© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
MEDICAL PRACTICE CME
Initial intravenous fluid prescription in general paediatric in-patients aged >28 days and <18 years: consensus statements
Lettie CK Leung, FRCP, FHKCPaed1; LY So, FHKCPaed, FRCPCH2; YK Ng, FHKCPaed3; Winnie KY Chan, FHKCPaed, FRCPCH4; WK Chiu, FHKCPaed, FRCPCH5; CM Chow, FHKCPaed, FHKAM (Paediatrics)6; SY Chan, RN, MSc (HSM)4; KC Chan, FHKCPaed, FRCPCH7; for the IVF Working Group
1 Department of Paediatrics, Kwong Wah Hospital, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong
3 Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital. Hong Kong
4 Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong
5 Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Hong Kong
6 Department of Paediatrics, Prince of Wales Hospital, Hong Kong
7 Department of Paediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
Corresponding author: Dr Lettie CK Leung (firstname.lastname@example.org)
Intravenous fluid (IVF) prescription has often been an ‘assumed’ skill in hospital-based paediatric practice, with little evidence-based guidance. Traditionally prescribed hypotonic fluids were responsible for many iatrogenic, hyponatraemia-related morbidity and mortality. Robust evidence is available to support recent guidelines that isotonic fluids are the most appropriate maintenance IVF for most hospitalised children. However, many other aspects of IVF prescription still lack evidence. Thus, an IVF Working Group was formed in 2016 under the Hospital Authority Paediatric Coordinating Committee to review IVF guidelines for local application, with the aim to provide guidance for initial IVF prescription and subsequent monitoring of paediatric in-patients in Hong Kong. Published randomised controlled trials, IVF guidelines, and practices of reputable children’s hospitals up to December 2019 were reviewed. Local survey findings and practical realities were considered. Extracted evidence and draft recommendations were presented to the group, using a consensus approach in areas where evidence was unavailable. After further input from designated reviewers, an IVF clinical pathway was finalised in November 2019 and endorsed by the Paediatric Clinical Coordinating Committee. This article represents an explanatory discussion of the pathway, with consensus statements established by Working Group members at the final meeting in June 2020. The consensus statements emphasise that IVF should be prescribed with the same care and consideration as medications, based on each patient’s pathophysiology. Evidence is presented regarding the use of isotonic maintenance fluid, comparing 0.9% sodium chloride with balanced solutions. These eight statements provide localised guidance for paediatricians in initial IVF prescription but do not replace clinical judgement.
The prescription of intravenous fluid (IVF) is an essential management modality in hospital paediatrics. The traditional practice of administering hypotonic maintenance IVF (0.18-0.3% sodium chloride [NaCl]) was based on the Holliday–Segar formula published in 19571; being calculated from estimated fluid and electrolyte requirements based on milk intake in healthy children. Holliday–Segar formula for maintenance fluid in 24 hours is calculated as below: (1) body weight (BW) of ≤10 kg: 100 mL/kg; (2) BW of 11-20 kg: 1000 mL + 50 mL/kg for each kg over 10; (3) BW of >20 kg: 1500 mL + 20 mL/kg for each kg over 20. However, since the 1990s, more than 100 cases of hyponatremia-related iatrogenic death or permanent neurologic impairment have been reported; nearly all studies have shown that hospital-acquired hyponatremia is related to hypotonic fluid administration.2 This is related to the high incidence of non-osmotic stimuli of antidiuretic hormone (SIADH) in sick children, which leads to an impaired ability to excrete free water.
Since the 1990s, there have been many randomised controlled trials (RCTs) and meta-analyses comparing hypotonic and isotonic fluids in children initially in postoperative and paediatric intensive care unit settings, but recently also in general paediatric settings. Based on the available high-quality evidence, the 2015 NICE guideline3 and the American Academy of Pediatrics maintenance fluid guidelines4 have strongly recommended the use of isotonic maintenance IVF for most paediatric patients aged >28 days.
In Hong Kong, there are no local guidelines regarding IVF prescription in children. A 2016 informal survey of 11 acute paediatric units within the Hospital Authority showed that dextrose-containing 0.3% NaCl and 0.45% NaCl were the main maintenance fluids used; no units routinely used isotonic fluids. Our recent survey5 of more than 60 000 hospital admissions of children aged 1 month to 18 years in the year 2015 also showed variations among hospitals in terms of IVF practices. Hyponatraemia commonly occurred in 8.8% of admissions. In total, 110 patients exhibited true, non-dilutional severe hyponatraemia (<127 mmol/L); this was hospital-acquired in 22 patients (presumably related to hypotonic IVF) and some of them exhibited neurological complications. In this context, the current practice statement is intended to guide all clinicians who prescribe IVF in children, encouraging methodological prescription practices to minimise fluid and electrolyte morbidities.
Basic intravenous fluid concepts
Osmolality versus tonicity
Osmolality is the concentration of a solution expressed as the number of solute particles per kilogram of solution (plasma). Tonicity is a measure of the effective osmolality between two fluid compartments separated by a semi-permeable membrane (eg, a cell membrane). For our purposes, tonicity refers to the sodium concentration of the fluid. Dextrose does not affect tonicity because it is rapidly metabolised in the blood stream.
Normal saline versus balanced solution
The compositions of available IVF preparations in Hong Kong are detailed in Table 1. Normal saline (0.9% NaCl) may not be as “normal” as its name suggests. Compared with plasma, 0.9% NaCl has higher sodium (Na 154 vs 140 mmol/L) and chloride (Cl 154 vs 103 mmol/L) concentrations; moreover, large volumes of 0.9% NaCl lead to hyperchloraemic acidosis in adults and children.6
Balanced solutions are solutions with more physiologically appropriate electrolyte compositions (Table 1). They contain buffers with mild alkalinising effects. For example, Hartman’s and Ringer’s lactate solutions contain sodium lactate, which is metabolised into bicarbonate by the liver. Plasma-Lyte 148 contains acetate, which is similarly metabolised (within 15 minutes) by the liver and skeletal muscle. Acetate metabolism has several advantages: it is not entirely dependent on hepatic function, it is preserved in severe shock, and it will not disrupt reported serum lactate levels. Furthermore, Hartman’s and Ringer’s lactate solutions contain calcium, which may contribute to extravasation and cause incompatibility with blood or drugs such as cefotaxime. In contrast, Plasma-Lyte 148 contains magnesium, for which limited drug compatibility information is available.
There is increasing evidence that 0.9% NaCl is associated with increased rates of mortality, acute kidney injury, metabolic acidosis, and coagulopathy in critically ill adults7 8 and acute kidney injury in non–critically ill adults,9 compared with balanced solutions. These effects have been attributed to its supraphysiologic chloride concentration, which causes renal vasoconstriction.6 10 In children with septic shock, hyperchloraemia is also associated with acute kidney injury and mortality11 12 13; this implication will be discussed later.
After publication of the NICE IVF guideline, an IVF Working Group (ie, the IVFWG) was formed in June 2016 under the Evidence-based Practice Working Group of the Hospital Authority Paediatric Clinical Coordinating Committee to form recommendations regarding maintenance fluid prescription. A retrospective survey of hyponatraemia with a focus on IVF practices was commissioned and published5; lessons from the survey were taken into consideration. Additionally, a literature search was performed using the keywords (“intravenous fluid” OR “isotonic” OR “hypotonic” OR “maintenance fluid”) AND (“child”) in MEDLINE and EMBASE databases; results from January 2000 to December 2019 were collected. All RCTs and meta-analyses regarding maintenance IVF were reviewed. For our review (ie, maintenance fluids in general paediatric settings), we only included paediatric RCTs where medical patients constituted more than 50% of the study population. We excluded studies in which surgical or intensive care patients comprised the majority of patients, as well as studies in which IVF served both rehydration and maintenance purposes. The certainty of evidence and strength of each recommendation were determined in accordance with GRADE methodology (https://www.gradeworkinggroup.org/"). Extracted evidence was presented to the IVFWG. In areas for which the evidence level was high, clear recommendations were made. In areas for which trial data were lacking, the preferred treatment was determined by a consensus approach based on the knowledge and clinical experience of the IVFWG members.
The first draft recommendations were presented to IVFWG members in February 2019. After publication of the American Academy of Pediatrics guideline4 in December 2018, IVF guidelines were amended by many reputable international children’s hospitals. These amended guidelines were also used as reference information; their applicability to patients in Hong Kong were further discussed within the group. The consensus document was submitted to a panel of five external reviewers chosen by the Evidence-based Practice Working Group to widen input from all subspecialty sectors. In accordance with the reviewers’ comments, a clinical pathway was finalised in November 2019 (Fig) and endorsed by the Paediatric Clinical Coordinating Committee. This article represents an explanatory discussion of the pathway, with consensus statements established by IVFWG members at the final meeting in June 2020. In this article, each statement includes an indication of whether it was established on the basis of evidence or IVFWG member consensus.
Figure. Initial IVF prescription in general paediatric medical in-patients aged >28 days and <18 years
Scope of consensus statements
These consensus statements aim to facilitate initial IVF prescription (ie, prescription principles, with a focus on maintenance fluids) and subsequent monitoring for general paediatric in-patients. They are not meant to replace clinical judgement, nor do they represent a comprehensive discourse regarding fluid resuscitation, specific conditions, or treatment of dysnatraemia.
The target population for these statements comprises children aged >28 days to <18 years who have been admitted to a general paediatric ward for medical conditions. Based on the exclusion criteria of the majority of prospective studies of maintenance fluids, Table 2 lists patients excluded from guidance in these statements. Their IVF needs should be individually assessed (see Statement 2).
Table 2. Criteria for exclusion from the intravenous fluid consensus statements and clinical pathway
Statement 1. Intravenous fluid should be administered only when the enteral route is considered inappropriate or inadequate; IVF should be discontinued once enteral route can be substituted. (Consensus)
Enteral fluid administration is always safer and preferable because the child can autoregulate the amount of ingested fluid. The indication and continued need for IVF should be reviewed regularly; IVF should be stopped when enteral intake is adequate. If the patient is unable to increase enteral intake and has been receiving IVF for 5 days, parenteral nutrition should be considered.
Statement 2. Intravenous fluid should be prescribed with the same care and consideration as used for medication. Individual clinical situations must be assessed, with specific attention to the patient’s volume status, pathophysiological and biochemical state. (Consensus)
No single solution can provide maintenance water and electrolyte needs for all children because needs vary among individuals and disease states. It is crucial to understand the pathophysiological state of a particular patient (Table 314). Before prescribing, clinicians should ask: Why am I prescribing IVF? What disease state, abnormal volume status, and water or electrolyte imbalance am I starting with? Based on these considerations, which type and rate of fluid should I choose? How will I monitor the effects and side-effects of my treatment, with the awareness that requirements may change as the patient’s condition evolves?
Table 3. Understanding the patient’s pathophysiology: conditions requiring special considerations when intravenous fluids are prescribed (modified from Moritz et al14)
Statement 3. When IVF is prescribed, the three components of prescription (deficit replacement, maintenance, and management of ongoing loss) should be considered separately. (Consensus)
The goal of IVF is maintenance of fluid and electrolyte homeostasis. Hypovolaemia is a physiological stimulus for antidiuretic hormone release; therefore, deficits should be replaced to achieve euvolaemia. Patients then require IVF to maintain their ideal volume status, with continued clinical and biochemical monitoring of ongoing loss. These three components require different considerations of fluid types and rates. Fluids intended to replace deficits or ongoing losses may be co-administered with maintenance fluids for easier adjustments.
A clinical pathway depicting initial IVF prescription for general paediatric in-patients is illustrated in the Figure.
Statement 4. Replacement of fluid deficit should usually be with non-glucose-containing isotonic fluids at the appropriate rate. (Consensus)
Deficit replacement fluids restore hydration by replacing fluids already lost. Volume deficits are isotonic deficits; therefore, they should normally be replaced with isotonic fluids at the appropriate rate for the patient’s particular pathophysiological state. For example, 10 to 20 mL/kg/hour for 2 to 4 hours may be appropriate for a normonatraemic dehydrated child with gastroenteritis without shock.15 16 The rate should be slower in patients with pre-existing cardiac or renal disease; the deficit replacement volume should be administered over a longer period (eg, 48 hours) in patients with diabetic ketoacidosis or hypernatraemic dehydration.
4.1 Regarding evidence for fast (20-60 mL/kg in 1-2 hours) versus slow (in 2-4 hours) rates of fluid replacement in patients with acute gastroenteritis, available RCTs have shown heterogeneous results and have generally been conducted in resource-limited settings.17 Fast rates of rehydration have not demonstrated clearly superior results. Considering recent concerns regarding aggressive fluid expansion, more research is warranted before guidelines can be established.
4.2 Notably, 0.9% NaCl has been the traditional fluid of choice for both volume resuscitation and deficit replacement. As previously mentioned, there are concerns that high volumes of 0.9% NaCl cause hyperchloraemia-related adverse effects in critically ill adults and children.6 Some paediatric anaesthetist guidelines18 19 favour administration of balanced fluids over 0.9% NaCl for resuscitation/replacement. However, there is no evidence thus far from small studies in non–critically ill children that balanced solutions are superior.20 21 It may be prudent for clinicians to monitor for hyperchloraemia and consider the use of more physiologically appropriate solutions in sick children.22
Statement 5. Initial IVF and maintenance IVF types: most children aged >28 days to <18 years should receive isotonic solutions with appropriate potassium chloride and dextrose as maintenance IVF. (High-quality evidence, strong recommendation)
Intravenous fluid administration is intended to meet anticipated water and electrolyte needs from insensible losses and urinary output. When prescribing initial IVF, clinicians should consider that most hospitalised children are at risk of osmotic (appropriate) and non-osmotic (inappropriate) antidiuretic hormone secretion (Table 3), causing an inability to excrete free water through dilute urine. This puts the child at risk of positive water balance and hyponatraemia when hypotonic fluids are administered.
5.1 Earlier RCTs regarding fluid tonicity were mainly in surgical and paediatric intensive care unit patients. Our literature search revealed high-quality evidence from 10 RCTs involving general paediatric in-patients, indicating that isotonic fluids significantly reduce the risk of hyponatraemia compared with hypotonic fluids (including 0.45% NaCl). Table 423 24 25 26 27 28 29 30 31 32 lists the characteristics and GRADE evidence levels of these studies. Most RCTs used 0.9% NaCl with 20 mmol/L potassium chloride (KCl) in the isotonic arm, whereas the PIMS trial,25 which included >690 children used Plasma-Lyte 148. Eight of the 10 studies included 0.45% NaCl in the hypotonic fluid arm. Study appraisal of these RCTs (total 1945 patients) showed that eight of the 10 were methodologically sound (GRADE evidence level ≥3). Hence, high-quality evidence indicates that hypotonic fluids (including 0.45% NaCl) carry a significantly greater risk of hospital-acquired hyponatraemia (relative risk=3.7-6.5), as well as a risk of failed sodium status improvement in patients with baseline hyponatraemia.
Table 4. Randomised controlled trials concerning tonicity of maintenance IVF among general paediatric in-patients
5.2 Regarding potential harm, there is no evidence from these studies that isotonic maintenance fluids increase the risk of hypernatraemia. However, other side-effects (eg, fluid overload, hypertension, and hyperchloraemic acidosis) have not been sufficiently evaluated. This highlights the importance of continuous monitoring.
5.3 Three isotonic fluids containing 5% dextrose (D5) are available in Hong Kong: 0.9% NaCl D5, Ringer’s lactate D5 balanced solution, and Plasma-Lyte 148 D5 balanced solution (compositions listed in Table 1). Guidelines adopting robust methodologies3 4 have not indicated a preference for any particular isotonic fluid composition; however, Children’s Hospital Colorado guidelines indicate a preference for balanced solutions (rather than 0.9% NaCl) as maintenance fluid for all age ranges, citing the need to monitor for hyperchloraemic acidosis with ‘unbalanced’ 0.9% NaCl.33 However, because there is a lack of direct comparative studies, this recommendation is more opinion-than evidence-based.
5.4 A note of caution is needed regarding the selection of isotonic fluids in young infants because most RCTs recruited infants from age 3 months; all RCTs contained few young infant patients. Because of their immature kidneys, young infants may require electrolyte monitoring to ensure hypernatraemia and/or hyperchloraemic acidosis do not occur, especially when 0.9% NaCl is used. Thus, we suggest using dextrose-containing balanced solutions with lower NaCl content as maintenance IVF for patients aged 1 to 3 months.
5.5 When maintenance IVF treatment is considered for older infants, the widely available 0.9% NaCl D5 is a suitable choice, especially if the treatment is supplementary or will be administered for short-term use. However, because of its high chloride content, clinicians should consider the potential risk of hyperchloraemic acidosis when 0.9% NaCl D5 is used in large volumes or for long durations, particularly in sick patients.
5.6 The slightly more expensive (HK$20/L more) Plasma-Lyte 148 D5 balanced solution is also a suitable isotonic solution for general use, especially in sick patients or patients exhibiting shock because of its lower chloride content. The mild alkalinising effect of this solution may benefit patients with acidaemia, although caution is needed when the solution is used in patients with hypocalcaemia or metabolic alkalosis. Plasma-Lyte 148 D5 balanced solution contains potassium at physiologically appropriate concentrations which can provide maintenance needs, but it should not be used in patients with hyperkalaemia.34
5.7 In the uncommon situations involving free water deficit, excessive non-renal or renal free water, or hypotonic fluid loss (Table 3), hypotonic fluids may be needed. These situations are usually associated with hypernatraemia, which should be corrected slowly (at a concentration <10 mmol/L/24 hours). Paired serum and urinary osmolarity and electrolyte monitoring are helpful in these situations.
5.8 There is no evidence-based recommendation regarding the addition of KCl, although many guidelines suggest the addition of 10 to 20 mmol/L KCl to maintenance IVF after confirmation of normal serum potassium and creatinine levels, as well as confirmation that there is no risk of renal impairment. Potassium supplementation is important when there is a delay in reinitiation of oral intake. Balanced solutions generally do not require additional potassium supplementation,33 though their physiological KCl concentration is inadequate to treat hypokalaemia.
Statement 6. Calculations of maintenance IVF rate should include all oral, enteral, drug, and blood products, normally using the Holliday–Segar formula. Patients at risk of SIADH may require fluid restriction. (Consensus)
Traditionally, daily IVF volumes should be calculated using the Holliday–Segar formula. However, evidence regarding appropriate fluid volumes in hospitalised children is lacking. McNab et al35 examined four (mostly surgical) RCTs which included restricted rates in their intervention arms. The limited evidence available36 37 showed that 0.45% NaCl at <70% maintenance rates did not protect against hyponatraemia, suggesting that fluid type is more important than fluid rate for prevention of hyponatraemia.
The IVFWG has these consensus opinions, pending more evidence:
6.1 When determining fluid volumes, volumes calculated using the Holliday–Segar formula should rarely exceed adult volumes (2 L/day for girls and 2.5 L/day for boys) or 100 mL/hour.3 In patients for whom accurate calculation of insensible water loss is important (eg, patients with obesity, acute kidney injury, chronic kidney disease, or cancer), body surface area may be useful when calculating fluid requirements at 300 to 400 mL/m2/24 hours plus urine output3; or in patients weighing >10 kg, fluid requirements calculated as 1500 mL/m2/24 hours.38
6.2 In patients at risk of SIADH (Table 3), volumes may be restricted to 60% to 80% maintenance. Patients with central nervous system conditions (eg, meningitis, encephalitis, or major head injury) may require fluid restriction to 50% for management of cerebral oedema.
Statement 7. Ongoing fluid loss should be replaced using fluids with comparable electrolyte compositions. (Consensus)
7.1 Increased ongoing losses (eg, vomiting, diarrhoea, ostomy, and third space losses) should be taken into account and replaced with comparable fluids (Table 53 9 10 39 40 shows electrolyte compositions of various body fluids). For vomiting and non-choleric diarrhoea, both 0.45% NaCl or 0.9% NaCl solutions (with added potassium) are recommended.
Table 5. Electrolyte compositions of various fluids (modified from NICE3, Kaptein39, CHOP IVF clinical pathway40)
7.2 Abnormal urine electrolyte losses can vary widely; thus, monitoring of paired urine and serum electrolyte levels, as well as creatinine and osmolarity parameters, may be needed. In some situations, even isotonic fluids may be insufficient to prevent hyponatraemia (eg, patients with central nervous system injury with cerebral salt wasting or patients with SIADH in whom urine osmolality is >500 mOsmol/kg); these patients require measurement of urinary electrolytes and osmolality.
Statement 8. All children receiving IVF should undergo regular clinical and biochemical monitoring to assess their responses to therapy and changes in clinical status. Monitoring frequencies should be based on a risk assessment involving the child’s age, clinical and volume statuses, stability, IVF proportion, and presence of biochemical abnormalities. (Consensus)
8.1 An infusion pump should be used for all children requiring maintenance IVF.
8.2 Children receiving IVF should have an accurate weight recorded on admission or as soon as clinically possible; daily weight should be recorded as needed, specifically noting weight fluctuations ± 3% in 24 hours. Daily fluid balance (ie, input, output, and abnormal ongoing loss) should be recorded.
8.3 Clinical assessment of fluid status (ie, body weight, heart rate, capillary refill time, hydration, and blood pressure), fluid balance, oral fluid tolerance, and the continued need for IVF should be reviewed often (preferably at least twice daily).
8.4 The plasma electrolyte profile (sodium, potassium, urea, creatinine, chloride, and acid-base level) should be checked at the initiation of IVF, then rechecked in accordance with the risk level and proportion of maintenance fluid supplied as IVF. In young infants, high-risk patients, and patients receiving prolonged IVF treatment, reassessments should be performed at least daily or more frequently if an electrolyte abnormality is present, or if the patient is particularly unwell. The blood glucose level should be checked if there is a risk of hypoglycaemia (eg, in young infants). Paired serum and urinary osmolarity and electrolyte profiles may be useful to guide fluid prescription in patients with electrolyte abnormalities.
While there is strong evidence that isotonic solutions are the most appropriate maintenance IVF for the vast majority of hospitalised children, a reflexive approach to IVF prescription should be avoided. Intravenous fluid should be prescribed with the same care used for medications; with the rate and type of fluid tailored to the individual’s clinical and pathophysiological statuses. Regular monitoring and reassessment with appropriate fluid readjustment are critical considerations. Many aspects of IVF treatment continue to exhibit a lack of evidence, such as the selection of 0.9% NaCl or balanced solution, as well as the fluid rate and optimal potassium supplement composition. When more evidence is available, these practice statements with the accompanying algorithms should be reviewed.
Concept or design: LCK Leung, KC Chan.
Acquisition of data: LCK Leung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: LCK Leung.
Critical revision of the manuscript for important intellectual content: All authors.
Acquisition of data: LCK Leung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: LCK Leung.
Critical revision of the manuscript for important intellectual content: All authors.
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
Conflicts of interest
All authors have disclosed no conflicts of interest.
The authors would like to thank reviewers of the Intravenous Fluid Clinical Pathway (Dr KW Hung, Dr YW Kwan, Dr SN Wong, Dr SWC Wong, and Dr MM Yau) for their invaluable comments.
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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