬁ rst 24 hours to reduce s[Na] by ~ 10mmol/ L5(eTWD x 10)/ (sNa2140)52.5L, Plus 1.5L to compensate for the 24 hour obligatory water losses. Total54L, given over 24hrs at 166ml/hour.

The volumes obtained from these equations are indicative: the correction needs good clinical acumen and close monitoring.

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REFERENCES [1] Uptodate: Aetiology and evaluation/Treatment of hypernatremia (Viewed 05.2015). [2] Overgaard-Steensen, C. and Ring, T. Clinical review: Practical approach to hyponatraemia and hypernatraemia in critically ill patients. Critical Care (2013), Vol. 17, pp. 206. http://www.ccforum. com/content/17/1/206 [3] British Medical Journal Best Practice. Assessment of Hypernatraemia 07.2014 http://bestpractice.bmj.com/best-practice/monograph/58/emergencies.html [4] Adrogue, H.J. and Madias, N.E., Hypernatremia. New England Journal of Medicine (2000), Vol. 342, pp. 1493–1499. [5] Bhave, G. and Neilson, E.G. Volume depletion versus dehydration: how understanding the diﬀ erence can guide therapy. American Journal of Kidney Diseases (2011), Vol. 58, p. 302–309. [6] Kahn, A., Brachet, E. and Blum, D. Controlled fall in natremia and risk of seizures in hypertonic dehydration. Intensive Care Medicine (1979), Vol. 5:27–31. 108. [7] Fang, C., Mao, J. and Dai, Y. Fluid management of hypernatraemic dehydration to prevent cerebral oedema: a retrospective case control study of 97 children in China. Journal of Paediatric Child Health (2010), Vol. 46, pp. 301–303. [8] Masters, P. Southern Derbyshire Shared Care, Pathology Guidelines, Hypernatraemia in Adults. 02.2015. http://www.derbyhospitals.nhs.uk/easysiteweb/getresource.axd?assetid=12188&type=0 &servicetype=1

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MANAGEMENT OF HYPOKALAEMIA

Hypokalaemia (HoK) is a serum potassium concentration (s[K]) ,3.5mmol/L. This is the commonest electrolyte disorder in hospitalised patients; most cases are mild. It can be life-threatening if severe[1–4].

HoK-related Symptoms Often asymptomatic. S/S are prominent when the reduction in s[K] and Signs (S/S)[1–7] occurs rapidly or is large.

Muscle weakness – ascending, can involve respiratory muscles, ileus, rhabdomyolysis secondary to decreased muscle blood fl ow. Cardiac: ECG changes – fl attening T, ST depression, increased amplitude U waves (V4–V6), prolonged QT, arrhythmias – Sinus Bradycardia, A/VEs, AVB, VT, and VF. The progression of ECG changes varies widely between patients; VF can be the fi rst presentation. Glucose Intolerance; Metabolic Alkalosis; Polyurea

S/S develop usually when s[K] is ,3 and resolve with correction of HoK

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Common Causes a. K depletion (the commonest cause): Renal loss: u[K].20mmol/L – diuretics, mineralocorticoid The cause is usually excess, glucocorticoid therapy, Mg depletion, Renal Tubular clear from the Disease; also occurs secondary to GI ﬂ uid loss and volume history[1–6] depletion Extra-renal loss: u[K],20mmol/L – gastro-intestinal ﬂ uid loss; skin b. Intracellular shift (redistributive HoK): insulin or bicarbonate

treatment, theophylline, β2 agonists, periodic paralysis, chloroquine intoxication, rapid blood cell proliferation – e.g. GCSF therapy c. Reduced intake (rare): anorexia nervosa

Beware of blood taken from drip arm! If cause not obvious, refer to Renal or Endocrine Team for further evaluation

Investigations[1–6,8] Immediate:

It is fundamental If s[K],3: check ECG, and s[Mg] to understand K Repeat urgent K on plasma sample (lithium heparin) as release of distribution for a K1 from cells during clotting may give a falsely higher level in serum selective investigation FBC/glucose approach Further, if cause unclear, select as clinically indicated: [Serum HCO3, 2 21 Cl , Mg , PO4, Ca and Urine (paired spot sample with serum) K, Cl, PH (RTA), Ca (BS), P AR (CS, LS]

HCO3, if: 1. Normal: anorexia nervosa, laxatives 2. Metabolic acidosis in absence of diarrhoea: consider RTA, refer to Renal team 3. Metabolic alkalosis: indicates chronic depletion (see table) u[K]: if cause not obvious

HoK: many patients, up to 40%, are also Mg deﬁ cient. Hypomagnesaemia can induce renal K wasting. Combined deﬁ ciency may potentiate the risk of cardiac arrhythmias – both are pro-arrhythmic. Simultaneous repletion of the Mg stores will facilitate more rapid correction of hypokalaemia and is recommended in severe cases of hypokalaemia[4,8]

Abbreviations: A/VEs5Atrial/Ventricular Ectopics; AVB5Atrio-Ventricular Block; VT5Ventricular Tachycardia; VF5Ventricular Fibrillation; u[K]5Urine Potassium concentration; s[Mg]5Serum Magnesium concentration; GCSF5Granulocyte Colony Stimulating Factor; RTA5Renal Tubular Acidosis; BS5Barter’s Syndrome; P AR5Plasma Aldosterone and Renin; CS5Cushing’s Syndrome; LS5Liddle’s Syndrome.

Treatment is shown on the next page.

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Hypokalaemia (continuation)

K level (mmol/l) Treatment[1–4,6,8–11] 3.0–3.4 Prompt identiﬁ cation and treatment of underlying cause (mild) Potassium loss: gradual oral correction (over days to weeks[2]): – In most patients GI losses: vomiting/metabolic alkalosis – give KCl: Sando-K, 1–2 – Usually tabs tds (36–72mmol/d) with extra ﬂ uids – alternatively KayCeeL asymptomatic 25ml od-tds (25–75mmol/d). [KHCO (KCitrate – 40mmol): if (including no ECG 3 diarrhoea/metabolic acidosis] changes) Renal losses – e.g. CCF/diuretics: give a K-sparing diuretic after stabilisation, Amiloride is better tolerated.

Monitor s[K] daily to ascertain response and to avoid hyperkalaemia[2,3]. Continue treatment, around three days, until K is in normal range[11]. Rapid IV correction if on digoxin (HoK of any severity increases predisposition to arrhythmia[2]); or symptoms present – see below Correct concomitant electrolytes deﬁ cits: particularly hypomagnesaemia; patients can be refractory to potassium replacement alone Concurrent metabolic acidosis: treat hypokalaemia before addressing acidosis Prevent recurrence: address precipitating factors and ensure adequate dietary potassium intake[2,4].

Redistributive HoK: cautious correction if serious complications present or imminent – paralysis or arrhythmia. Beware of rebound hyperkalaemia and fatal arrhythmias, particularly in HPP[3].

2.5–2.9 (moderate) + Treatment measures stated above 1 Rapid oral correction: asymptomatic Urgent ECG, s[Mg] – ask the lab to add it if not already done Replace with oral K1, choices as above, at higher doses: Sando-K – 2 tabs 6 hourly. IV route (see below) if oral or enteral route not possible – nil by mouth or severe dyspepsia/diarrhoea Close daily clinical and biochemical monitoring

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< 2.5 (severe) Treatment measures stated above1IV correction:

Severe if: Continuous ECG monitoring or telemetry ,2.5 and/or Secure proper IV access: large veins, or CV line if access poor. Use Symptomatic: infusion pump to prevent overly rapid potassium administration. Paralysis, arrhythmia - Give 1L NS 0.9%/40mmol KCl IV, over 4hrs. Do not use 5% Dextrose. (or pre-existing [Use 1L 0.45% saline/40mmol KCl in DKA/HHS] cardiac disease e.g. It is not recommended to exceed 2–3mmol K/kg/BWT/24hrs[11]. ACS, Digoxin toxicity Monitor s[K] levels after every 40–80mmol K, and daily to ascertain …) the response, as it is diﬃ cult to predict. Avoid volume overload. Close monitoring until S/S resolved and K level .3; then switch to oral therapy as per the mild/moderate regime above.

If life threatening/intractable cardiac arrhythmia: double infusion rate, up to 40mmol/hr[3], and contact resuscitation team. If life

threatening cardiac arrhythmia: add IV MgSO4, 10mmol over 30 minutes, even before the s[Mg] is known[4].

Renal impairment: cautious K replacement – risk of overcorrection (hyperkalaemia) – contact renal team if severe renal failure or patient on dialysis Use pre-mixed infusion ﬂ uid. NEVER add KCl to infusion bags[9]

Abbreviations: CCF5Congestive Cardiac Failure; HPP5Hypokalaemic Periodic Paralysis; CV5Central Venous; DKA5Diabetic Ketoacidosis; HHS5Hyperosmolar Hyperglycaemic State; BWT5Body Weight; Hr(s)5Hour(s)

Hypokalaemia: further evaluation if the cause is unclear:

Hypokalaemia: further evaluation if the cause is unclear:[1–6]

Extra-renal loss: metabolic (M) Renal loss: metabolic acid-base status acid-base status

Normal M Acidosis M Alkalosis M Alkalosis M Acidosis Variable

AN Laxative RTA, DKA Mg abuse Depletion

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Metabolic Alkalosis

Low u[Cl] High u[Cl] (.10mmol/L) – (high u[K]) <10mmol/L (low u[K])

Normotensive Normotensive Hypertensive

Volume Diuretics use, High (P) Normal (P) Low (P) contraction: BS, GS: (1/2 Aldosterone (A) A and R A and R due to low Mg) surreptitious vomiting a. Low R: Conn’s (CS) Cushing’s – AME – b. High R: RVD U Cortisol, (liquorice LD-DST: ingestion), refer to CAH, LS endocrine Abbreviations: AN5anorexia nervosa; u[Cl]5urine chloride concentration; BS5Barter’s syndrome; GS5Gitleman’s syndrome; P5Plasma; R5Renin; LD-DST5low dose dexamethasone Suppression test; RVD5Reno-vascular Disease; AME5apparent mineralocorticoid excess; CAH5congenital adrenal hyperplasia

CONCLUSION Due concern and appropriate management should be given to patients’ with hypokalaemia as it can be fatal.

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PRACTICAL EXERCISE All units are in mmol/L unless stated otherwise A 74-year-old male was admitted with fever, vomiting, diarrhoea and shortness of breath for three days. He was confused, with dry mucus membranes, reduced skin turgor, supine BP 95/55, 75/50mmHg on sitting up, tachycardia, tacchypnoea, fever and body weight 70Kg. s[Na] 158, s[K] 2.8, sCr 119μmol/L, sUrea 12mmol/L, s glucose 9mmol/L, s osmolality 333mOsm/Kg and a spot urine – u[Na] 7, u[K] 26, urine osmolality 846mOsm/Kg. A clinical diagnosis of acute confusion secondary to pneumonia was made.

Q1: What is the cause of hypokalaemia? A1: Hypokalaemia is due to a combination of: a. Vomiting: Main factor is the increased Distal Tubular (DT) renal potassium loss due to increased bicarbonate delivery to DTs, in addition hypovolaemia stimulates aldosterone secretion. Upper GI K loss/reduced intake b. Diarrhoea: Lower GI loss/reduced intake Increased DT renal K loss due to hypovolaemia-induced RAAS activation

Q 2. What is the cause of hypernatraemia? A 2. Chronic hypernatraemia is due to: a. Hypotonic sodium and potassium loss secondary to vomiting and diarrhoea b. Pure water loss secondary to fever and tacchypnoea

Q 3. How would you correct hypokalaemia, hypernatraemia and hypovolaemia? A 3. Therapeutic approach: a. The ﬁ rst aim is to correct hypovolaemia. He became haemodynamically stable after receiving 1.5L of NS (120mmol KCl per litre) within three hours, the repeat s[Na] was 158, s[K] was 3. b. The second aim is to correct hypokalaemia and gradual correction of hypernatraemia over 2–3 days.

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Estimating ﬂ uid replacement using Formula 2, see chapter on hyponatraemia, to correct hypokalaemia and hypernatraemia: the desired water replacement in the ﬁ rst 24 hours to reduce s[Na] by ~ 10mmol/L using (5% D10.18% saline110mmol KCl per L) is:

1L of (0.18% saline+10mmol KCl) will reduce s[Na] by 3.3mmol/l, obtained from the equation (formula 2): (402166)/(35 11). Therefore, the volume required to reduce s[Na] by 10mmol/l510/3.353L, Plus 1.5L to compensate for 24 hour obligatory water losses5Total of 4.5L over 24 hours. 3L were given IV at 125ml/hr, he became more lucid during the day and managed to take 1.5L orally. Close monitoring: UOP; s[Na], s[K], and serum glucose every 2 hours.

REFERENCES

[1] Unwin, R.J., Luft, F.C. and Shirley, D.G. Pathophysiology and management of hypokalemia: a clinical perspective. Nature Reviews Nephrology (2011), Vol. 7, pp.75–84. doi:10.1038/ nrneph.2010.175. [2] Gennari, F.J. Hypokalemia. New England Journal of Medicine (1998), pp.339:451. [3] Uptodate. Clinical manifestations and treatment of hypokalemia in adults (Accessed 04.2015). [4] Alfonzo, A., Isles, C., Geddes, C. and Deighan, C.. Potassium disorders – clinical spectrum and emergency treatment. Resuscitation (2006), Vol. 70, pp.10–25. [5] Rastegar, A. and Soleimani, M. Fluid, Electrolytes and Acid-Base Disturbances. Nephrology Self- Assessment Program, ASN, (2015), Vol. 14, No. 1. [6] The British Medical Journal Best Practice. Assessment of Hypokalaemia. 08.2014. http:// bestpractice.bmj.com/best-practice/monograph/59/diagnosis.html [7] Moore, R. and Stuart, L.L. Hypokalaemia and Hyperkalaemia. Nephrology Secrets, 3rd Edition, 2012. [8] Cohn, J.N., Kowey, P.R., Whelton, P.K. and Prisant, L.M. New guidelines for potassium replacement in clinical practice. Archives of Internal Medicine (2000), Vol. 160, pp.2429–36. [9] NPSA Patient safety alert. Potassium chloride concentrates solution Alert 01. 2002. London: National Patient Safety Agency. [10] Guideline for the management of hypokalaemia in adults. Produced by Medicines Information, CGH: August 2010 http://www.gloshospitals.nhs.uk/SharePoint110/Antibiotics%20Web%20Documents/ TG/Hypokalaemia%20Guidelines.pdf [11] Guidelines for potassium replacement in hypokalaemia. Nottingham City Hospital NHS Trust. Update 05.2013b. https://www.nuh.nhs.uk/handlers/downloads.ashx?id=35682

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MANAGEMENT OF HYPERKALAEMIA

Hyperkalaemia is a serum potassium concentration (s[K])$5.5mmol/L. It is the most serious of all electrolyte disorders. It is often asymptomatic, even if severe. It can cause cardiac arrest without warning[1–7]. Hyperkalaemia is the commonest electrolyte disorder causing cardiorespiratory arrest[8].

Symptoms and Are uncommon, non-specifi c, and tend to occur at s[K] of $7.0. Signs (S/S) (s[K] in S/S are prominent when the increase in s[K] occurs rapidly or is large. [1–10] mmol/l) Muscle: weakness – ascending, fl accid paralysis – DD: GBS Cardiac (*ECG Changes): conduction abnormalities and arrhythmias, cardiac arrest without warning Common Causes: 1. Reduced urinary K excretion, (the commonest causes): Renal failure, GFR < 20ml/min – 75% cases[9]. A thorough history and Decreased mineralocorticoid activity: physical examination Hyporeninaemic hypoaldosteronism (damaged JGA) – CKD, usually discloses the diabetic nephropathy, NSAIDs cause and guides the Drugs: reduced aldosterone secretion – ACE inhibitors, management[1–10] Heparin, NSAIDs, CNIs Drugs: aldosterone receptor blockers – SPL, Eplerenone Mineralocorticoid defi ciency Drugs: Epithelial Sodium Channel (ENaC) blockers: Ameloride, Trimethoprim

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2. Increased K release from cells (IC to EC shift): Uncontrolled hyperglycaemia – (hyperosmolality, insulin deﬁ ciency) Metabolic acidosis Drugs: Na-K-ATPase inhibitors – Digoxin toxicity, suxamethonium, β blockers (rare) Tissue necrosis/lysis: rhabdomyolysis/TLS/severe burns Spurious (pseudo-hyperkalaemia) – the commonest cause of reported hyperkalaemia[3]: delayed analysis; haemolysis via small needle; release from blood cells in haematological disorders Hyperkalaemic Periodic Paralysis 3. Increased K intake (rare, unless concurrent decreased K excretion): High K diet in CKD; Blood transfusion, etc

Investigations[1–7] Obtain an ECG looking for signs* of hyperkalaemia if s[k] $6[4]. Urgent repeat K on plasma sample (lithium heparin), especially if the result is unexpected or isolated with no ECG changes Emergency s[K]: a BG analyzer can be used pending lab result[4].

FBC/HCO3 in venous blood Urine K; sOsm as appropriate

*The ECG changes: their presence, severity and progression correlate poorly with s[K][1–3,9]. Thus calcium salts are given in severe hyperkalaemia, even without ECG changes[2,3]. Changes associated with Hyperkalaemia: none (majority[9]); early – peaked T, prolonged P-R interval; late – ﬂ attened or absent P wave, widening QRS complex to a sine wave pattern, VT, VF and asystole.

Abbreviations: DD5Diﬀ erential Diagnosis; GBS5Guillain-Barré Syndrome; NSAIDs5Non-Steroidal Anti- Inﬂ ammatory Drugs; ACEi5Angiotensin Converting Enzyme inhibitors; CNIs5Calcineurin Inhibitors; IC5Intracellular; EC5Extracellular; TLS5Tumour Lysis Syndrome; TPN5Total Parenteral Nutrition

TREATMENT Treatment is based mainly on clinical experience and accepted practice rather than controlled trials[1,4,11]. The classiﬁ cation into mild, moderate and severe hyperkalaemia provides a guide to clinical decision-making. However, treatment decisions should consider the cause, speed and the degree of s[K] elevation[4]. This is illustrated in the following two examples:

1. Mild hyperkalaemia in patients with stable CKD (1/2 RAASi), is common and well tolerated – maintain low K diet, consider diuretics, optimise RAASi dose, consider oral NaHCO3 to maintain near normal s[HCO3], stop RAASi during acute illness, monitor[1–3,12]. 2. In contrast, even a mild hyperkalaemia in association with, for instance, tissue breakdown, may require emergency treatment if it is acute, rapidly increasing and/or symptomatic[3].

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Treatment: Follow the sequential ﬂ owchart:

s[K] (mmol/l) ECG Treatment[1– 12] Changes

5.5–5.9 (Mild) No Acute in-patient set up: do not wait for a repeat plasma [K] especially if ECG signs present Urgent management using ABCDE approach, EWS system and appropriate referral/plan formulation [4]. Prompt identifi cation and treatment of the cause: Stop off ending drugs, ensure low K diet – avoid fruits Ensure good hydration/relief OUP etc Consider calcium resonium 15gqds PO/lactulose or 30g enema, refer to local drug formulary [4,8]. Monitor s[K] – for treatment effi cacy and rebound hyperkalaemia. NB: many patients are total body K deplete, may develop hypokalaemia during correction Measures to prevent recurrence: re-assess diet and dialysis access Non-resolving or worsening AKI: refer to the renal team

6.0–6.4 No Apply all treatment measures listed above (Moderate) Cardiac monitoring if rapid elevation in s[K] is anticipated: Consider insulin/dextrose, doses given next box[3–4].

$6.5 No Emergency treatment: (Refer to hospital if in the community) (Severe) 1. Apply all treatment measures listed above1 Urgent treatment 2. Cardiac monitoring ideally in HDU. Secure proper IV access – for severe HrK: a large vein or CV line if access poor s[K] $6.5; and/ 3. Give 10ml of Calcium Gluconate 10% IV (or calcium chloride) or ECG changes over fi ve minutes[2,3]. Repeat calcium gluconate after fi ve present; and/ minutes as necessary until the ECG normalises – may need up or symptoms to 50ml; while awaiting defi nitive s[K] correction. Caution if present: patient on digoxin‡ Give calcium 4. Give 10u of actrapid insulin 150ml of 50% D IV over 5–10 gluconate, etc minutes steps 1–7 Insulin can be administered as a single agent without dextrose if blood glucose .15mmol Watch for, avoid hypoglycaemia – consider 500ml 10% D IV over 10hrs[3]. 5. Add: nebulised salbutamol 10-20mg, caution in IHD patients. β2 agonists: weakened eff ect if on BB and/or digoxin, and ineff ective in some dialysis patients – hence, not recommended as a single agent[2,3,9]. 6. Consider HD early if persistent hyperkalaemia or RF present (oligo/anuric UOP, rising sCr, or severe acidosis) 7. Refer to renal team as s[K] will rebound.

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Any ECG Yes 1. Apply all treatment measures listed above Changes Cardiac arrest: hyperkalaemia should be considered as part of identifying and treating a reversible cause using the ‘4 Hs and 4 Ts’ approach. Start treating for hyperkalaemia in high risk patients even before the laboratory results[4,5,8]

Monitoring treatment: Monitor serum U&Es two hourly (and blood glucose at 30 minutes and hourly for six hours, after IV insulin) until s[K] stable and ,6.0. Monitor UOP. Seek expert advice as appropriate.

‡Calcium gluconate 10%, 10ml diluted in 100ml 5% D, is given slowly over 20 minutes. Rapid calcium administration (hypercalcaemia) may precipitate myocardial digoxin toxicity. Digoxin toxicity: can cause hyperkalaemia and arrhythmias and the administration of digoxin antibody (Fab) fragments may represent the preferred approach[3], and consider HD.

Abbreviations: RAASi5Renin/Angiotensin/Aldosterone inhibitors; OUP5Obstructive Uropathy; D5Dextrose; IV5Intravenous; CV5Central Venous; hr5Hour; IHD5Ischaemic Heart Disease; BB5Beta Blockers; HD5Haemodialysis; sCr5Serum Creatinine; 4 Hs5Hypovolaemaia, Hypoxia, Hyper-hypokalaemia, Hypothermia; 4 Ts5Toxins, Tamponade, Tension pneumothorax, Thrombosis - pulmonary and coronary.

CONCLUSION Due concern and appropriate management should be given to patients’ with the most serious electrolyte disorder.

REFERENCES

[1] Nyirenda, M.J., Tang, J.I., Padﬁ eld, P.L. and Seckl, J.R. Hyperkalaemia. British Medical Journal (2009), pp.339. doi: http://dx.doi.org/10.1136/bmj.b4114. [2] McVeigh, G., Maxwell, P. and O’Donnell, S. Guidelines and Audit Implementation Network (GAIN). Guidelines for the treatment of Hyperkalaemia in Adults August (2014). [3] Uptodate. Causes and evaluation/Treatment and prevention of hyperkalemia in adults. (Accessed 05.2015). [4] Alfonzo, A., Soar, J. and MacTier, R. Treatment of Acute Hyperkalaemia in Adults. The Renal Association (March 2014). http://www.renal.org/guidelines/joint-guidelines/treatment-of-acute- hyperkalaemia-in-adults#sthash.Jym11RUd.dpbs. [5] Alfonzo, A., Isles, C. and Geddes, C. Potassium disorders - clinical spectrum and emergency treatment. Resuscitation (2006), Vol. 70, pp.10–25. [6] British Medical Journal Best Practice. Assessment of Hyperkalaemia. 01.2015. http:// us.bestpractice.bmj.com/best-practice/monograph/60.html.

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[7] Rastegar, A. and Soleimani, M. Fluid, Electrolytes and Acid-Base Disturbances. Nephrology Self- Assessment Program, ASN (2015), Vol. 14, No. 1. [8] Soar, J., Deakin, C.D. and Nolan, J.P. European Resuscitation Council guidelines for resuscitation 2005. Section 7. Cardiac arrest in special circumstances. Resuscitation (2005), Vol. 67 (Supplementary. 1), pp.S135–70. [9] Acker, C.G., Johnson, J.P. and Palevsky, P.M. Hyperkalemia in hospitalised patients: causes, adequacy of treatment and results of an attempt to improve physician compliance with published therapy guidelines. Archives of Internal Medicine (1998), Vol. 158, pp.917–24. [10] Mahoney, B.A., Smith, W.A. and Lo, D.S. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev2005;(2):CD003235. DOI: 10.1002/14651858.CD003235.pub2. [11] Kim, H.J. and Han, S.W. Therapeutic approach to hyperkalaemia. Nephron (2002), 92 (supplementary) Vol. 1, pp.33–40. [12] Reardon, L.C. and Macpherson, D.S. Hyperkalemia in outpatients using angiotensin-converting ensyme inhibitors. How much should we worry? Archives of Internal Medicine (1998), Vol. 158, No. 26.

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MANAGEMENT OF HYPOCALCAEMIA

Hypocalcaemia is a serum (albumen-adjusted) total calcium, (s[Ca]) ,2.20mmol/L (normal range 2.2–2.6mmol/L)[1–4]. Severe hypocalcaemia, if untreated, can lead to serious neurological and cardiovascular complications[1– 4]. Causes: (commonly caused by Hypothyroidism and VD deﬁ ciency)[1–8]

iPTH: Hypoparathyroidism (the commonest in-patie nt cause)[1–3]: Inappropriately Post-surgery is the commonest cause[1,5,6]; usually secondary to total low or normal thyroidectomy[5]. Hypocalcaemia is transient or permanent[4]. ,1.5pmol/L Auto-immune [1,2,4]. Genetic (rare)[1,2,4,6]. Irradiation, storage or inﬁ ltrative diseases of the PTG (rare) Hypomagnesaemia (can cause PTH end organ-resistance and impaired PTH secretion)[1,4,8], see hypomagnesaemia chapter

iPTH: Vitamin D defi ciency (VD) (The commonest community cause[1–4]) High Reduced intake1reduced exposure to UVL, malabsorption[1,4,6]. .1.5pmol/L Functional VD defi ciency: decreased 25- (liver) or 1-hydroxylation (kidney)[1,3,4,6]. [Severe VD defi ciency can cause rickets and osteomalacia]

PTH resistance[1–4,8]: target organs (kidney/bone) resistance to PTH: (Pseudohypoparathyroidism, hypomagnesaemia) Renal disease (low calcitriol and hyperphosphatemia)[4,8].

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Extravascular deposition: Hyperphosphatemia: Ca-PO4 is deposited mostly in bone, but also in extra-skeletal tissues[4], as in TLS, Rhabdomyolysis and CKD[3,4,8]. Acute pancreatitis[3–5,8]. Sepsis or severe illness: impaired PTH secretion/end organ resistance and reduced calcitriol production[2,4,7,8]. Widespread osteoblastic metastasis: possible in carcinoma prostrate; breast[2,4,8].

PTH: Drugs[1–4] Normal Inhibitors of bone resorption (OCIs): (bisphosphonates, calcitonin, denosumab), especially if VD defi cient[2–4]. Cinacalcet [4], consider PPI-associated hypomagnesaemia[5]. Ca Chelation: Citrate in massive blood transfusion [2–5,7]. It reduces sCa1 but not s[Ca][4]. Symptoms and Signs[1–9] Asymptomatic or non-specifi c if mild and/or chronic. Prominent when the decrease in s[Ca] occurs rapidly or is large [1–5,8,9]. Neuromuscular Excitability: paresthesia, carpopedal spasm, severe cases can progress to tetany, seizures Neuropsychiatric Symptoms: depression, cognitive impairment Bone: pain and fractures (if osteomalacia present) CVS: Prolonged QT and ventricular fi brillation or heart block in severe cases. Other: dry skin, cataract. Investigations (the diagnosis is often clear from the history and physical examination [4])

Do all necessary tests before starting treatment[1,3].

s[Ca] (adjusted for albumin), ALP, UEs, s[PO4], s[Mg] iPTH: the single most important diagnostic test[1,4]. Selective tests[1,4], based on history and physical examination, to determine the cause: a. Low or normal iPTH: indicates hypoparathyroidism. b. High iPTH: UEs deranged (CKD); if UEs normal check: 1. 25HCC – VD defi ciency if low; if normal: suggest pseudohypoparathyroidism[1,2]. [1] 2. High ALP/low PO4 suggest VD defi ciency/osteomalacia . Poor correlation between the ionised (free) serum calcium (sCa21) and s[Ca], especially in states of low albumin or acid/base imbalances: a. Pseudohypocalcaemia: in hypoalbuminaemic states the s[Ca] is low but the sCa21 is normal[1,2,4]. Hence, the albumin-correction equation[1,2,4,8]. b. The adjusted calcium calculation is not valid in acidosis or alkalosis: the affi nity of calcium to albumin is increased in alkalosis; acute respiratory alkalosis can be associated with reduced sCa21, but not s[Ca] and development of symptoms – paraesthesia. Consider checking sCa21 [1,2,4,8].

Abbreviations: iPTH5intact PTH; PTG5Parathyroid Gland, UVL5Ultra-Violet Light, TLS5Tumour Lysis Syndrome, OCIs5Osteoclast Inhibitors.

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Treatment choice depends on the biochemical severity and rate of onset of hypocalcaemia, in addition to the symptoms and the underlying cause. Managing hypocalcaemia is based mainly on clinical experience and accepted practice rather than controlled trials[1,2,4].

s[Ca] (mmol/L) Treatment [1–10]

(Chronic) Mild, Prompt identiﬁ cation and treatment of the underlying cause asymptomatic Oral calcium: give 25–50mmol (2000mg) elemental Ca/day[2–5] s[Ca] 2.0–2.2 (e.g. Ca carbonate 1250mg 2 tab BD[3], alternatively Sandocal 1000mg bd[5]), before meals[8]. Monitor s[Ca] as per monitoring section below Treatment: Oral calcium1 Add: Cause-speciﬁ c treatment Oral VD Hypoparathyroidism

Hypoparathyroidism: give Calcitriol 0.5μg or alfacalcidol 1μg od – increase dose every 4–7 days to achieve a s[Ca] in the lower end of the reference range to avoid hypercalc iuria[1,2,5,6,8].

Post-thyroidectomy, repeat calcium 24hrs later, if s[Ca][5]: .2.1: discharge and re-check s[Ca] within one week 1.9–2.1: increase Sandocal™ 1000 to three BD – 1.9–2.1 for .72hrs post-operatively despite Ca supplementation: start 1-alfacalcidol 0.25μg/day (or calcitriol) with close monitoring

Post-parathyroidectomy: judicious pre-operative preparation will avoid the development of hungry bone syndrome[5,8]. Close monitoring, treat hypocalcaemia as per its severity, see guidance. Ergocalciferol (VD2) and cholecalciferol (VD3) are ineff ective, as PTH is needed for the 1α-hydroxylation[1,4]. This is also true in advanced CKD because of 1α-hydroxylase defi ciency[4]. Recombinant PTH is not a standard care measure because of its cost, subcutaneous use, and long term safety is not established[4]. Vitamin D defi ciency

Give VD, either VD2 or VD3 at 1000–2000u daily. Combined Ca-VD 2tab (800u) od[1]. Symptomatic VD deﬁ ciency or non-responders can be treated with VD (D2 or D3) 50 000 IU orally once a week for eight weeks[1,2]. Long-term maintenance is usually 1000iu/VD3/day. Monitoring

Initially, s[Ca] levels should be monitored weekly, until deﬁ ciency is corrected and then monthly while optimal dose is determined, thereafter: Monitor s[Ca]: every 3–6 months[2,4,5]. Monitor urine [Ca] annually. Hypercalciuria is the main side eﬀ ect, if detected reduce VD dose to avoid nephrocalcinosis[1,2,8]. Refer to endocrine, renal, or other teams as appropriate

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(Acute) severe 1. Hospital admission/ECG monitoring – too rapid Ca infusion can induce s[Ca]#1.9, and/or hypotension and serious dysrhythmias[1–4,10] symptomatic: 2. Secure proper IV access – a large vein or CV line if access poor. CPS, tetany, 3. IV Calcium gluconate is the preferred form for peripheral IV calcium. seizures 10–20ml of 10% calcium gluconate (2.25–4.5mmol), diluted in 50–100ml of Prolonged QT/ 5% dextrose and infused slowly over 10–20 minutes[1–7,10]. Its eﬀ ect lasts for CCF only 2–3 hours. 4. Repeat treatment until symptoms clear[1,5] Treatment: IV Ca1 Follow by slow, continuous IV infusion of a dilute solution of Ca to oral VD prevent recurrence of hypocalcaemia[1,3,8,10]. Use infusion pump

5. Dilute 100ml of calcium gluconate 10% (10 ampules) in 1 litre 5% D or 0.9% NS and infuse at 50ml/hour[1,3,4,7,10]. Monitor s[Ca], titrate rate of infusion to achieve s[Ca] at the lower end of the reference range[1,4,5]. [An infusion of 10ml/kg of this solution is estimated to increase s[Ca] by 0.3–0.5mmol/l[1]] The usual maximum total daily dose is 15 ampoules of 10ml of 10% calcium gluconate (i.e. 33.75mmol Ca) 6. Phosphate and bicarbonate should not be infused with calcium to avoid precipitation of Ca salts[2,8]. 7. NB. CaCl2 is more likely to cause phlebitis and tissue necrosis if extra-vasated[1,2,4–6,9]; should be given via central vein[2,5]

Oral Ca supplements, as above, should be given concurrently[2,6].

8. If PTH is deﬁ cient or non-functional calcitriol (preferred – more potent1 rapid onset of action) should be given at 1μg/day[1,2,4]. 9. When patient is asymptomatic and s[Ca] at the target, monitor, apply treatment outlined in the ﬁ rst box, as indicated1further management

Further Management

Give disease-speciﬁ c treatment as per treatment of mild, asymptomatic cases box above

Hypomagnesaemia-associated hypocalcaemia: the association frequently co-exist due to malabsorption or poor dietary intake[8]. HoM causes PTH deﬁ ciency and PTH resistance[1.2,4]. Correct hypomagnesaemia ﬁ rst, unless the patient presents with severe symptoms[1,2,4,7]. Give IV MgSO4, 24mmol/24 hours in 500ml 0.9% NS or 5% D, to achieve normal s[Mg] level[5]. Monitor s[Mg]/s[Ca]. Hyperphosphataemia-related hypocalcaemia[2,4,7,8]: the increased Ca3PO4 product induces precipitation of Ca-PO4 in soft tissues resulting in hypocalcaemia. Thus, acute hypocalcaemia in TLS or Rhabdomyolysis should not be treated with Ca, unless symptomatic from hypocalcaemia (e.g. tetany or cardiac arrhythmia), until the hyperphosphatemia is corrected[4,8]. This is to avoid further calcium-phosphate precipitation in vasculature and soft tissue. Hemodialysis is often indicated in such patients[1,3,4,8].

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CKD-associated hypocalcaemia: correction of hyperphosphataemia and calcitriol defi ciency (secondary to reduced renal mass/increased FGF-23) is the primary goal. Metabolic acidosis: replace s[Ca] to near normal range fi rst, before correcting the acidosis[3,8]. Failure to do this may result in convulsions or cardiac arrest[3,8]. Digoxin: IV calcium must be used cautiously as it may precipitate digitalis intoxication; calcium enhances the eff ects of digoxin on the heart[1–3,8].

Hungry Bone Syndrome (HBS): It follows parathyroidectomy. The sudden drop in PTH level results in acute mineralisation of osteoid. This causes a rapid drop in serum calcium (Ca), magnesium and phosphate. HBS can result in seizures and tetany. Associated hypomagnesaemia can be severe, prolonged and symptomatic; accompanied by hypophosphatemia[8,9]. It may require high doses IV Calcitriol (0.25-1mcg) and prolonged periods of high doses of Ca supplementation[8]. Good preparation and giving Ca and calcitriol supplementation for several days pre- operatively prevents HBS[8].

REFERENCES [1] Cooper, M.S. and Gittoes, N.J.L. Diagnosis and management of hypocalcaemia. The British Medical Journal (2008), Vol. 336, No. 7656, pp.1298–1302. doi: 10.1136/bmj.39582.589433.BE [2] Fong, J. and Khan, A. Hypocalcemia: Updates in diagnosis and management for primary care. Canadian Family Physician (2012), Vol. 58, No. 2, pp.158–162. [3] United Kingdom Medicines Information (UKMi) pharmacists for NHS healthcare professional 2011. How is acute hypocalcaemia treated in adults? Medicines Q&As. [4] Uptodate: Etiology/Treatment of hypocalcemia in adults (Viewed 06.2015). [5] Society for Endocrinology 2013. Emergency Endocrine Guidance. Acute Hypocalcaemia, in adult patients. https://www.endocrinology.org/policy/docs/13-02_EmergencyGuidance- AcuteHypocalcaemia_(inAdults).pdf [6] Murphy, E. and Williams, G.R. Hypocalcaemia. Medicine (2009), Vol. 37, No. 9, pp.465–8. [7] Ariyan, C.E. and Sosa, J.A. Assessment and Management of Patients with Abnormal Calcium. Critical Care Medicine (2004), Vol. 32, No. 4, pp.S146–S154. [8] Bushinsky, D.A. and Monk, R.D. Electrolyte Quintet: Calcium. The Lancet (1998), Vol. 352, pp.305–11. [9] Witteveen. J.E., van Thiel, S., Romijn, J.A. and Hamdy, N.A. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. European Journal of Endocrinology (2013), Vol. 168, No. 3, pp.R45–53. doi: 10.1530/EJE-12-0528. [10] British National Formulary August 2015 (Viewed 06.09.2015).

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MANAGEMENT OF HYPERCALCAEMIA

Hypercalcaemia is a serum, albumin-corrected, Calcium Concentration (s[Ca]) of $2.6mmol/L on two occasions, at least one week apart[1,2]. It is the commonest metabolic disorder associated with malignancy; occurs in 10–15% of patients. Early recognition of hypercalcaemia is crucial – it has high morbidity and is potentially life threatening[1,2,4]. Prompt treatment results in excellent outcomes[3]. Management depends on a careful history and physical examination and a purposeful selective approach to investigations[1,4]. Causes: (Commonly caused by PHPT and Malignancy in .90% cases[1,2,4,5]) PTH: a. PHPT: the commonest cause, .50% of all cases[1,4,6,7] inappropriately b. Familial Hypocalciuric Hypercalcaemia (FHH)[1,4,6,7] normal or high (Consider endocrine opinion for further evaluation) .1.5pmol/L c. THPT in CKD[6]. PTH: 1. Malignancy-Associated Hypercalcaemia (MAH): the second commonest suppressed cause[1,2,5–7]. Usually severe. Commonest causes are lung, breast and ,1.5pmol/L haematological cancers[2,5]. A late, poor prognostic sign. (i.e. non-PTH 2. Drugs: excess VD/Ca21 intake; lithium, oestrogens, progestogens, mediated) tamoxifen, thiazides, vitamin A excess (OC-mediated bone resorption) [1–7].

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3. Granulomatous disease (activation of extra-renal 1α-hydroxylase increased calcitriol): e.g. sarcoidosis, Tuberculosis, IBD[1,2,4,6]. 4. Others: CKD (calcium-based Pi binders 1/2 VD, 1/2 adynamic bone disease), adrenal insuﬃ ciency, thyrotoxicosis (stimulate osteoclastic bone resorption), immobilisation[1–7]. Symptoms and Signs (S/S)[1–10] The extent of hypercalcaemia-associated S/S relates to the severity and rate of onset of hypercalcaemia. Asymptomatic or non-speciﬁ c S/S if mild and/or chronic. Symptoms include the mnemonic Stones,̒ Bones, Abdominal moans and Psychic groans̕:

Skeletal: bone pain, fractures (osteoporotic in HPT or pathological in malignancy). Neuropsychiatric an Neuromuscular: anxiety, depression, muscle weakness (lethargy, confusion and coma – in patients with severe rapidly increasing s[Ca]). Gastrointestinal: constipation, nausea, vomiting (dehydration), abdominal pain, pepticulcer and pancreatitis. Renal: polyuria, polydipsia,and dehydration (N DI), renal colic (nephrolithiasis) and renal impairment (nephrocalcinosis) and dRTA CVS: acute – shortened QT interval, arrhythmias are rare. Chronic – hypertension, deposition of calcium in heart valves, coronary arteries and myocardial ﬁ bres. Other: itching, keratitis, conjunctivitis and corneal calciﬁ cation. Investigations[1,2,4,5]

s[Ca], Albumin, UEs. Repeat after one week to conﬁ rm the result. Intact PTH (iPTH): the single most important diagnostic test Clinically-guided tests to identify the underlying cause if iPTH suppressed: PTHrP (possibly carcinoma lung), ALP (osteolytic HrC – possibly carcinoma breast), VD metabolites, Igs/SEP, TSH.

Abbreviations: PHPT5Primary Hyperparathyroidism; N DI5Nephrogenic Diabetes Insipidus; dRTA5Distal Renal Tubular Acidosis; VD5Vitamin D; IBD5Inﬂ ammatory Bowel Disease;

Treatment choice depends on the severity and rate of onset of hypercalcaemia, in addition to the symptoms and the underlying cause. Managing hypercalcaemia is based mainly on clinical experience and accepted practice rather than controlled trials[3].

Calcium level Treatment[1–12] Mild 1. Prompt identifi cation and treatment of the underlying cause – stop 2.65–2.9 thiazides and any vitamin A, D or Ca supplements. [5] (Asymptomatic) 2. Immediate treatment not usually necessary . Refer to endocrine or other teams as appropriate[1,4]. Almost All 3. Monitor: repeat s[Ca] after one week if the cause is unconfi rmed. patients (Fast increasing s[Ca] suggest malignancy; refer urgently[2]). 4. Ensure adequate oral fl uid intake[2]; will also promote renal Ca excretion– avoid excessive fl uid loading[1,2,7]. Caution in cardiac, renal disease and old age[2]. Asymptomatic, mild hypercalcemia is often discovered on routine screening: patients generally do not benefi t from normalisation of s[Ca][4,6].

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Moderate Asymptomatic – Apply all treatment measures listed above 3.0–3.4 Symptomatic – treat as severe hypercalcaemia, box below

Severe Apply all treatment measures listed above 1 $3.5 Immediate admission to hospital[1–3,6,7]. All patients Rehydration to achieve euvolaemia: IV 0.9% normal saline (NS) ~ 3–4L/24hrs[1,3,5–7,12]. Continue with IV NS as necessary. Caution – avoid excessive ﬂ uid loading as above[1,2,7]. Zoledronic Acid* (ZA) 4mg in 100ml 0.9% NS infusion over 15 minutes – superior (more eﬃ cacious1longer duration of action) to pamidronate for MAH[1,3,5,6,11,12]; complete normalisation of s[Ca] levels in , three days in 80–100% of patients[1]. Monitoring: daily s[Ca], [Mg], [Pi] and UEs Give Calcitonin if symptoms are severe (see further treatments) Loop Diuretics (LD): their routine use is not indicated[1,3,5,12]. Judicious use of loop diuretics if volume overload develops inadvertently[1,3,5,12].

Further treatments All patients

Calcitonin : has the most rapid onset of action, within 4–6hrs. Give alongside ZA, dose 4iu/kg, im or sc, 6–12 hourly. It lowers s[Ca] by ~ 0.5mmol/l. The eﬀ ect is short, lasts for few hours. Use for a maximum of 48hrs, limited eﬃ cacy thereafter because of tolerance[1–6,12].

Dialysis (HD/PD): consider for severe (s[Ca] 4.5 to 5mmol/L), refractory hypercalcaemia with neurologic symptoms and stable circulation or in those with severe hypercalcemia complicated by renal failure[1,3–7].

Further: Cause-speciﬁ c treatment

PHPT: surgical treatment is indicated for all patients with specifi c PHPT-related symptoms[9]. Cinacalcet is accepted in PHPT where surgery is indicated but clinically inappropriate[1,2]. Cautious correction of vitamin D defi ciency, to levels of 50–75nmol/l[1,2,9]; and bisphosphonates for osteoporosis[2]. MAH §: admit if moderate, severe or symptomatic hypercalcaemia and treat as above[1,2,5]. If severe, symptomatic MAH refractory to ZA, consider denosumab‡ - initial dose 60mg subcutaneously, with repeat dosing based upon response[1,5]. Further, see notes below. Granulomatous disease (secondary to calcitriol excess); haematological malignancy: glucocorticoides (Prednisolone 20–40mg orally daily), eff ective within 2–5 days[1,3,5–7]. Calcitriol excess responds poorly to bisphosphonates.

Abbreviations: UOP5Urine Output; HD5Haemodialysis; PD5Peritoneal Dialysis *Bisphosphonate: Disodium Pamidronate (DSP): an alternative to ZA, 60-90mg in 250ml-1L NS 0.9% IV over 4hrs. Bisphophonates are eﬀ ective by the 2nd to 4th day[5]. s[Ca] usually returns to normal within seven days.

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Renal impairment: caution, bisphosphonates are excreted by the kidneys[5]. No dose adjustment if serum creatinine (sCr)#300. If sCr.300 – ensure adequate hydration; give pamidronate, ½ the normal dose at slower rate; repeat in few days if ineﬀ ective[3,5]. Side eﬀ ects of IV bisphosphonates: include fever, arthralgia, myalgia, fatigue, bone pain, impaired renal function and osteonecrosis of the jaw in association with long term use[5].

§Malignancy-Associated Hypercalcaemia (MAH): Treat as above. Duration of response to bisphosphonates is 3–4 weeks[1,2]. Hence, re-check s[Ca] after two weeks – without treatment of the underlying cancer, hypercalcaemia usually returns 2–4 weeks. ZA can be re-administered as necessary to control hypercalcaemia[1,2]. Consider oral Bisphosphonate for recurrent, .three episodes, hypercalcamia. However, patients with metastatic bone disease usually receive IV ZA or pamidronate every 3–4 weeks as part of their treatment to prevent skeletal complications[5]. This measure will also prevent recurrent hypercalcemia[1,2,5].

‡Denosumab: It is a human monoclonal antibody to the Receptor Activator of Nuclear factor Kappa B Ligand (RANKL), an OC diﬀ erentiating factor. It inhibits OC formation, decreases bone resorption, increases Bone Mineral Density (BMD), and reduces the risk of fracture. Denosumab is not excreted through the kidneys, hence no restrictions in CKD patients. Beware of the risk of hypocalcaemia[1,5].

REFERENCES [1] Minisola, S., Pepe, J., Piemonte, S. and Cipriani, C. The diagnosis and management of hypercalcaemia. The British Medical Journal (2015), pp.350. doi: http://dx.doi.org/10.1136/bmj. h2723 [2] National Institute for Health Care Excellence. Hypercalcaemia, Clinical Knowledge Summaries. 12, (2014). http://cks.nice.org.uk/hypercalcaemia#!topicsummary [3] Ahmad, S., Kuraganti, G. and Steenkamp, D. Hypercalcemic Crisis: A Clinical Review. The American Journal of Medicine (2014), DOI: http://dx.doi.org/10.1016/j.amjmed.2014.09.030. [4] Carroll, M.F. and Schadea, S.D. A Practical Approach to Hypercalcemia. American Family Physician (2003), Vol. 67, No. 9. http://www.aafp.org/afp/2003/0501/p1959.pdf [5] Uptodate: Treatment of hypercalcemia (viewed 06.2015). [6] Ariyan, C.E. and Sosa, J.A. Assessment and Management of Patients with Abnormal Calcium. Critical Care Medicine (2004), Vol. 32, No.4, pp.S146–S154. [7] Bushinsky, D.A. and Monk, R.D. Electrolyte Quintet: Calcium. The Lancet (1998), Vol. 352, pp. 305–11. [8] The British Medical Journal Best Practice. Assessment of hypercalcaemia. http://bestpractice. bmj.com/best-practice/monograph/159.html

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[9] Bilezikian. J.P., Brandi, M.L. and Eastell, R. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the fourth international workshop. Journal of Clinical Endocrinology & Metabolism (2014), Vol. 99, No. 10. DOI: http://dx.doi. org/10.1210/jc.2014-1413. [10] Clines, G.A. Mechanisms and treatment of hypercalcemia of malignancy. Current Opinion in Endocrinology, Diabetes and Obesity (2011), Vol. 18, No. 6, pp.339–46. doi: 10.1097/ MED.0b013e32834b4401. [11 ] Major, P., Lortholary, A. and Hon, J. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomised, controlled clinical trials. Journal of Clinical Oncology (2001), Vol. 19, pp. 558. [12] LeGrand, S.B., Leskuski, D. and Zama, I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Annals of Internal Medicine (2008), Vol. 149, pp.259–63.

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MANAGEMENT OF HYPOMAGNESAEMIA

Hypomagnesaemia (HoM) is a serum magnesium level (s[Mg]) ,0.7mmol/L. Magnesium is mainly an Intracellular (IC) ion and the s[Mg] may be normal despite signiﬁ cant total body depletion. The serum contains only ~0.5% of total body Mg (TBMg)[1–3].

Symptoms and Are generally non-specifi c and could be attributed to other frequently Signs (S/S) associated electrolyte defi ciency; occur when s[Mg] falls to ,0.5mmol/l. S/S (Similar to are prominent when the reduction in s[Mg] occurs rapidly or is large. hypocalcaemia)[1–3] 1. Neuromuscular eff ects: weakness, hyper-excitability (tetany, tremor, seizures), coma 2. Cardiac: widened QRS, T abnormalities; severe HoM: prolonged PR and QT; arrhythmias: atrial and ventricular; increased risk of digitalis toxicity 3. Metabolic: Hypokalaemia; Hypocalcaemia – common associations Common Causes a. Increased GI losses: PPI (possibly impaired Mg absorption), vomiting, [1–3] diarrhoea, laxatives abuse, malabsorption; rarely reduced intake b. Increased Renal losses: Diuretics, CNIs, CTx, Osmotic diuresis The cause is (e.g. hyperglycaemia), resolving ATN – post-renal transplant, Familial, usually clear from e.g. Gitelman’s/Barter’s syndromes (rare) the history c. Re-distributive (uncommon): DKA, Insulin therapy

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Investigations[1–3] UEs, s[Ca]. If cause unclear from the history: 24hr urine Mg to diﬀ erentiate renal from GI losses

Abbreviations: GI5Gastrointestinal; PPI5Proton Pump Inhibitor; CNI5Calcineurin Inhibitors; CTx5Cytotoxic medications; ATN5Acute Tubular Necrosis; hr5Hour

Treatment, follow the sequential ﬂ owchart:

s[Mg] (mmol/l) Treatment[1–7]

0.5–0.7 Prompt identifi cation and treatment of the underlying cause (Mild) – usually Stop off ending drugs: PPI, optimise diuretics asymptomatic Monitor and seek expert advice as appropriate Treat as per the next box guidance if symptomatic, or on a clinical risk benefi t decision[1,5]

0.3–0.49 Apply all treatment measures listed above 1 (Moderate) Oral Mga: 24 (up to 50) mmol Mg daily. Mg glycerophosphate Asymptomatic (1 tablet = 4mmol Mg) 2 tablets tds with or after food. Try an alternative if ineﬀ ective or causing side eﬀ ects – diarrhoea is common Mg dosing is empirical – monitor s[Mg] (Ca, K, PO4) daily; $5 days treatment is usually required to replete the IC Mg stores. Long term replacement may be needed if a reversible cause is not found and removed.

0.3–0.49 Apply all treatment measures listed above 1 (Moderate) IV Mgb under continuous ECG monitoring: use a large vein (may cause Symptomatic tissue damage if extravasted), and infusion pump. Give magnesium sulphate 50% (2mmol/mL; Ig54mmol)[6]: Day 1: 20mmol (5gms) in ½ or 1L 5% D (or saline) over 3hrs; repeat as necessary Day 2 onwards: 20mmol in 500mL 5% D (or saline) over six hours Lower diluent volumes in volume overload states If haemodynamically unstable, e.g. VT: give 8mmol over 10–15 minutes, repeat once if necessary[6].

Monitor s[Mg] after each dose, and daily. UP to 160 mmol may be required to correct the deﬁ ciency over several days [6]. Continue for 2–3 days with oral (preferably) Mg after s[Mg] normalisation to replete the IC stores. Monitor PR, BP, RR, UOP, and for signs of hypermagnesaemia

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,0.3 (Severe) Apply all treatment measures listed above

Hypomagnesaemia frequently causes secondary hypocalcaemia (PTH-end organ resistance and reduced PTH secretion) and hypokalaemia, rendering them refractory to correction until the magnesium defi cit is corrected[8]. Hypomagnesaemia-related hypocalcaemia: correction of Mg defi ciency fi rst, unless severe hypocalcaemia symptoms present, will often lead to spontaneous normalisation of calcium.

Abbreviations: PPI5Proton Pump Inhibitor; CNIs5Calcineurin Inhibitors; CTx5Cytotoxic Agents; ATN5Acute Tubular Necrosis; IV5Intravenous; Ca5Calcium; K5Potassium aAlternative oral preparations if Mg glycerophosphate intolerant: Maalox 10–20ml qds (10ml Maalox56.8mmol Mg) may take 6–8 weeks. The aluminium (with constipating eﬀ ect) contained in Maalox may reduce the chance of diarrhoea. Magnesium Citrate 150mg tablets; contains 6.2mmol Mg/tablet. Oral preparations are not well absorbed from the GIT, hence the use of magnesium sulphate as an osmotic laxative[4]. Counsel the patient, as all are unlicensed. Magnaspartate (sachets 6.5g/10mmol: 1–2/day) is replacing the oral preparations in the United Kingdom recently licensed[9]. bIV Mg: Magnesium sulphate is the salt of choice. Ideally, the infusion rate should be no .4mmol/hr. Fluid restricted patients: the maximum concentration is 20% (20mmol in 25ml50.8mmol/ml) via a peripheral vein. A practical regimen, less likely to cause venous irritation, is 20mmol magnesium diluted to 100ml, infusion over 5hrs.

Avoid parenteral Mg in patients with heart block or myocardial damage[5]. Renal impairment: Mg is renally excreted and should be used cautiously because of the higher risk of adverse eﬀ ects. If eGFR ,30 reduce dose to #50% under close monitoring[1,5,6]. Use cautiously in myasthenia gravis and respiratory insuﬃ ciency[5].

IV Mg: induces a rapid but temporary elevation in s[Mg] that partially inhibits the stimulus to Mg re-absorption in the loop of Henle. Consequently, up to 50% of the infused Mg will be excreted in the urine. In addition, Mg uptake by the cells is slow; therefore adequate repletion requires sustained correction, preferably oral, as above[10]. IV Mg: is advocated in some acutely ill patients without documented sMg depletion. The American College of Cardiology and the American Heart Association recommend 1–2 grams of magnesium sulphate as an IV bolus over ﬁ ve minutes for torsades de pointes treatment[3].

Patients with chronic renal magnesium wasting, including Bartter’s, Gitelman’s syndrome and cisplatin nephrotoxicity or diuretic-induced hypomagnesaemia who cannot discontinue diuretic therapy, may beneﬁ t from the addition of a potassium- sparing diuretic, e.g. Amiloride. These drugs may lower magnesium excretion by increasing its reabsorption in the distal nephron[3,10].

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Magnesium deﬁ ciency has been implicated in asthma, and some studies suggest that magnesium therapy is eﬀ ective[11].

Monitoring: s[Mg] should be checked daily as serum levels may be artiﬁ cially high whilst magnesium equilibrates with the intracellular compartment. Monitor serum levels of calcium and other electrolytes in patients with hypomagnesaemia.

Adverse eff ects of Magnesium therapy: Oral Mg is usually well tolerated; high doses can cause diarrhoea. Adverse eff ects of parenteral Mg include skin fl ushing, hypocalcaemia, hypotension and AV block. Hypermagnesaemia is unlikely to occur following oral magnesium supplementation, except in patients with renal failure. Signifi cant hypermagnesaemia is rare, patients at higher risk of include the elderly and patients with renal impairment[5,6].

Symptoms of hypermagnesaemia: include ﬂ ushing, hypotension due to peripheral vasodilatation, muscle weakness, loss of deep tendon reﬂ exes due to neuromuscular blockade, respiratory depression, confusion, coma, cardiac arrhythmias and cardiac arrest.

REFERENCES [1] Martin, K.J., Gonzalez, E.A. and Statopolsky, E. Clinical Consequences and Management of Hypomagnesaemia. Journal of the American Society of Nephrology (2009), Vol. 20, pp.2291–2295. [2] Noronha, J.L. and Matuschak, G.M. Magnesium in critical illness: metabolism, assessment, and treatment. Intensive Care Medicine (2002), Vol. 28, pp.667–679. [3] Topf, J.M. and Murray, P.T. ‘Hypomagnesaemia and hypemagnesaemia’. Reviews in Endocrine and Metabolic Disorders (2003), Vol. 4, No.2, pp.195–206. [4] Ayuk, J., Gittoes, J.L. How should hypomagnesaemia be investigated and treated? Clinical Endocrinology (2011), Vol. 75, pp.743–746. [5] NHS Medicines Q&As UKMi. How is acute hypomagnesaemia treated in adults? 12.2010. http://www.gwh.nhs.uk/media/151067/9-5-1-3_ukmi_guidance_on_treatment_of_acute_ hypomagnesaemia_in_adults.pdf. [6] British National Formulary. 70th edition. Pharmaceutical Press; 09.2015-03.2016. [7] Uptodate text book. Evaluation and treatment of hypomagnesemia (viewed 06.2015). [8] Kelepouris, E., Kasama, R. and Agus, Z.S. Eﬀ ects of intracellular magnesium on calcium, potassium and chloride channels. Mineral and Electrolyte Metabolism (1993), Vol. 19, pp.277–281.

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[9] NHS Medicines Q&As UKMi. What oral magnesium preparations are available in the United Kingdom and which preparation is preferred for the treatment and prevention of hypomagnesaemia? 04.2015 (viewed 12.2015). [10] Agus, Z.S. Hypomagnesemia. Journal of the American Society of Nephrology (1999), 10. pp.1616– 1622. [11] Mohammed, S. and Goodacre, S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Journal of Emergency Medicine (2007), Vol. 24, pp.823.

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MANAGEMENT OF HYPOPHOSPHATAEMIA

Hypophosphataemia (HoP) is a Serum Phosphate Concentration (s[PO4]),0.8mmol/L.

PO4 is primarily intracellular, so the s[PO4] does not accurately reﬂ ect total body phosphorus stores and the degree of HoP does not always correlate to the presence of symptoms[1,2]. HoP becomes clinically signiﬁ cant only when combined with total body phosphate depletion[1]. Management depends on comprehensive history, thorough physical examination and selective investigations.

Symptoms and Signs (S/S) [1–6]

Symptomatic HoP is uncommon, develops in PO4 deplete patients, with acute, severe HoP; level ,0.32mmol/L. Possible S/S include: Hypophosphatemia-induced decrease in Intracellulay Adenosine Triphosphate (ATP) levels can cause:

CNS : Parasthaesias, confusion, seizures and coma CVS : Impaired myocardial contractility secondary to ATP depletion in myocardial cells: severe acute heart failure Increased ventricular arrhythmias in the setting of acute myocardial infarction Respiratory failure: due to weakness of the diaphragm; ventilator weaning problems Skeletal and other smooth muscle: a proximal myopathy, dysphagia and ileus Rhabdomyolysis (acute, severe HoP) – described mainly in chronic alcoholics

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Haematological eﬀ ects: Predisposition to haemolysis, decreased phagocytosis and granulocyte chemotaxis and defective clot retraction and thrombocytopenia – aggravate mucosal haemorrhage

Hypophosphatemia-induced changes in mineral metabolism: Hypercalciuria; Osteomalacia – due to decreased bone mineralisation

Common causes (The cause is usually clear from the history) [1–7] 1. Decreased intestinal absorption Poor intake (e.g. alcoholism) rare; usually in association with other causes: Steatorrhea and chronic diarrhoea or

Antacids containing magnesium or aluminium: they bind PO4 and form insoluble complexes

VD deﬁ ciency – failure to stimulate intestinal PO4 absorption and renal PT reabsorption 2. Increased renal excretion

Hyperparathyroidism (PTH inhibits PT PO4 reabsorption): usually mild – (common): PHPT SHPT : Post-transplant (THPT); VD deﬁ ciency Fanconi syndrome (rare) – multiple myeloma is the commonest cause in adults Others: osmotic diuresis, including Diabetic Ketoacidosis (DKA), proximally acting diuretics, acute volume expansion, metabolic acidosis 3. Transcellular shift (redistributive Hypophosphataemia): Stimulation of glycolysis: production of phosphorylated CHO compounds is enhanced, which

induces IC shift of PO4, thus decreasing s[PO4]. Insulin: increased secretion, mainly during recovery from malnutrition (re-feeding syndrome) Recovering Diabetic Ketoacidosis (DKA) – insulin treatment Acute alkalosis (e.g. hyperventilation): alkalosis stimulates glycolysis Hungry bone syndrome Sepsis: HoP correlates to severity and can be used as a prognostic parameter in sepsis 4. Removal by “continuous” renal replacement therapies Investigations[1,2,5,6] Immediate:

PO4, Calcium, Magnesium, ALP, UEs Further investigations if the diagnosis is not clear from the history:

Measure urinary PO4 excretion – 24hr urine collection, or a spot sample: Inappropriately high phosphate excretion indicates renal loss Parathyroid Hormone, 25 Hydroxycholecalciferol Referral to specialist if the cause of HoP is uncertain, severe (<0.3mmol/L), or symptomatic, or if there is a family history of short stature or skeletal deformities consistent with rickets

Abbreviations: IC ATP5Intracellular Adenosine Tri-Phospate; VD5Vitamin D.

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[1–5,8–10] PO4 level Treatment (mmol/l)

0.65–0.75 Identify and correct the underlying cause (mild)

0.32–0.64 Identify and correct the underlying cause (moderate) Has no signiﬁ cant clinical consequences and aggressive Intravenous (IV) [5] Asymptomatic PO4 replacement is unnecessary

High PO4 diet: dairy products, meat, dietician advice – if no improvement:

Consider Oral correction:

® Phosphate Sandoz eﬀ ervescent tablets (mmol: 16.1 PO4, 20.4Na and 3.1K [9] [8] per tablet ). 1–2 tablets tds; adjusted daily according to s[PO4] .

Monitor s[PO4] daily. Continue for two days after s[PO4] normalisation to replete the IC stores.

Oral PO4 is well tolerated except in high doses – may cause diarrhoea; reduce the dose if it develops Do not give with aluminium, calcium or magnesium salts[10]. a. Sodium restriction conditions (e.g. CCF): caution because of the high sodium (and potassium) content of the preparations

b. Hyperkalaemia: give PO4 in the form of sodium glycerophosphate c. Hypocalcaemia: ﬁ rst correct concomitant hypocalcaemia to prevent [8] further reduction in Calcium level when PO4 is replaced .

d. VD replacement if deﬁ cient: enhances intestinal Ca/PO4 absorption

Renal impairment: caution, PO4 is renally excreted

, 0.32 Apply all treatment measures listed above + (Severe) If no improvement on oral therapy, or if oral/nasogastric route is not possible, Asymptomatic seek specialist advise and:

Give intravenous (iv) phosphate*:

Secure adequate IV access; use infusion pump

Infusion of Phosphate Polyfusor® (500ml550mmol PO4, 81mmol sodium, 9.5mmol potassium) – preferred because of its less K contents[8]. Alternatively use potassium acid phosphate, 13.6% in 250ml 0.9% normal

saline (NS), [9mmol of each: K and PO4]; see formulary.

Suggested IV PO4 dose: 0.2 (if asymptomatic) – 0.5 (if symptomatic) mmol/kg/day up to a maximum of 50mmol/day; given over 12–24hrs; see formulary[8].

s[PO 4] level should be checked at the end of the infusion and daily

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Repeat infusion every 24 hours until s[PO4] .0.6 Hyperkalaemia: use 9mmol sodium glycerophosphate instead Monitor for pain and thrombophlebitis specially if peripheral veins used

*IV PO4 is rarely necessary. It is potentially dangerous – can cause fatal hypocalcaemia due to binding of calcium, renal failure due to calcium phosphate precipitation in the kidneys and possibly fatal arrhythmias. It must NEVER be used without relevant specialist advice and experience.

, 0.32 (severe) Apply all treatment measures listed above1 Symptomatic Give IV phosphate: as stated above

Monitor s[PO4], calcium, magnesium and potassium every 6hrs

Switch to oral replacement when the s[PO4] 6hrs reaches 0.48mmol/L

Monitor s[PO4] daily until resolved

Abbreviations: VD5Vitamin D; PT5Proximal Tubules; PTH5Parathyroid Hormone; PHPT5Primary Hyperparathyroidism; SHPT5Secondary Hyperparathyroidism; ALP5Alkaline phosphatase; UEs5Urea and Electrolytes; CCF5Congestive Cardiac Failure.

CONCLUSION

Anticipate the need for PO4 replacement in at risk patients, e.g. refeeding syndrome, to prevent HoP.

REFERENCES [1] Gaasbeek, A. and Meinders, A.E. Hypophosphatemia: an update on its etiology and treatment. American Journal of Medicine (2005), Vol. 118, No. 10, pp.1094–101. [2] Geerse, D.A., Bindels, A.J. and Kuiper, M.A.. Treatment of hypophosphatemia in the intensive care unit: a review. Critical Care (2010), Vol. 14, R147. http://ccforum.com/content/14/4/R147 [3] Subramanian, R.M.B., Khardori, B.S. and Romesh, M.D. Severe Hypopho sphataemia: Pathophysiologic Implications, Clinical Presentations and Treatment. Medicine (2000), Vol. 79, No. 1, pp.1–8. [4] Uptodate. Causes/Signs and symptoms/Evaluation and treatment of hypopho-sphatemia (Viewed 06.2015) [5] Amanzadeh, J. and Reilly, R.F. Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nature Clinical Practice Nephrology (2006), Vol. 2, No. 3, pp.136–48. [6] Glendenning, P., Bell, D.A. and Clifton-Bligh, R.J. Investigating hypophosphataemia. The British Medical Journal (2014), pp. 348. doi: http://dx.doi.org/10.1136/bmj.g3172

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[7] Kim, Y.J., Kim, M.G. and Jeon, H.J. Clinical manifestations of hypercalcemia and hypophosphatemia after kidney transplantation. Transplantation Proceedings (2012), Vol. 44, pp.651–6. [8] UKMi Q&A - How is acute hypophosphataemia treated in adults? 2012 (viewed 06.2015) [9] The British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary (March 2015), No. 69. [10] Sweetman, S. (Ed.): Martindale. The Complete Drug Reference, online edition. The Pharmaceutical Press, London. Accessed via www.medicinescomplete.com

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MANAGEMENT OF ACUTE KIDNEY INJURY

Recognition and Assessment Acute Kidney Injury (AKI) i s a rapid decline in kidney function, occurring over hours to days, resulting in a failure to maintain ﬂ uid, electrolyte and acid-base homoeostasis.

An abrupt (within 48hrs) absolute increase in the serum creatinine (s[Cr]) of $0.3mg/dL (26μmol/L) from baseline; or a percentage increase in the s[Cr] of $50% within seven days

Or oliguria of < 0.5mL/kg/h for .6hrs[1]

Staging of AKI:

Stage Serum Creatinine (SCr) (mmol/l) Urine O (UOP) 1 1.5–1.9 times baseline ,0.5ml/kg/hr for 6–12 hours OR $0.3mg/dl ($26.5mmol/l) increase 2 2.0–2.9 times baseline ,0.5ml/kg/hr for X12 hours 3 3.0 times baseline OR Increase in SCr to ,0.3ml/kg/hr for X24 hours OR $ 4.0mg/dl ($ 353.6mmol/l) OR Anuria for X12 hours Initiation of RRT OR, In patients ,18 years, decrease in eGFR to ,35ml/min per 1.73m2 Adapted from[1]

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Risk Factors: All emergency admissions should have blood for Urea and Electrolytes (UEs) on admission compare with base line, and subsequently as appropriate and electronic alerts should be in place[2,3]. More attention to at risk patients for applying primary prevention measures[1,3]:

Age $65, Sepsis, deteriorating National Early Warning Score (NEWS), Chronic Kidney Disease (CKD), heart failure, liver disease, diabetes mellitus, previous AKI, oliguria (UOP ,0.5ml/kg/hour), hypovolaemia, neurological or cognitive impairment, use of potentially nephrotoxic drugs (NSAIDS, aminoglycosides, ACEi, ARB, diuretics), use of iodinated intravenous contrast and patients with possible obstruction[3].

Causes: Disease Category Incidence Pre-renal: acute renal hypoperfusion 28% Intrinsic renal: acute diseases of renal parenchyma (predominantly ATN, 58% accounts for ~ 85%* cases) Large renal vessels disease 1% (TED, HT emergency, scleroderma) Small renal vessels and glomerular disease 4% (including AVR) ATN* 45% (ischemic – 50%): unresolved pre-renal; toxic (35%): drugs, contrast; sepsis Tubulointerstitial disease 2% (AIN, ACR, viral, drugs, inﬁ ltrative) Intra-tubular obstruction (MG, Hb, MM, drugs) Post-renal: obstruction of the urinary tract – (prostate, stones, extrinsic 10% compression, clots) Abbreviations: TED5Thrombo-Embolyic Disease, HT5Hypertension, AVR5Acute Vascular Rejection, ATN5Acute Tubular Necrosis, AIN5Acute Interstitial Nephritis, ACR5Acute Cellular Rejection, MG5Myoglobin, MM5Multiple Myeloma

Acute on CKD in 13% of AKI cases: mostly due to ATN and pre-renal disease.

Adapted from:[4]

Hospital-acquired AKI is often multifactorial, with contributions from hypotension, sepsis and drugs

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Assessment 1. Detailed history: with particular reference to features associated with volume depletion, sepsis, cardiogenic or multi-system disorder Past medical history (risk factors). Obtain previous UEs for evidence of pre-existing CKD Careful drug history: antibiotics, NSAIDs, diuretics, ACEi, ARB, non-prescribed drugs 2. Purposeful physical examination: assessment of hydration status – skin turgor, pulse, JVP, lying/standing BP, meticulous documentation and vigil review of input output ﬂ uid balance charts and signs of ﬂ uid overload Look for: signs of urinary tract obstruction – palpable bladder; fundi – papilloedema; skin rash; arthritis 3. Look for evidence of Multiple Organ Failure (MOF)

Patient looks severely ill/exhausted/obtund Hypotension (MAP ,80mmHg) despite initial ﬂ uid administration. Presser agents/inotrope dependency

Impaired gas transfer: hypoxaemia (PaO2,10kPa) despite 40% O2 Metabolic acidosis – compensated or non-compensated CXR: pulmonary venous congestion

It is crucial to early identify the developing or established MOF and refer to ICU for further assessment and management

Investigations Urgent for all patients:

Urine dipstick (preferably non-catheter): blood, leucocytes, protein, nitrites and glucose FBC; clotting, UEs, Ca, Pi, LFTs, glucose, CK, CRP ABG to assess acidosis, hypoxia ECG – manifestations of hyperkalaemia or arrhythmias US KUB within 24hrs if no cause identiﬁ ed; 6hrs in trauma or if obstruction is suspected CXR – signs of: ﬂ uid overload, infection, Wegner Granulomatosis or Goodpasture’s syndrome Blood and urine cultures – if sepsis is suspected HB, HC and HIV if clinically indicated or dialysis is anticipated

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Selected patients with active urinary sediment (Blood, Protein, Casts):

Immunology screen (ANA/C3/C4/ANCA/Anti-GBM) – acute Gn/vasculitis Serum Igs, electrophoresis and urine electrophoresis Urine myoglobin to conﬁ rm rhabdomyolysis LDH, blood ﬁ lm to aid diagnosing thrombotic micro-angiopathies

Diff erential Diagnosis: Pre-renal vs ATN – avoid over intravenous fl uid resuscitation, especially in ATN patients for fear of fl uid overload

Pre-renal ATN S Ur/Cr ratio .20:1 10:1 U SG/ Osmolality 1.015/.500 1.010/ 300mOsm/kg

U Na/ FENa+ ,20/,1% .40mmol/l /.2%

FENa5the percentage of the sodium ﬁ ltered at the glomerulus that is secreted in the urine.

Markers of CKD: elevated iPTH, small kidneys < 9cm, anaemia, high phosphate, low bicarbonate

RESPONSE Referral to Renal Team Discuss with the renal team any patient with[3]: AKI of unclear cause (e.g. no evidence of volume depletion, sepsis, etc.) Inadequate response to treatment Active urinary sediment (proteinuria or haematuria without evidence of UTI or trauma due to catheterisation) Multi-system disorder Stage 3 AKI; Residual eGFR #30; CKD 4 and 5 Kidney transplant (Refer patients with obstructive uropathy to the urology team)

IMMEDIATE TREATMENT: Treatment is largely supportive AKI: Volume AKI: Sepsis AKI: Euvolaemic AKI: Cardiogenic depletion patients shock Volume resuscitation • Volume • Supportive • Supportive resuscitation* treatment treatment • Take cultures • Refer to renal • Refer to • Prompt antibiotic team cardiology administration as per local protocols

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*Volume resuscitation (see chapter on intravenous ﬂ uids): o Correct with IV isotonic crystalloid (0.9% NS/or Hartmann’s solution) o Once rehydrated, continue IV crystalloid to match urine output130ml/hr under monitoring of electrolyte levels

o Consider CV line: keep CVP 10–14cm H2O o If BP low despite the above consider pressor agents/inotropes

• Discontinue/avoid nephrotoxins e.g. NSAIDs/(ACEi, ARB – temporarily until improvement and stabilisation[3]) • Drugs in adjusted renal dose • Do not oﬀ er low dose dopamine to treat AKI[1,3] • Do not oﬀ er diuretics unless in volume overload[1,3]

Renal Support Urgent referral to the nephrologist/intensivist for those who need emergency RRT (continuous HF, HDF, HD – according to local resources and expertise) for life threatening complications if medical treatment fails[1,3]:

Pulmonary oedemaa Severe Severe acidosisc Uraemic hyperkalaemiab complications: e.g. pericarditis Urgent oximetry/ Do not wait for IV Normal Saline Analgesia (avoid ABG/ECG/CXR a repeat K level 1000ml followed NSAIDs) O2 therapy before starting by 1.26% sodium Heparin-free Stop IV ﬂ uids treatment bicarbonate dialysis IV furosemide 500ml over 4hrs 40mg/repeat if Oral sodium patient is improving bicarbonate or awaiting RRT Avoid volume IV morphine overload 2.5mg110mg metoclopramide Consider GTN infusion a Fluid overload in critically ill patients, including those with AKI, is associated with worse outcome[5]. b Treatment of Hyperkalaemia, see chapter on hyperkalaemia. c AKI-related metabolic acidosis: can usually be corrected with bicarbonate and should rarely require urgent dialysis if not accompanied by volume overload or uremic symptoms[6]. No standard criteria (PH or HCO3 level) for initiating dialysis for acidosis exist as there is no available data[1]. Involve the dietician to ensure adequate nutrition[1,7]

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Starting RRT should be based on the condition of the patient as a whole and trends in laboratory tests, not on an isolated urea, creatinine or potassium value[1,3]. [1,3] The optimal time for starting RRT is unclear . Early as opposed to late starting of RRT in AKI was not associated with diﬀ erences in mortality (ICU/hospital), or in renal recovery among survivors in a small RCT[8]; another smaller RCT[9] and a heterogeneous systematic review[10] and observational studies suggested beneﬁ t from starting early[1].

Monitoring Treatment

Physiological surveillance (NEWS) should be performed for all patients with AKI to identify early signs of deterioration that may require escalation in the level of care[6] Daily weight and ﬂ uid balance charts – input/output. Beware of the diuretic phase. Daily biochemical screen Monitoring of underlying cause Avoid urinary catheter unless very essential

Subsequent Management/Rehabilitation Depends on the precipitating cause, treatment administered and the outcome

Resolved pre-renal AKI: can be managed and followed up by general physicians Intrinsic renal disease (ATN in ~ 85% cases): general physicians can follow up uncomplicated, completely resolved ATN. Renal physicians will follow those with non- or partially resolved AKI and patients needing immunosuppression or RRT.

Discharge Policy Arrange Outpatient Department (OPD) follow up if renal function remains abnormal.

Prevention of AKI: The mainstay of AKI prevention is good medical care Ensure adequate hydration status Prevention of hypotension Prompt treatment of sepsis Avoid nephrotoxic agents

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CONCLUSION

The ISN has put the human rights case for the initiative: A goal of “zero preventable deaths from AKI by 2025”… No one should be dying of untreated AKI in low-resource regions by 2025[11]

PRACTICAL EXERCISE A 27-year-old footballer was involved in a road traﬃ c accident. He sustained blunt chest and abdominal trauma and multiple bone fractures. He was tacchycardic and hypotensive on arrival to emergency department. Fluid resuscitation included 4L normal saline and three units of blood – haemodynamically stabilised. Non-contrast CT showed massive haematoma related to right mid-shaft femur fracture.

Disease Progression: Day 2: He became unwell, complaining of abdominal pain. BP 90/50 mmHg, moderate ankle swelling. UOP dropped to 15ml/hr, had total ﬂ uids of 11L IV since admission. Abdomen was severely distended. Serum creatinine 92μmol/L, and serum lipase was high. CXR: revealed elevated diaphragms, and US showed massive ascites. Day 3: remained hypotensive, tachycardic, oligo-anuric despite adequate ﬂ uid

therapy, moderate ankle swelling and CVP was 17cmH2O. Serum creatinine was 185μmol/l, s{K} and bicarbonate were normal. u[Na] 11mmol/L, with bland urine sediment.

Questions: Q1. What is the cause of the AKI? A1. Abdominal Compartment Syndrome (ACS) causing increased renal vein pressure and decreased renal perfusion

Q2. Name a bedside, deﬁ nitive diagnostic test? A2. Measurement of Intra-Abdominal Pressure (IAP): bladder (intra-vesical) pressure was 30mmHg (IAP: normal range 5–7mmHg).

Q3. What is the immediate therapeutic intervention? A3. Emergency paracenthesis, urine output and serum creatinine improved.

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Q4. Additional therapy includes: a. Administering IV colloids aiming for a higher CVP b. Avoiding analgesics and sedation c. Immediate pharmacological paralysis and ventilation d. Starting renal replacement therapy e. Involving the surgical team A4. Additional therapy includes statement, (e), open abdominal decompression may be required if the condition deteriorates. Ensure suﬃ cient pain control and sedation to improve abdominal wall compliance and relaxation.

REFERENCES

[1] KDIGO Clinical Practice Guideline for AKI. KI Supplements (2012), Vol. 2, Issue 1 http://www. kidney-international.org. [2] Stewart, J., Findlay, G. and Smith, N. Adding insult to injury. A review of the care of patients who died in hospital with a primary diagnosis of acute kidney injury. The National Confi dential Enquiry into Patient Outcome and Death Report (2009), (viewed 03.2015). [3] National Institute for Health and Care Excellence. Acute kidney injury: Prevention, detection and management of acute kidney injury up to the point of renal replacement therapy. [CG169] 08.2013. www.nice.org.uk/guidance/cg169 (viewed 03. 2015). [4] Liaño, F. and Pascual, J. The Madrid Acute Renal Failure Study Group. Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Kidney International (1996), Vol. 50, pp.811-818; doi:10.1038/ki.1996.380. [5] Bouchard, J., Soroko, S.B., Chertow, G.M. and Himmelfarb, J. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney International (2009), Vol. 76, pp.422–427. [6] Gauthier, P.M. and Szerlip, H.M. Metabolic acidosis in the intensive care unit. Critical Care Clinics (2002), Vol. 18, pp.289–308. [7] The Renal Association (United Kingdom). Acute Kidney Injury Guidelines 03.2011 (viewed 03.2015). [8] Bouman, C.S., Oudemans-Van Straaten, H.M. and Tijssen, J.G. Eff ects of early high-volume continuous venovenous hemofi ltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomised trial. Critical Care Medicine (2002), Vol. 30, No. 10, pp.2205–2211. [9] Sugahara, S. and Suzuki, H. Early start on continuous hemodialysis therapy improves survival rate in patients with acute renal failure following coronary bypass surgery. Hemodialysis International, (2004), Vol. 8, No. 4, pp.320–325. [10] Karvellas, C.J., Farhat, M.R. and Sajjad, I. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Critical Care 2011; 15:R72 doi:10.1186/cc10061. [11] Mehta, R., Cerdá, J. and Burdmann, E.A. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. The Lancet (2015), Vol. 385, No. 9987, pp.2616–2643 http://dx.doi.org/10.1016/S0140-6736(15) 60126-X

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WASD APPENDIX A

The Observation Chart and the National Early Warning Score (NEWS) Concept

Assessment Tool for acute-illness severity The whole appendix is based on the Royal College of Physicians (UK) (RCP) publication*, including the adapted chart (Observation chart/ NEWS Score and Response) shown below. Readers are encouraged to refer to the original RCP publication. The manuscript is prepared by Dr W. Eltoum, MBBS (UMTS – Khartoum), DTM&H (Liverpool).

What is National Early Warning Score (NEWS) NEWS is a simple scoring system in which a score is allocated to six simple, routinely measured, physiological parameters: i) Respiratory rate ii) Oxygen saturations iii) Temperature iv) Systolic blood pressure v) Pulse rate vi) Level of consciousness.

z These measurements should be undertaken when patients present to, or are be- ing monitored in hospital. They form the basis of the NEWS. z It is a very helpful surveillance system for patients in hospitals, tracking their clinical condition, alerting the clinical team to any clinical deterioration and triggering a timely clinical response. z Abiding by a national NEWS helps standardize care, assessment, and response to acute illness.

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Why should we use NEWS? This assessment tool was created by the Royal College of Physicians (UK) to standardize the way of assessing and monitoring acutely unwell inpatients. NEWS is used to improve the following: 1. The assessment of acute illness 2. The detection of clinical deterioration 3. Initiation of a timely and competent clinical response.

How to use it? First step: Perform. A doctor or a nurse has to measure parameters of the patient and plot the results on an observation chart, given below. Second step: Record. The parameters, on the observation chart, are graded according to their severity 1–3, where 1 is less severe and 3 is more severe. The individual parameter scores should then be added up to obtain the aggregate NEWS score for the patient. Third step: Respond. The NEWS score value should determine the clinical risk (low/ medium/ or severe), the urgency of the clinical response, and the clinical compe- tency of the responder/s, see Response (Action) table shown after the Observation Chart.

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Observation Chart/ NEWS Score and Response (Action taken) Chart

Hospitals are encouraged to adapt the Observation Chart; it may need simpliﬁ cation according to the available resources. Every patient should have an observation and ﬂ uid balance chart by his/her bed! *Reference: Royal College of Physicians. National Early Warning Score (NEWS): standardising the assessment of acute-illness severity in the NHS. RCP, 2012

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WASD APPENDIX B

Twenty-four hour Fluid Prescription Chart Date: _____ / _____ / ______

Patient Name: ______

Date of Birth: _____ / _____ / ______M / F

Hospital Name: ______

Number: ______Weight: ______Kg: ______

PERSCRIPTION ADMINISTRATION Date Fluid Vol. Rate Route Drug Dose Signed Start Start Batch Given/ Added Date time number checked by

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Twenty-four hour Fluid Input/Output Chart

Date: _____ / _____ / ______

Time In Out Signature

Oral in Infusion 1 Infusion 2 Other Total in Urine Other Total out losses 0600

0700

0800

0900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

2400

0100

0200

0300

0400

0500

Total at 0600

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WASD APPENDIX C

Check list for Fluid Prescription

Clinical assessment of volume/ hydration status: Observations: PR, BP, Temperature, RR, O2 Saturation Mucus membranes, skin turgor, capillary reﬁ ll, peripheral/ pulmonary oedema Urine output/other losses Biochemical assessment: UEs, Hb, and Haematocrit

Daily Requirements

Water: 25–30ml/kg/day (~2.2–2.5L/day) Sodium: 1–2mmol/kg/day (~100mmol/day) Potassium: 1mmol/kg/day (~ 60–70mmol/day)

Remember the 5Rs for Fluid Prescription 1. Resuscitation ABCDE assess: if severe fl uid defi cit then initiate fl uid challenge – 2502500 ml 0.9% normal saline

2. Routine Maintenance

Assess daily ﬂ uid requirement for maintenance (see above, daily requirements). NB. Avoid prescribing .3L and/or .24hour per prescribing episode.

3. Replacement Estimate ﬂ uid losses: e.g. vomiting, diarrhoea, and NG tubes, and add to maintenance ﬂ uids

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4. Re-distribution

Estimate fl uid excesses: e.g. peripheral or pulmonary oedema, and ‘subtract’ from maintenance fl uids Third spacing: e.g. severe sepsis, add to maintenance fl uid

5. Re-assess

Acutely unwell patients need re-assessing after each ﬂ uid prescription For stable patients try to prescribe 24h ﬂ uids until next day team assessment UEs to be checked at least every 48h – look for electrolyte imbalance

Screen for AKI, high risk of AKI if $2 of:

1. Age .65 years 2. Use of nephrotoxic drugs prior to admission 3. Liver disease or heart failure 4. CKD Review drug chart for nephrotoxic drugs

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