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CONTROVERSY 443

General paediatrics case controlled studies of cerebral Arch Dis Child: first published as 10.1136/adc.86.6.443 on 1 June 2002. Downloaded from ...... oedema complicating DKA and there is conflicting evidence as to the role of iatrogenic factors in fatal cases.613How- Fluid management in diabetic ever, excessive rates of fluid administra- tion, particularly early in resuscitaion,14 and failure of plasma to rise as plasma declines, have been iden- C D Inward, T L Chambers tified as risk factors. Studies using computed tomography ...... suggest that subclinical cerebral swelling Have we got it right yet? may be a common occurrence in children presenting with DKA,15 16 although this has been disputed.17 If cerebral swelling oung people with depend- may be considered and treated as a vari- is a relatively common event it is not ent mellitus are three ant of renal disorder with clear why only a minority progress to times more likely to die in child- hypertonic . herniation. In addition, fatal herniation Y 1 hood than the general population. De- has occurred in the absence of any fluid spite advances in management over the FLUID AND ELECTROLYTE LOSSES therapy. Therefore, although clearly not past 20 years, the incidence of mortality The fluid and electrolyte losses of DKA the only cause, it seems reasonable to associated with are predominantly caused by hypergly- conclude that fluid management may be (DKA) remains unchanged. Cerebral caemia with resultant and a factor contributing to the development oedema is the predominant cause of this osmotic . In addition, the kidney of overt cerebral oedema. On the basis of mortality; young children are particu- has a low threshold for ketoacids, which the available evidence it would seem larly at risk, with an incidence of 0.7–1% are excreted into the with an prudent to avoid rapid rates of fluid of episodes of DKA.23 The mortality accompanying cation, further exacerbat- infusion and to maintain serum sodium appears to be greatest among patients at ing the electrolyte loss. Relative acute concentrations in order to avoid the first presentation,134if there has been a dehydration with a larger sodium loss potential danger of excess free long history of symptoms prior to will result primarily in intravascular administration which may exacerbate admission,3 and during the first 24 hours dehydration, but a more prolonged de- the development of symptomatic brain of treatment.4 In a recently published velopment will result in a greater degree swelling. retrospective multicentre analysis of of intracellular dehydration, with rela- Failure to follow guidelines for the children with DKA, low pCO2 levels and tive maintenance of intravascular vol- management of DKA has been well high serum sodium concentration at ume, particularly if the patient remains documented.18 Of particular concern is presentation were identified as particu- polydipsic.9 There are thus wide varia- the evidence that clinicians have been lar risk factors for the development of tions in fluid, acid–base, and electrolyte consistently shown to overestimate the cerebral oedema, together with bicarbo- deficiencies, during both development degree of dehydration in this 5 19 20

nate therapy. However, in the accompa- and treatment of DKA, yet few protocols condition. Nevertheless, the assump- http://adc.bmj.com/ nying editorial, Dunger and Edge point acknowledge this. tion underlying most DKA protocols is out that this may simply be revealing an There is clear evidence that volume that rehydration is desirable and achiev- association between severe DKA and depletion triggers the release of counter able in 24 hours, using a volume calcu- dehydration and the risk of cerebral regulatory hormones including catecho- lated by “maintenance plus deficit”. oedema.6 The pathogenesis of cerebral lamines, , and oedema remains poorly understood but as well as renin, aldosterone, and ar- THE NEED FOR CHANGE? there may be many contributing ginine .10 11 These hormones, From a renal perspective the term 7 factors. whose combined actions are directed “maintenance fluid” is a misnomer. True on September 28, 2021 by guest. Protected copyright. The aim of management of DKA is to towards preserving intravascular vol- maintenance fluid volume in children is restore metabolic homoeostasis while ume, also cause insulin resistance. An the sum of the insensible losses plus the minimising the risks of complications important effect of fluid administration obligate urine production and is prob- including hypoglycaemia, hypokalaemia, is therefore reducing the stimulus for the ably only 40% of recommended cardiac failure, and in children the secretion of the counter regulatory hor- amounts.21 Water requirements are re- development of cerebral oedema. How mones. Indeed it has been shown that lated to energy expenditure. The recom- best to achieve this remains contentious, plasma glucose starts to fall following mended “maintenance” volumes are with particular controversy centred on fluid administration prior to giving insu- based on calculations of insensible losses optimal fluid management. The most lin, although insulin is required for (estimated as 50 ml/100 cal/day) plus appropriate volume, type, and rate of correction of the metabolic .12 66.7 ml/100 cal/day to replace urine fluid to be given have all been the subject output.22 This allows for production of of debate. A survey in 1994 of UK RISK FACTORS FOR CEREBRAL isotonic urine. As normally functioning paediatricians found a threefold varia- OEDEMA kidneys are capable of fourfold concen- tion in the amount of fluid recom- The importance of prompt restoration of traton of the glomerular filtrate, “main- mended within the first 12 hours.8 Since the circulating volume for patients pre- tenance fluids” will provide sufficient then national guidelines have been de- senting with DKA is clear. However, the volume for both insensible and obligate veloped by the British Society for Paedi- observation that symptomatic cerebral losses as well as the extra needed for atric (BSPE). However, it oedema often occurs several hours after rehydration. A 5% dehydrated child with remains uncertain whether the recom- treatment has begun, usually at a time normally functioning kidneys can be mended strategy, using a volume calcu- when plasma glucose has started to fall rehydrated using “maintenance” fluid lated by “maintenance plus deficit”, is and to improve, has only—albeit slowly. the safest and most appropriate way to led to concern that the treatment itself In non-diabetic dehydration it is cus- manage rehydration in children with may contribute to the development of tomary to assess whether the dehydra- DKA. We suggest that childhood DKA cerebral oedema. There have been few tion is hypertonic, hypotonic, or isotonic

www.archdischild.com 444 CONTROVERSY and whether there is simple contraction ...... 21 Molteni KH. Initial management of of the extracellular compartment or hypernatraemic dehydration in the breastfed Arch Dis Child: first published as 10.1136/adc.86.6.443 on 1 June 2002. Downloaded from Authors’ affiliations infant. Clin Pediatr 1994;33:731–40. whether compensatory mechanisms are C D Inward, T L Chambers, Bristol Royal 22 Holliday MA, Segar WE. The maintenance operating. Hospital for Children, Bristol, UK need for water in parenteral fluid therapy. It is accepted that safe therapy of Pediatrics 1957;19:823–32. Correspondence to: Dr C D Inward, Bristol 23 Hollidat M. The evolution of therapy for hypertonic dehydration should be both Royal Hospital for Children, Upper Maudlin dehydration: should deficit therapy still be prolonged and cautious to avoid the Street, Bristol BS2 8BJ, UK taught? Pediatrics 1996;98:171–7. development of fits and cerebral oedema 24 Oddie S, Richmond S, Coultard M. 23 24 Hypernatraemic dehydration and breast during rehydration. REFERENCES feeding: a population study. Arch Dis Child The cells of the central nervous system 1 Edge JA, Ford-Adams ME, Dunger DB. 2001;85:318–20. protect cell volume under hyperosmolar Causes of death in children with insulin 25 Lee JH, Arcinue E, Ross BD. Organic dependent diabetes 1990–96. Arch Dis Child osmolytes in the brain of an infant with conditions by producing intracellelular 1999;81:318–23. . N Engl J Med osmotically active molecules, “idiogenic 2 Edge JA, Hawkins MM, Winter DL, et al. 1994;331:439–42. osmoles”.25 Once formed these molecules Incidence presentation management and 26 Lebovitz HA. Diabetic ketoacidosis. Lancet outcome of cerebral oedema associated with dissipate slowly. Rapid reduction of 1995;345:767–71. diabetic ketoacidosis (DKA) in Great Britain. 27 Adrogue H, Barrero J, Eknoyan G. Salutary by the administration Arch Dis Child 1999;80(suppl 1):A11. effects of modest in the of free water under these conditions will 3 Bello FA, Sotos JF. Cerebral oedema in treatment of adults with ketoacidosis. JAMA diabetic ketoacidosis in children. Lancet create a gradient, causing movement of 1989;262:2108–13. 1990;336:64. 28 Harris GD, Fiordalisi I. Physiologic water into brain cells and thus brain 4 Rosenbloom AL. Intracerebral crises during management of diabetic ketoacidemia. A swelling. These considerations probably treatment of diabetic ketoacidosis. Diabetes 5-year prospective pediatric experience in 13 apply equally to hypernatraemic dehy- Care 1990; :22–33. 231 episodes. Arch Pediatr Adolesc Med 5 Glaser N, Barnett P, McCaslin I, et al. Risk 1994;148:1046–52. dration and diabetic ketoacidosis. factors for cerebral in children with 29 Johnston C. Fluid replacement in diabetic We suggest that the treatment of diabetic ketoacidosis. N Engl J Med ketoacidosis. BMJ 1992;305:522. 2001;344:264–9. dehydration of severe DKA should be 6 Dunger DB, Edge JA. Predicting cerebral based on the general principles used to oedema during diabetic ketoacidosis. N Engl treat dehydration combined with renal JMed2001;344:302–3. failure, taking into account the addi- 7 Edge JA. Cerebral oedema during treatment ...... COMMENTARY ...... 19 of diabetic ketoacidosis: are we any nearer tional relatively brief problem of an finding a cause? Diabetes Metab Res Rev osmotic diuresis. Halting the decompen- 2000;16:316–24. sation process is the initial therapeutic 8 Edge JA, Dunger DB. Variations in the he treatment of the child with dia- management of diabetic ketoacidosis in goal, followed by provision of sufficient children. Diabet Med 1994;11:984–6. betic ketoacidosis (DKA) is unfortu- fluid to allow the establishment of renal 9 Adrogue HJ, Wilson H, Boyd AE, et al. nately not based on very much Plasma acid-base patterns in diabetic T and hormonal homoeostasis over a pe- evidence, but rather on anecdote and ketoacidosis. N Engl J Med riod of time comparable to that taken for 1982;307:1603–10. precedent. Fluid management has devel- the problem to develop. There is no 10 Tulassay T, Rascher W, Korner A, et al. oped over several decades, with changes evidence that the use of modest fluid Atrial natriuretic peptide and other vasoactive occurring gradually in an attempt to avoid 26 27 hormones during treatment of severe diabetic regimens is harmful. Harris and ketoacidosis in children. J Pediatr complications (initially hypokalaemia, 19 28

colleagues have shown that in 149 1987;111:329–34. more recently cerebral oedema), rather http://adc.bmj.com/ episodes of childhood DKA, rehydration 11 Luzi L, Barrett EJ, Groop LC, et al. Metabolic than a logical approach to the particular effects of low-dose insulin therapy on glucose over 48 hours was associated with “no in diabetic ketoacidosis. Diabetes fluid and electrolyte deficits. This has deaths or near death episodes”, and 1988;37:1470–7. resulted in some anomalies in the man- Johnston reported that in adults a 12 Owen OE, Licht JH, Sapir DG. Renal function agement of DKA, and Inward and Cham- regimen of 48–72 ml/kg/day was safe.29 and effects of partial rehydration during diabetic ketoacidosis. Diabetes bers have now opened the debate about 1981;30:510–18. whether a revolution in fluid and electro- A PROPOSAL 13 Mahoney CP, Vleck BW, DelAguila M. Risk lyte management is necessary. factors for developing brain herniation during Twenty or so years ago there was a revo- DKA is associated with severe fluid on September 28, 2021 by guest. Protected copyright. diabetic ketoacidosis. Pediatr Neurol lution in the management of DKA with 1999;21:721–7. losses. Much of the information about the introduction of continuous intra- 14 Rosenbloom AL, Schatz DA, Krischer JP, et the specific fluid and electrolyte deficits venous insulin infusion. Perhaps it is al. Therapeutic controversy: prevention and in DKA was obtained in the 1930s from treatment of diabetes in children. J Clin now time for another review, not only of Endocrinol Metab 2000;85:494–522. work on two young men with diabetes the fluid management, but also of all 15 Krane EJ, Rockoff MA, Wallman JK, et al. whose fluid and electrolyte balance was other aspects. There are several inter- Subclinical brain swelling in children during studied in great detail before, while, and treatment of diabetic ketoacidosis. N Engl J ested parties—endocrinologists, neph- Med 1985;312:1147–51. after they were allowed experimentally rologists, general paediatricians, and 16 Hoffman WH, Steinhart CM, ElGammal T, et to become ill with DKA.1 The reported specialists in emergency medicine. We al. Cranial CT in children and adolescents fluid deficit appeared to be approxi- with diabetic ketoacidosis. Am J Neuroradiol wonder whether a summit meeting 1988;9:733–9. mately half from the intracellular and should be convened to consider this; per- 17 Smedman L, Escobar R, Hesser U, et al. half from the extracellular haps to commission research (the NHS Subclinical cerebral oedema does not occur compartments.1–3 This work formed the regularly during treatment for diabetic and the corporate spirit of British paedi- ketoacidosis. Acta Pediatr 1997;86:1172–6. basis for most of the DKA management 34 atrics are ideal for such multicentre 18 Singh RK, Perros P, Frier BM. Hospital protocols in existence. For obvious studies) and propose a second revolution management of diabetic ketoacidosis: are reasons, these studies have never been in DKA management. Who will step for- clinical guidelines implemented effectively? repeated in children, and yet body Diabet Med 1997;14:482–6. ward? 19 Harris GD, Fiordalisi I, Harris WL, et al. composition and fluid requirements are Minimizing the risk of brain herniation during very different from those in adults. ACKNOWLEDGEMENTS treatment of diabetic ketoacidemia: a Moreover, as Inward and Chambers retrospective and prospective study. J Pediatr We would like to thank Dr Fiona Cowan, Dr 1990;117:22–31. point out, factors such as the duration of Mary McGraw, and Mrs Rachel Owen for their 20 Grove LM, Nobel-Jamieson CM, Barnes ND, the episode of DKA will produce wide invaluable help in the preparation of the et al. Assessment of dehydration, fluid variations in fluid and electrolyte defi- manuscript. balance and insulin requirements in diabetic ketoacidosis. Proc Br Paediatr Assoc Annu ciencies. The water deficit is made up of Arch Dis Child 2002;86:443–445 Meet 1995;67:26. varying combinations from the osmotic

www.archdischild.com CONTROVERSY 445 diuresis, , and hyperventilation. of these adaptations should theoretically we have further research, which must be Sodium losses are also variable, depend- make the protocols “safer”, yet there is no national or even international and col- Arch Dis Child: first published as 10.1136/adc.86.6.443 on 1 June 2002. Downloaded from ing on the predominating fluid type lost evidence that the incidence of cerebral laborative, discussion (even involving and on the adequacy of renal perfusion. oedema has changed over the past 20 many disciplines) will not provide us There will also usually have been in- years.12 with all the answers. creased oral consumption of fluids of There is furthermore no evidence that J Edge different compositions, which may affect adopting the type of rehydration and John Radcliffe Hospital, Headley Way, the presenting fluid and electrolyte electrolyte replacement scheme sug- Headington, Oxon OX3 9DU, UK picture.5 It may not therefore be appro- gested by Inward and Chambers will priate to treat all children with identical have any impact on the incidence of cer- Arch Dis Child 2002;86:443–445 fluid regimens, particularly protocols ebral oedema. In the quoted study of REFERENCES extrapolated largely from studies in Harris and Fiordalisi in which children 1 Atchley DW, Loeb RF, Richards DW, et al. adults. were rehydrated slowly with sufficient On diabetic acidosis. A detailed study of In particular, it is very difficult to quan- sodium to produce a gradual rise in electrolyte balances following the withdrawal and reestablishment of insulin therapy. J Clin tify sodium losses. Plasma sodium levels plasma sodium concentrations, although Invest 1933;12:297–326. may be low, normal, or high, depending there were “no deaths or near death epi- 2 Nabarro JDN, Spencer AG, Stowers JM. more on renal perfusion and duration of sodes”, there were still six children in Treatment of diabetic ketoacidosis. Lancet 1952;i:983–9. than on total body losses. How- whom behaviour change or increasing 3 Hillman K. Fluid resuscitation in diabetic ever, in current guidelines, the amount of obtundation were treated with emergencies—a reappraisal. Intensive Care sodium given as normal early .11 It may therefore be increased Med 1987;13:4–8. 4 Waldhausl W, Kleinberger G, Korn A, et al. during rehydration (after the resuscita- vigilance and early rescue therapy which Severe hyperglycaemia: effects of rehydration tion period) depends on the length of prevented sequelae from cerebral on endocrine derangements and time it takes for the blood glucose to reach oedema rather than the type of fluid and glucose concentration. Diabetes 13 1979;28:577–84. 12 mmol/l, taking no account of sodium electrolyte therapy. Inward and Cham- 5 Vanelli M, Chairi G, Ghizzoni L, et al. requirement. This may result either in bers give very little detail of how a Ketoacidosis and hyperosmolality as first symptoms of mellitus following giving too little sodium relative to water if “renal” rehydration schedule would dif- ingestion of high-carbohydrate-containing the blood glucose falls too fast, or con- fer from current DKA guidelines which fluids. J Pediatr Endocrinol Metab versely giving too much if the blood frequently do suggest a more protracted 1999;12:691–4. 6 Kitabchi AE, Matteri R, Murphy MB. Optimal glucose falls too slowly. This aspect cer- rehydration period. insulin delivery in diabetic ketoacidosis (DKA) tainly does require review. Any guidelines for fluid and electrolyte and hyperglycemic, hyperosmolar nonketotic Over the years, adult oriented protocols management of DKA in children must be coma (HHNC). Diabetes Care 1982;5:78–87. have been adapted to reduce the risk of simple to calculate. Although no one 7 Luzi L, Barrett EJ, Groop LC, et al. Metabolic various complications. For example, hy- would disagree with Nabarro et al that effects of low-dose insulin therapy on glucose poglycaemia has largely been avoided by “the treatment of severe diabetic ketoaci- metabolism in diabetic ketoacidosis. Diabetes 67 1988;37:1470–7. the use of low dose insulin infusions, dosis should not be left to the house 8 Tattersall RB. A paper which changed and hypokalaemia by the use of early and physician”,2 it is generally the tired junior clinical practice (slowly). Jacob Holler on 8 potassium deficiency in diabetic acidosis adequate potassium replacement. A simi- doctor who works out the fluid prescrip- (1946). Diabet Med 1999;16:987–94.

lar process has been occurring in an tion. Given the plethora of DKA protocols 9 Duck SC, Wyatt DT. Factors associated with http://adc.bmj.com/ attempt to avoid cerebral oedema, the previously in existence, and the complex brain herniation in the treatment of diabetic ketoacidosis. J Pediatr 1988;113:10–14. main cause of morbidity and mortality. nature of many of their calculation 10 Harris GA, Fiordalisi I, Harris WL, et al. The cause of this devastating complica- methods,14 it would not be in the interests Minimizing the risk of brain herniation during tion is not known, but the timing of most of patients or doctors to produce guide- treatment of diabetic ketoacidaemia: a retrospective and prospective study. J Pediatr episodes has suggested that it may be lines which require very complicated 1990;117:22–31. related to the fluid management. Further- calculations. We have only recently 11 Harris GA, Fiordalisi I. Physiologic more, several studies (although not ran- started in this country to adopt National management of diabetic ketoacidemia. A 5-year prospective pediatric experience in domised controlled trials, or even case– (BSPED recommended) Guidelines, and 231 episodes. Arch Pediatr Adolesc Med on September 28, 2021 by guest. Protected copyright. control studies) have suggested that have yet to see whether this will impact 1994;148:1046–52. 12 Edge JA, Hawkins MM, Winter DL, et al.The factors in the fluid and electrolyte man- on the incidence of cerebral oedema. risk and outcome of cerebral oedema agement might play a part in the Thus, although there are reservations, developing during diabetic ketoacidosis. Arch aetiology.9–11 This has led to changes in the Inward and Chambers are right to open Dis Child 2001;85:16–22. 13 Edge JA. Cerebral oedema during treatment protocols, such as slowing down of fluid this debate. There are other anomalies in of diabetic ketoacidosis: are we any nearer replacement, lower volumes of “mainte- the treatment of DKA to be addressed by finding a cause? Diabetes Metab Rev nance” fluids, avoidance of sodium bicar- the proposed multidisciplinary discus- 2000;16:316–24. 14 Edge JA, Dunger DB. Variations in the bonate administration, and close observa- sion group, for which I would be management of diabetic ketoacidosis in tion of plasma sodium concentration. All delighted to step forward. However, until children. Diabet Med 1994;11:984–6.

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