Title: New guideline for perioperative management of people with inherited salt-wasting alkaloses
Abstract: Anaesthetists may be asked to provide anaesthesia for patients with severe hypokalaemia, hypomagnesaemia, or both. When these disorders are attributable to an acute illness and are easily correctable, management is straightforward. However, these abnormalities may occasionally be attributable to rare disorders of renal electrolyte handling, the so-called salt-wasting alkaloses. In these conditions, full and sustained correction of electrolyte abnormalities may be impossible and lead to unnecessary delay in treatment. Guidance is therefore required on the risks and benefits of anaesthesia in these conditions. Gitelman's and Bartter's syndromes are autosomal recessive disorders whose clinical features arise as a result of impairment of sodium chloride reabsorption within the renal tubule. They are therefore frequently grouped together under the heading of inherited salt-wasting alkaloses. The key features of these conditions are summarized in Table 1. The defect in Gitelman's syndrome lies in the thiazide-sensitive Na+–Cl− cotransporter in the distal convoluted tubule.1Simon DB Nelson-Williams C Bia MJ et al.Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter.Nat Genet. 1996; 12: 24-30Crossref PubMed Scopus (1046) Google Scholar The Bartter's phenotype results from mutations affecting one of a number of transporters in the thick ascending limb of the loop of Henle.2Naesens M Steels P Verberckmoes R Vanrenterghem Y Kuypers D Bartter's and Gitelman's syndromes: from gene to clinic.Nephron Physiol. 2004; 96: 65-78Crossref Scopus (122) Google Scholar The tubular defects seen mimic those of long-term thiazide (Gitelman's) or loop (Bartter's) diuretic use.Table 1Features of the inherited salt-wasting alkalosesBartter's syndromeGitelman's syndromeSite in nephron of defectLoop of HenleDistal tubuleEstimated prevalence1:1 000 0001:40 000Typical age at presentationNeonatal or early childhoodAdolescence or early adulthoodSerum potassiumLowLowSerum magnesiumNormal (except for Bartter's Type III)LowAcid–base statusMetabolic alkalosisMetabolic alkalosisUrinary calciumHighLowDiuretic class sharing biochemical featuresLoopThiazide Open table in a new tab Secondary hyperaldosteronism occurs in both conditions as a result of renal salt wasting and consequent volume contraction, resulting in hypokalaemia and metabolic alkalosis. Hypomagnesaemia is common in Gitelman's syndrome and in Bartter syndrome Type III. Hypocalciuria is seen in Gitelman's syndrome. Bartter's syndrome usually presents in early life and may be accompanied by growth retardation and developmental delay. In contrast, the clinical manifestations of Gitelman's syndrome generally do not become apparent until late childhood or adulthood. Although the Gitelman phenotype is less severe, symptoms such as salt craving, cramps, weakness, and fatigue are common, associated with reduced health-related quality of life and, for some patients, very disabling.3Cruz DN Shaer AJ Bia MJ Lifton RP Simon DB Yale G Bartter's Syndrome Collaborative Study GroupGitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.Kidney Int. 2001; 59: 710-717Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar A long QTc interval on ECG caused by magnesium and potassium depletion occurs in up to 40% of people with Gitelman's syndrome,4Bettinelli A Tosetto C Colussi G Tommasini G Edefonti A Bianchetti MG Electrocardiogram with prolonged QT interval in Gitelman disease.Kidney Int. 2002; 62: 580-584Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar and there are reports of ventricular tachycardia and sudden cardiac death in patients with salt-wasting alkalosis.5Phan TT Osman F Jones A El-Gaylani N Ventricular tachycardia associated with hereditary magnesium-losing nephropathy.Int J Cardiol. 2006; 113: e42-e43Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar 6Scognamiglio R Negut C Calò LA Aborted sudden cardiac death in two patients with Bartter's/Gitelman's syndromes.Clin Nephrol. 2007; 67: 193-197Crossref PubMed Scopus (40) Google Scholar Blood pressure is frequently low or normal in both conditions, at least until mid-adult life; renal excretory function usually remains normal. Treatment involves life-long supplementation with potassium chloride and, where needed, magnesium salts, together with potassium-conserving diuretics, such as amiloride and spironolactone. Non-steroidal anti-inflammatory drugs are sometimes used, because secondary increases in prostaglandin production may be seen. Inhibitors of the renin–angiotensin system are often used, although their use can be limited by hypotension, especially in younger patients. Although there are no specific surgical complications of salt-wasting alkaloses, patients with Bartter's and Gitelman's syndromes may require general anaesthesia for surgical procedures exactly as anyone else does. Anecdotal evidence suggests that current anaesthetic practice in this setting is highly variable, as the anaesthetist tries to balance the risk of general anaesthesia in the face of significant metabolic derangement against the harm and inconvenience to patients who may be denied surgery on account of abnormalities in potassium and magnesium balance that are chronic and stable. Although patients with salt-wasting alkaloses are frequently under the long-term care of nephrologists (if a diagnosis has been established), timely specialist advice may not be readily accessible outside tertiary centres, and some patients may be diagnosed for the first time when admitted for an intercurrent medical or surgical illness. Similar chronic electrolyte derangements can occur in patients on long-term diuretic therapy, although in these patients, if time permits, changes in diuretic treatment should be considered. It is in this context that a small working group has recently produced a clinical guideline, endorsed by the UK Renal Association and the Royal College of Anaesthetists and accredited by the National Institute for Health and Care Excellence, on the perioperative management of adult patients with inherited salt-wasting alkaloses undergoing elective or expedited surgical procedures.7Gallagher H Soar J Tomson C Guideline for the perioperative management of people with inherited salt-wasting alkaloses (Gitelman's syndrome and Bartter's syndrome) undergoing non-urgent surgical procedures. 2015http://www.rcoa.ac.uk/document-store/guideline-the-perioperative-management-of-people-inherited-salt-wasting-alkalosesGoogle Scholar The guideline draws on existing national and international standards governing the preoperative testing and perioperative care of surgical patients generally8NationalConfidential Enquiry into Patient Outcome and DeathThe NCEPOD Classification of Intervention. 2004http://www.ncepod.org.uk/classification.htmlGoogle Scholar, 9National Institute for Health and Care ExcellencePreoperative tests: the use of routine preoperative tests for elective surgery. 2003https://www.nice.org.uk/guidance/cg3Google Scholar, 10Royal College of NursingPerioperative fasting in adults and children: an RCN guideline for the multidisciplinary team. 2005https://www2.rcn.org.uk/__data/assets/pdf_file/0009/78678/002800.pdfGoogle Scholar, 11Association of Anaesthetists of Great Britain and IrelandRecommendations for Standards of Monitoring During Anaesthesia and Recovery. 4th Edn. 2007Google Scholar, 12Kristensen SD Knuuti J Saraste A et al.2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA).Eur Heart J. 2014; 35: 2383-2431Crossref PubMed Scopus (144) Google Scholar, 13Fleisher LA Fleischmann KE Auerbach AD et al.2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014; 130: 2215-2245Crossref PubMed Scopus (450) Google Scholar and makes recommendations specific to this patient group on preoperative assessment, minimal acceptable preoperative concentrations of potassium and magnesium, and intra- and post-procedural monitoring. The guideline was developed as part of the Renal Association's Rare Renal Diseases initiative (www.rarerenal.org). Literature searches were run on Cochrane, Medline, Embase, the British Nursing Index, CINAHL, and the Centre for Reviews and Dissemination (University of York) databases. Unsurprisingly, there were no systematic reviews or meta-analyses of randomized controlled trials nor any controlled studies of any description, with or without randomization. Accordingly, a narrative review was conducted to inform guideline development. Evidence specific to Bartter's14Abston PA Priano LL Bartter's syndrome: anesthetic implications based on pathophysiology and treatment.Anesth Analg. 1981; 60: 764-766Crossref PubMed Google Scholar, 15Nishikawa T Dohi S Baroreflex function in a patient with Bartter's syndrome.Can Anaesth Soc J. 1985; 32: 646-650Crossref PubMed Scopus (8) Google Scholar, 16Chenoweth D Successful use of isoflurane and vecuronium in a patient with Bartter's syndrome: a case study.AANA J. 1987; 55: 434-436PubMed Google Scholar, 17Higa K Ishino H Sato S Dan K Anesthetic management of a patient with Bartter's syndrome.J Clin Anesth. 1993; 5: 321-324Abstract Full Text PDF PubMed Scopus (4) Google Scholar, 18Brimacombe JR Breen DP Anesthesia and Bartter's syndrome: a case report and review.AANA J. 1993; 61: 193-197PubMed Google Scholar, 19Kannan S Delph Y Moseley HS Anaesthetic management of a child with Bartter's syndrome.Can J Anaesth J Can Anesth. 1995; 42: 808-812Crossref PubMed Scopus (9) Google Scholar, 20Roelofse JA van der Westhuijzen AJ Anesthetic management of a patient with Bartter's syndrome undergoing orthognathic surgery.Anesth Prog. 1997; 44: 71-75PubMed Google Scholar and Gitelman's21Van der Herten CGG De Baerdemaeker LEC Berrevoet F Szegedi LL Anaesthesia for a patient with Gitelman's syndrome undergoing abdominal hernia repair.Acta Anaesthesiol Belg. 2005; 56: 183-185PubMed Google Scholar, 22Bolton J Mayhew JF Anesthesia in a patient with Gitelman syndrome.Anesthesiology. 2006; 105: 1064-1065Crossref PubMed Scopus (5) Google Scholar, 23Shanbhag S Neil J Howell C Anaesthesia for caesarean section in a patient with Gitelman's syndrome.Int J Obstet Anesth. 2010; 19: 451-453Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar was largely confined to case reports, together with a single case series of five patients with presumptive Gitelman's syndrome, with preoperative potassium and magnesium concentrations ranging from 3.2 to 4.0 and from 0.49 to 0.66 mmol litre−1, respectively, who underwent surgical procedures requiring anaesthesia without acute electrolyte or postoperative complications.24Farmer JD Vasdev GM Martin DP Perioperative considerations in patients with Gitelman syndrome: a case series.J Clin Anesth. 2012; 24: 14-18Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The guideline group therefore also conducted a series of extended searches exploring the relationship between anaesthesia, hypokalaemia, and hypomagnesaemia more generally, from which a number of conclusions were drawn and applied to the salt-wasting alkalosis population. Most important was felt to be the need for a patient-based risk assessment. Such an assessment should include consideration of the nature of the proposed surgery, concurrent medications, notably digoxin, insulin, and β2-adrenoceptor agonists, and the presence of cardiovascular risk factors. This presence of pre-existing cardiac rhythm disturbance was felt to be key, drawing in particular from a prospective study of 150 surgical patients, which concluded that a history of dysrhythmia but not chronic hypokalaemia (2.6–3.4 mmol litre−1) was associated with the development of intra-operative dysrhythmia.25Vitez TS Soper LE Wong KC Soper P Chronic hypokalemia and intraoperative dysrhythmias.Anesthesiology. 1985; 63: 130-133Crossref PubMed Scopus (58) Google Scholar The time course of hypokalaemia is another critical factor determining the level of risk. Where the abnormality is stable, the ratio of intracellular fluid to extracellular fluid (ICF:ECF) potassium, which is essential for the maintenance of the membrane potential, is well maintained.26Gennari FJ Hypokalemia.N Engl J Med. 1998; 339: 451-458Crossref PubMed Scopus (486) Google Scholar Patients with salt-wasting alkaloses have metabolic abnormalities that are chronic and, in the absence of intercurrent illness, generally stable. In this setting, rapid preoperative correction may alter the ICF:ECF ratio. It is well recognized that emergency potassium replenishment in a hospital inpatient setting is associated with significant morbidity and mortality.27Lawson DH Adverse reactions to potassium chloride.Q J Med. 1974; 43: 433-440PubMed Google Scholar For these reasons, the working group concluded that preoperative i.v. administration of potassium and magnesium should be avoided for patients with salt-wasting alkaloses undergoing non-urgent surgery. Where patients did not meet acceptable electrolyte concentrations, it was felt that the most appropriate pathway was for the patient to be referred to a physician with expertise in the management of these conditions for management advice and the surgery rescheduled. Although there was inevitably a degree of publication bias that resulted in selective reporting of dysrhythmias in association with electrolyte imbalance, a large prospective study of patients undergoing major vascular or cardiac surgery did not support the notion that hypokalaemia carries significant risks. In these 447 patients, the overwhelming majority of whom had pre-existing cardiovascular disease and 9% of whom had a serum potassium <3.0 mmol litre−1, there was no relationship between serum potassium concentrations and cardiac rhythm disturbance.28Hirsch IA Tomlinson DL Slogoff S Keats AS The overstated risk of preoperative hypokalemia.Anesth Analg. 1988; 67: 131-136Crossref PubMed Google Scholar The group also found at most limited evidence that magnesium depletion in isolation is arrhythmogenic, although it can exacerbate the dysrhythmic potential of hypokalaemia.29Fawcett WJ Haxby EJ Male DA Magnesium: physiology and pharmacology.Br J Anaesth. 1999; 83: 302-320Abstract Full Text PDF PubMed Scopus (504) Google Scholar Our view was therefore that the minimal acceptable concentration of potassium for anaesthesia should be modulated by the presence or absence of concurrent severe hypomagnesaemia. Although acknowledging that definitive evidence is lacking, we have indicated a series of thresholds at which it was felt that surgery could reasonably proceed in asymptomatic and otherwise uncomplicated patients. We felt that it was important that these decisions were taken on the basis of contemporaneous (within 24 h) electrolyte results, rather than those measured at pre-assessment. Such an approach should also facilitate an assessment of electrolyte stability. We recommended that standard national guidelines were followed on the need for fasting before surgery. Where the serum magnesium concentration is ≥0.5 mmol litre−1, the guideline suggests a safe lower limit for potassium of 3.0 mmol litre−1; for those patients in whom the abnormality was demonstrably stable and the proposed procedure was minor, one could consider proceeding with surgery where the serum potassium ≥2.8 mmol litre−1. However, in the presence of a serum magnesium of <0.5 mmol litre−1 it was felt that the lower limit for serum potassium should be set substantially higher, at 3.3 mmol litre−1. There will be a subset of patients with salt-wasting alkalosis in whom these concentrations will not be achieved despite specialist input, and in these patients the guideline suggests that it would be appropriate to offer surgery after a thorough discussion of the risks and benefits, with carefully monitored replacement of potassium, magnesium, or both, during surgery if necessary. The group suggests that monitoring during anaesthesia and recovery should broadly follow national guidance for the general population. Systems must be in place to allow the rapid assessment and correction of electrolyte abnormalities, with continuous ECG monitoring available during recovery. Although day-case surgery may be a reasonable option for stable patients undergoing minor operations, where more major procedures (for example, abdominal hysterectomy, endoscopic prostatic resection, lumbar discectomy, and thyroidectomy) are undertaken, it is suggested that electrolytes should be measured immediately after surgery and subsequently according to clinical circumstances. There must be the option for postoperative high-dependency care, including facilities for serial intra-arterial potassium sampling, for those patients at greatest risk, such as those in whom potassium concentrations are unstable, where a paralytic ileus is anticipated, or in patients where hypokalaemia may be exacerbated by fluid losses during or after surgery because of vomiting or other causes. An individual anaesthetist will be faced by a patient with Gitelman's or Bartter's syndrome very infrequently. These are rare disorders, with estimated prevalences of 1:40 0001Simon DB Nelson-Williams C Bia MJ et al.Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter.Nat Genet. 1996; 12: 24-30Crossref PubMed Scopus (1046) Google Scholar and 1:1 000 000, respectively,30Rudin A Bartter's syndrome. A review of 28 patients followed for 10 years.Acta Med Scand. 1988; 224: 165-171Crossref PubMed Scopus (96) Google Scholar that through the presence of significant, and sometimes major, pre-existing metabolic disturbances present unique challenges to the anaesthetic team. Until now, there has been no formal advice to guide perioperative practice. The fact that this practice may be inconsistent should therefore not be unexpected. This guideline was developed systematically, on the basis of the best available, albeit frequently indirect, evidence. We hope that it will serve as a useful resource to reduce variation and improve the care of this patient group, although it should be seen as a supplement rather than a replacement for traditional anaesthetic risk assessment, to support clinical decisions that should always be taken on an individual patient basis. Contributed fully to the planning and drafting of this editorial and to all stages in the process of guideline development: H.G., J.S., C.T. None declared. We are grateful for the support provided by the Epsom and St Helier NHS Trust Library Services, and in particular that of Ms Potenza Atiogbe. We would also like to thank Professor Fiona Karet and Dr Andrew Lewington who offered feedback on working drafts of the guideline.