• 
• 

Three Part Question

In [non-oliguric hyperkalaemic very low birth weight (VLBW) neonates] which [medical interventions] reduce [serum potassium levels effectively]?

Clinical Scenario

A 720 g neonate in the intensive care unit develops severe hyperkalaemia with cardiac arrhythmia. The specialist registrar decides to give a calcium gluconate bolus and start an insulin and dextrose infusion. The new registrar queries why salbutamol and ion exchange resins were not considered as these therapies are frequently used in the management of hyperkalaemia in older children and adults.

Search Strategy

Pubmed and Medline 1966–2006; Embase 1974–2006; Cinahl 1982–2006 using Dialog Datastar
Cochrane Library (2006, Issue 4).
Search date: August 2006. Search terms: [neonatal hyperkalaemia or hyperkalaemia AND neonate or hyperkalaemia AND preterm neonate or hyperkalaemia and newborn] AND [treatment or therapy or drug therapy or insulin/dextrose infusion or insulin/glucose infusion or salbutamol or calcium or calcium gluconate or calcium resonium or ion exchange resin or sodium bicarbonate or exchange transfusion or peritoneal dialysis]. Limited to newborn, human and English language.

Search Outcome

Cochrane Library: One relevant systematic review.
Search terms: [neonatal hyperkalaemia or hyperkalaemia AND neonate or hyperkalaemia AND preterm neonate or hyperkalaemia and newborn] AND [treatment or therapy or drug therapy or insulin/dextrose infusion or insulin/glucose infusion or salbutamol or calcium or calcium gluconate or calcium resonium or ion exchange resin or sodium bicarbonate or exchange transfusion or peritoneal dialysis]. Limited to newborn, human and English language.
Total number of hits: 343. Number of relevant hits: seven, of which three were randomised controlled trials, one was a retrospective review and three were case series.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ohlsson et al, 1987, Canada	ELBW (n=8) preterm neonates (<27 weeks gestation, birth weight <1000 g) with hyperkalaemia (SK levels >7.4 mmol/l) commenced on oral doses of CPS or SPS at 1 g/kg/dose	Case series (level 4)	Benefits and adverse effects of exchange resins in neonates	Complications (n = 5) (2 isolated abdominal mass, 1 abdominal mass+distension, 1 NG embedded in gastric mass, 1 perforation with intra-abdominal resin). 3 neonates with an uncomplicated course during treatment	Oral administration of resin to critically ill preterm neonates (<26/40) with a proven or suspected functional ileus should be avoided
Lui et al, 1992, Australia	ELBW premature infants (n=99) over a 3-year period were retrospectively reviewed n=15 developed hyperkalaemia (SK>7.4 mmol/l). n = 12 received hypertonic insulin/dextrose (I/D) infusion	Retrospective study (level 2b)	Normokalaemia	All infants showed an initial response. Time taken for SK to fall below 6.5 mmol/l was 5 (SD 2) h	Hypertonic dextrose/insulin infusion is effective in controlling severe hyperkalaemia in immature infants
Hu et al, 1999, Taiwan	VLBW infants (n = 40) with non-oliguric hyperkalaemia were randomly assigned to receive regular insulin (R/I) infusion (n=20) or kayexalate resin enema (n=20)	RCT (level 1b)	Evaluation of efficacy of glucose/insulin infusion vs kayexalate in treatment of hyperkalaemia in VLBW infants	Significant shorter duration of hyperkalaemia and lower incidence of intraventricular haemorrhage noted in R/I group. No difference in peak potassium level or incidence of cardiac dysrhythmias between the 2 groups	Use of early continuous R/I therapy for the treatment of hyperkalaemia in VLBW infants is more effective than kayexalate in decreasing the duration of hyperkalaemia anddecreasing the incidence of intraventricular haemorrhage
Malone et al, 1991, USA	ELBW preterm neonates (n=12) with hyperkalaemia were randomly assigned to receive insulin/dextrose (I/D) infusion (n=7) or sodium polystyrene sulfonate (n=5)	PRCT (level 1b)	Comparison of glucose and insulin infusion with rectal administration of cation exchange resin for the treatment of hyperkalaemia in VLBW infants	Kayexalate (n = 5) treatment failed (increased SK > 0.5 mmol/l within first 6 h of treatment I/D infusion (n=7). Within 24 h all SKs 7 mmol/l 0 had increased >0.5 mmol/l p=0.001 Significant reduction in SK in G/I group compared with resin group in the first 6 h of Rx. p=0.002	Failure of resin probably related to slow mechanism of action and inability to be specific for potassium Further studies needed to determine if ability to exchange potassium is decreased in the preterm gastrointestinal tract I/D therapy seems preferable in initial management of hyperkalaemia in VLBW infants
Dilmen et al, 1992, Turkey	LBW neonates (n = 2) with hyperkalaemia (SK 9.5 and 7.8 mmol/l) in whom therapy with insulin and glucose was considered to be inappropriate, were commenced on salbutamol infusion	Case series (level 4)	Hypokalaemic effect of salbutamol in the treatment of hyperkalaemia in newborn infants	SK fell from 9.5 to 5.5 mmol/l and 7.8 to 6.1 mmol/l in patients 1 and 2, respectively, 7 h after salbutamol infusion (0.1 µg/kg/h) was commenced	Tremor and slight increase in heart rate were noted during the infusion which resolved after cessation of treatment. Infuse carefully in patients on ventilator or with PDA as tachycardia may complicate course. Careful monitoring of blood potassium, glucose and ECG is essential
Singh et al, 2002, USA	Preterm neonates (n = 22) with hyperkalaemia were randomly assigned to receive albuterol (n = 8) or saline nebulisations (control; n=11	PRCT double-blinded (level 1b)	Evaluation of the efficacy of inhaled salbutamol for the treatment of hyperkalaemia in premature neonates	SK reduction in first 4 h, from 7.06 (SD 0.23) mmol/l to 6.34 (SD 0.24) mmol/l (p = 0.003) vs no significant change in saline group. SK reduction continued at 8 h, 5.93 (SD 0.3) mmol/l (p = 0.04)	Effect most pronounced in first 4 h, with a less marked decline by 8 h
Setzer et al, 1984, USA	Neonates (n=3) with symptomatic hyperkalaemia received an exchange transfusion with low potassium-containing saline-washed red blood cells reconstituted with fresh frozen plasma	Case series (level 4)	Can iatrogenic hyperkalaemia after exchange transfusion be avoided by the use of blood products containing low potassium levels?	Mean SK prior to exchange transfusion 9.23 mmol/l and post transfusion 6.3 mmol/l	Exchange transfusion with blood units prepared by washing stored red blood cells with saline and reconstituting them with blood group specific/compatible FFP may be useful as an emergency measure in anticipation of more prolonged management with resin/dialysis

Comment(s)

Non-oliguric hyperkalaemia is a common and potentially life threatening complication in preterm neonates in the intensive care setting. Hyperkalaemia affects up to 50% of VLBW premature infants (Gruskay, Lorenz, Omar, Shaffer). It often causes cardiac arrhythmias and can lead to periventricular leukomalacia and death (Shortlans). Hyperkalaemia may occur as a result of increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. This loss of potassium has been shown to be unrelated to leakage following cell disruption associated with bruising, intracranial haemorrhage, haemolysis, perinatal asphyxia, acidosis and glucose tolerance (Gruskay, Lorenz, Omar, Ohlsson). It is suggested that this potassium loss is due to immature function of the erythrocyte Na+/K+-ATPase (Omar, Ohlsson). Treatments used in premature infants with non-oliguric hyperkalaemia aim to decrease the arrhythmogenicity of hyperkalaemia, redistribute potassium into the intracellular space or remove potassium from the body. Insulin and dextrose (I/D) decrease serum potassium concentration by transporting potassium into the intracellular space. A retrospective study of 12 preterm neonates treated with I/D infusion showed a good initial response in all infants. Serum potassium concentration decreased to <6.5 mmol/l after 5 (SD 2) h of treatment (Stefano). A randomised controlled trial of rectal ion exchange resins (kayexalate) and insulin and glucose (I/D) infusion in 40 premature neonates showed a significantly shorter duration of hyperkalaemia and a significantly lower incidence of intracranial haemorrhage in the I/D group (Lui).Treatment with ion exchange resins failed in a second randomised controlled trial (SK increased by >0.5 mmol/l 6 h after initiation of treatment). The mortality rate was 80% in this group of patients compared with 14% in the I/D group (Hu). Complications of ion exchange resins include impaction and/or rectal perforation (Malone). Salbutamol is used frequently in the treatment of hyperkalaemia in older children and adults with hyperkalaemia secondary to renal failure. In vitro studies of neonatal red blood cells maintained in 10 mmol potassium chloride solution showed a 50% increase in potassium flux on exposure to salbutamol via stimulation of the Na+/K+-ATPase (Angelopoulous). However, there is limited evidence to support its use in the preterm neonate. Hyperkalaemia was successfully treated with salbutamol infusion (0.1 µg/kg/min) in two newborn infants with minimal side effects (Dilmen). Treatment with insulin and glucose infusion was deemed inappropriate in both of these cases due to the presence of hypoglycaemia. A randomised controlled trial of nebulised salbutamol and saline in 19 low birth weight hyperkalaemic neonates showed a significant reduction in serum potassium concentration at 4 h with a lesser decrease in serum potassium levels at 8 h in the salbutamol group (Singh). Salbutamol appears to be well tolerated by premature infants but potential side effects include tachycardia, tremor and hyperglycaemia. Exchange transfusion may be considered in cases where all other therapeutic options have failed. Reports have demonstrated significant reduction in serum potassium concentrations and reversal of hyperkalaemia induced arrhythmias with such treatment (Setzer). However, a long preparation time is necessary as saline washed red blood cells reconstituted with fresh frozen plasma are recommended. Exchange transfusion can be complicated by the development of necrotising enterocolitis and death (in 0.3%). Recently a Cochrane review of interventions for hyperkalaemia has been completed (Vemgal). Only three randomised controlled trials were eligible for inclusion and the authors concluded that no firm recommendations for clinical practice could be made. Randomised controlled trials to compare I/D infusions with salbutamol and novel interventions for the management of neonatal hyperkalaemia are essential.

Editor Comment

CPS, calcium polystyrene sulfonate; ELBW, extremely low birth weight; FFP, fresh frozen plasma; LBW, low birth weight; PDA, patent ductus arteriosus; SK, serum potassium; SPS, sodium polystyrene sulfonate; VLBW, very low birth weight.

Clinical Bottom Line

Insulin and dextrose infusion should form the first line of therapy in hyperkalaemia of the premature infant. (Grade A) Oral and rectal ion exchange resins should be avoided as they are ineffective and associated with significant and potentially life threatening complications. (Grade A) No substantial data show the superiority of salbutamol over insulin/dextrose for premature infants (Grade D) Exchange transfusion may be used as a last resort therapy. (Grade D)

References

1. Gruskay J, Costarino AT, Polin RA, et al. Nonoliguric hyperkalaemia in the premature infant weighing less than 1000 grams. J Pediatr 1988; 113: 381–6.
2. Lorenz JM, Kleinman LI, Markarian K. Potassium metabolism in extremely low birth weight infants in the first week of life. J Pediatr 1997; 131: 81–6.
3. Omar SA, De Cristofaro JD, Agarwal BI, et al. Effect of prenatal steroids on potassium balance in extremely low birth weight neonates. Pediatrics 2000; 106: 561–7.
4. Shaffer SG, Kilbride HW, Hayen LK, et al. Hyperkalaemia in very low birth weight infants. J Pediatr 1992; 121: 275–9.
5. Shortlans D, Trounce JO, Levine MI. Hyperkalaemia, cardiac arrhythmias, and cerebral lesions in high risk neonates. Arch Dis Child 1987; 62: 1139–43.
6. Ohlsson A, Hosking M. Complications following oral administration of exchange resins in extremely low birth weight infants. Eur J Pediatr 1987; 146: 571–4.
7. Stefano JL, Norman ME, Morales MC, et al. Decreased erythrocyte Na+, K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalaemia. J Pediatr 1993; 122: 276–84.
8. Lui K, Thungappa U, Nair A, et al. Treatment with hypertonic dextrose and insulin in severe hyperkalaemia of immature infants. Acta Paediatr 1992; 81: 213–16.
9. Hu PS, Su BH, Peng CT, et al. Glucose and insulin infusion versus kayexalate for the early treatment of non-oliguric hyperkalaemia in very low birth weight infants. Acta Pediatr Taiwan 1999; 40: 314–18.
10. Malone TA. Glucose and insulin versus cation exchange resin for the treatment of hyperkalaemia in very low birth weight infants. J Pediatr 1991; 118: 121–3.
11. Angelopoulous M, Leitz H, Lambert G, et al. In vitro analysis of the Na+/K+-ATPase activity in neonatal and adult red blood cells. Biol Neonate 1996; 69: 140–5.
12. Dilmen U, Toppare M, Senses DA, et al. Salbutamol in the treatment of neonatal hyperkalaemia. Biol Neonate 1992; 62: 424–6.
13. Singh BS, Sadiq HF, Noguchi A, et al. Efficacy of albuterol inhalation in treatment of hyperkalaemia in premature neonates. J Pediatr 2002; 141: 16–20.
14. Setzer ES, Ahmed F, Goldberg RN, et al. Exchange transfusion using washed red blood cells reconstituted with fresh frozen plasma for treatment of severe hyperkalaemia in the neonate. J Pediatr 1984; 104: 443–6.
15. Vemgal P, Ohlsson A. Interventions for non-oliguric hyperkalaemia in preterm neonates. Cochrane Database Syst Rev 2007; 24: (1): CD005257.