Peters, MJ

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  1Peters MJ. Arch Dis Child Educ Pract Ed 2021;0:1–3. doi:10.1136/archdischild-2020-320078Guideline reviewFluid resuscitation in diabetic ketoacidosis and the BPSED guidelines: what we still don’t knowMark J Peters   1,21Great Ormond Street Institute of Child Health, UCL, London, UK2PICU, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UKCorrespondence toDr Mark J Peters, Great Ormond Street Institute of Child Health, UCL, London WC1N 3JH, UK;  mark. peters@ ucl. ac. ukReceived 17 October 2020Revised 20 November 2020Accepted 10 February 2021To cite: Peters MJ. Arch Dis Child Educ Pract Ed Epub ahead of print: [please include Day Month Year]. doi:10.1136/archdischild-2020-320078© Author(s) (or their employer(s)) 2021. Re- use permitted under CC BY- NC. No commercial re- use. See rights and permissions. Published by BMJ.The 2020 British Society for Paediatric Endocrinology and Diabetes (BSPED) guideline differs from the previous itera-tion and the more conservative National Institute of Health and Care Excellence 2016 guideline for diabetic ketoacidosis in children and young people (2015). It recommends a more liberal approach to initial fluid resuscitation and a reduced enthusiasm for using inotropes. This contrasts with shock resuscitation guid-ance elsewhere. In septic shock acute fluid resuscitation is now recommended to be more selective and conservative, and the early use of vasoactive drugs is supported.1So why did BSPED make a new recom-mendation for diabetic ketoacidosis (DKA)? Recent correspondence2 suggests that it arose from: (A) expert interpre-tation of physiological data suggesting hypoperfusion as the precursor to cerebral oedema; (B) the Pediatric Emergency Care Applied Research Network (PECARN) fluid in DKA randomised controlled trial3 and (C) regional audit data. Such evidence is not compelling.Physiological and imaging data suggest cerebral hypoperfusion may not be present at baseline. In 1948, Kety et al4 measured cerebral blood flow (CBF) in adults with DKA: none had CBF below the normal range and several were hyperaemic. Glaser et al5 interpreted MRI scans of patients in DKA as suggesting increased CBF. Some of this excess may have resulted from treat-ment. If concern about hypoperfusion is key, it is not clear why increasing perfu-sion with inotropes rather than fluid is discounted. Inotropes have the advantage of not reducing osmolarity, and rapid falls in osmolarity probably contribute to cere-bral oedema. The PECARN study3 was prompted by concerns about this mecha-nism. It compared high and lower volume and tonicity fluid regimens in children with DKA. There was no difference in the primary outcome of significant neuro-logical deterioration. Children at high risk of cerebral oedema at baseline were excluded, and clinically evident brain injury was so rare: 12 episodes (0.9%) that the study was not powered to inform on relative risk. Last, use of unpublished audit data in the development of guide-lines is unconventional. Most guidelines state the methodologies in advance and specifically avoid the use of non- peer- reviewed data as a potential source of bias.Perhaps something more fundamental needs to be considered when discussing intravenous fluid resuscitation. This is a very difficult area to study. There is no high- performing, or universally accepted, definition of shock in children; hypoten-sion definitions are problematic, and the severity of shock does not always relate to the probability of a poor outcome; positive acute physiological responses (improvements in heart rate and perfu-sion) correlate poorly with outcomes, the risks and benefits of fluid resuscitation are highly sensitive to the cause of shock (eg, myocarditis less benefit than hypo-volaemia), the timing (early resuscitation more benefit than late resuscitation) and the healthcare system in which the resusci-tation is being provided (greater risk when no access to positive pressure ventilation, lower risk on an intensive care unit).1 Defining shock is especially problematic in DKA. Acidosis and hypocarbia cause a range of clinical features independent of tissue oxygen delivery, for example, tachycardia, tachypnoea and reduced skin perfusion,6 7 and adaptive metabolism (eg, raised serum lactate8) that can easily be misinterpreted as signs of shock.The degree of physiological disturbance with severe acidosis, tachypnoea and poor perfusion would be associated with very Protected by copyright. on March 23, 2021 at UCL Library Services.http://ep.bmj.com/Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2020-320078 on 19 March 2021. Downloaded from Peters MJ. Arch Dis Child Educ Pract Ed 2021;0:1–3. doi:10.1136/archdischild-2020-3200782Guideline reviewpoor prognosis if it resulted from septic shock or other systemic insults. DKA is different. How different can be illustrated with the physiologically based scoring system the Paediatric Index of Mortality 3. The values of a base excess −30 mmol/L, with an arterial partial pressure for oxygen (PaO2) of 10 kPa in 25% oxygen and a systolic blood pressure of 100 mm Hg estimates a risk of mortality of 9.7% without DKA but only 1.2% with DKA.9 This estimate fits with the reported mortality of DKA (0.5%–2%).‘What is the risk of death from shock?’ should be the key question when balancing the risks and bene-fits of fluid resuscitation. Trial evidence illustrates this point (figure 1). ‘Early- goal directed therapy’ (EGDT) describes an approach of increased monitoring for subclinical shock. EGDT results in more aggres-sive fluid resuscitation and dramatically improved outcome in randomised trials in adults and children. However, this effect is only seen when the control group mortality is very high (39%–49%).10 11 When similar trials were repeated in lower risk populations (control group mortality 18%–22%), they offered no net benefit.12–14 Indeed, the only large high- quality trial of fluid resuscitation in children observed that fluid increased mortality in acute infective illness. Mait-land’s Fluid Expansion as Supportive Therapy study had a ‘no fluid bolus group’ mortality of 7% and fluid resuscitation increased this to >10%.15 So, the ‘space’ for fluid resuscitation to improve outcomes was rela-tively limited, and the potential for harm was high. Of relevance to the management of fluids in DKA is that it carries a low risk of mortality—only a tiny subset of whom die from shock—on the continuum shown in the exploratory plot (figure 1). Therefore, poten-tial opportunities for aggressive fluid resuscitation to improve outcomes are limited, and the potential for harm appears high. An aim for future guidelines might be a more approach stratified for the specific risks of cerebral oedema versus shock in an individual case.What we don’t yet know about the BSPED guide-lines is: why they choose to recommend more aggres-sive resuscitation in a low- risk situation? Fluids carry a potentially important risk of harm even in the absence of the predominant additional risk of cerebral oedema. The general principle should be that we do not inter-vene without evidence. We don’t yet know where the balance of risks and benefits sits for early volume expansion in DKA. But any change requires a justifica-tion than can be considered by the potential users of the guideline.Twitter Mark J Peters @pus27Competing interests None declared.Patient consent for publication Not required.Provenance and peer review Commissioned; externally peer reviewed.Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non- commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non- commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.ORCID iDMark J Peters http:// orcid. org/ 0000- 0003- 3653- 4808REFERENCES 1 Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis- associated organ dysfunction in children. Intensive Care Med 2020;46:10–67. 2 Wright N, Thomas R. Response to: management of fluids in paediatric diabetic ketoacidosis: concerns over new guidance. Arch Dis Child 2020;105:1020–1.Figure 1 Randomised controlled trials of liberal versus conservative fluids resuscitation: relative risk of mortality in the more liberal group is shown against the mortality in the more conservative fluid group. There is a strong (r=0.69) correlation between the log of the relative risk and the conservative group mortality with the equation y=0.69e0.026x that is unlikely to be due to chance (p=0.02). In other words, fluid resuscitation is effective in shock with a high mortality risk but harmful in low- risk populations.10 11 13–16 DKA is a very low- risk population.Protected by copyright. on March 23, 2021 at UCL Library Services.http://ep.bmj.com/Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2020-320078 on 19 March 2021. Downloaded from Peters MJ. Arch Dis Child Educ Pract Ed 2021;0:1–3. doi:10.1136/archdischild-2020-320078 3Guideline review 3 Kuppermann N, Ghetti S, Schunk JE, et al. Clinical trial of fluid infusion rates for pediatric diabetic ketoacidosis. N Engl J Med 2018;378:2275–87. 4 Kety SS, Polis BD, Nadler CS, et al. The blood flow and oxygen consumption of the human brain in diabetic acidosis and coma 1. J Clin Invest 1948;27:500–10. 5 Glaser NS, Wootton- Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr 2004;145:164–71. 6 Lillie J, Boot E, Tibby SM, et al. Management of fluids in paediatric diabetic ketoacidosis: concerns over new guidance. Arch Dis Child 2020;105:1019–20. 7 Mitchell JH, Wildenthal K, Johnson RL. The effects of acid- base disturbances on cardiovascular and pulmonary function. Kidney Int 1972;1:375–89. 8 Cox K, Cocchi MN, Salciccioli JD, et al. Prevalence and significance of lactic acidosis in diabetic ketoacidosis. J Crit Care 2012;27:132–7. 9 Straney L, Clements A, Parslow RC, et al. Paediatric index of mortality 3: an updated model for predicting mortality in pediatric intensive care*. Pediatr Crit Care Med 2013;14:673–81. 10 Rivers E, Nguyen B, Havstad S, et al. Early goal- directed therapy in the treatment of severe sepsis and septic shock.  N Engl J Med 2001;345:1368–77. 11 de Oliveira CF, de Oliveira DSF, Gottschald AFC, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34:1065–75. 12 ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal- Directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496–506. 13 The ProCESS Investigators. A randomized trial of protocol- based care for early septic shock. N Engl J Med 2014;370:1683–93. 14 Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal- directed resuscitation for septic shock. N Engl J Med 2015;372:1301–11. 15 Maitland K, Akech SO, Russell EC. Mortality after fluid bolus in African children. N Engl J Med 2011;365:1348–53. 16 Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the classic randomised, parallel- group, multicentre feasibility trial. Intensive Care Med 2016;42:1695–705.Protected by copyright. on March 23, 2021 at UCL Library Services.http://ep.bmj.com/Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2020-320078 on 19 March 2021. Downloaded from 

Fluid resuscitation in diabetic ketoacidosis and the BPSED guidelines: what we still don't know

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