Hyperkalemia is a risky and potentially life-threatening condition, especially when it occurs in infants born prematurely. In premature infants, serum potassium usually reaches a peak at 24 h of age and returns to normal by 72 h.1,2 Non-oliguric hyperkalemia in neonates is defined as a serum potassium level greater than 6.0 mmol/L and is more commonly observed in extremely low birthweight (ELBW) infants2–4 or in pre-term infants even with normal renal function for their age. Although the pathophysiology is not completely understood, it seems to be related to immaturity in regulating the internal distribution of potassium.5 Hyperkalaemia in the neonate may occur as a result of increased potassium intake, decreased renal excretion, a shift of potassium from the intracellular to extracellular space, or medications. For instance, a digoxin overdose and β2 adrenergic blockers can induce hyperkalemia by inhibiting Na+-K+ adenosine triphosphatase (Na+-K+ ATPase).6 A recent study reported that non-oliguric hyperkalemia in premature infants can be caused by severe birth asphyxia and thereby contribute to extensive periventricular white matter injury.7 Futhermore, persistent hyperkalemia in infants is a medical emergency that may also lead to complications such as cardiac arrhythmia, intraventricular hemorrhage, periventricular leukomalacia, and death.4,8,9 Therefore, infants at risk of hyperkalemia must be identified and treated as early as possible.
In the past, glucose-insulin infusion has usually been considered the first therapeutic choice for treating hyperkalemia in premature infants. Insulin can regulate the Na+-K+ ATPase in the cell membranes by increasing the rate of ATP hydrolysis that occurs in order to maintain intracellular and extracellular potassium concentrations. However, in spite of the fact that some previous studies have recommended specific dosages of insulin in order to reduce the possible side effects of hypoglycemia, such side effects still occur frequently.7 As such, in order to prevent the possibility of hypoglycemia resulting from insulin, glucose is usually included with the insulin in order to counteract the insulin’s potential side effects. On the other hand, given the difficulty of prescribing precise dosages of insulin and glucose, iatrogenic hyperglycemia it is not uncommon. Either hypoglycemia or hyperglycemia in premature infants can result in acute or chronic life-threatening conditions such as seizure, cerebral damage, and intraventricular hemorrhage.10–12 As the infant liver is still underdeveloped and has limited capacity for glycogen production and storage, the prevention of vigorous blood sugar fluctuations in infants is essential.13,14
Salbutamol is a kind of β2 adrenergic agonist that can activate adenylate cyclase via the binding of β2 adrenoreceptors. This mechanism will stimulate the production of cyclic adenosine monophosphate with the help of ATPase and, in turn, facilitate the transfer of potassium into cells.15 Though many studies have demonstrated that salbutamol is effective in treating hyperkalemia,16–19 prospective clinical comparison studies have been rare. In previous studies, intravenous salbutamol injections have been used as a means of treating hyperkalemia in neonates, with those studies reporting that such injections successfully reduce serum potassium levels without marked side effects.20,21 Nebulized salbutamol also had been reported to yield significantly better results than intravenously administered forms of the drug.18,22 In the present study, we sought to compare the value, effectiveness, and potential side effects of nebulized salbutamol and glucose-insulin infusion in order to assess whether nebulized salbutamol is a safer alternative treatment for hyperkalemia in premature infants.
All the premature infants included in this study were cared for according to the clinical guidelines of the newborn intensive care unit of Cheng Ching General Hospital, Taichung, Taiwan. We excluded premature infants born with any major congenital malformations (including chromosomal abnormalities), infants with confirmed or suspected sepsis or pneumonia, infants in a terminal state on admission, infants with umbilical anomalies, and infants with skin infections.
2.2. Ethics statement
This study was approved by the Institutional Review Board of Cheng Ching General Hospital (IRB No: HP110006). Written informed consent was obtained from the parents or guardians of each of the minors before any study related procedures were performed.
2.3. Study design
Prospectively double-blind, randomized clinical study was set up under the IRB approval and went through as followings: Forty premature infants (gestation age ≤36 weeks) with non-oliguric hyperkalemia (central serum potassium level greater than 6.0 mmol/L) within 72 h of birth were enrolled in this study. They were randomly assigned into two groups (according to their chart number is singular or plural): each Group A infant (n = 20, chart number is singular) received a glucose-insulin infusion and each Group B infant (n = 20, chart number is plural) received a Ventolin® (salbutamol) respirator solution (Glaxo Canada Inc; Montreal, Canada) via nebulizer. The glucose-insulin infusion consisted of 10–15 mg of glucose and 1 unit of regular insulin bolus (RI), maintained at a rate of 6 mg/kg/min. Salbutamol (400 μg in 2 ml saline solution) was administered as an aerosol using an endotracheal tube. The central serum potassium, blood glucose, heart rate, and blood pressure of each infant were measured before treatment and at 3, 6, 12, 24, and 72 h post-treatment.
2.4. Analytic procedures
For each infant, the central serum potassium level and blood glucose level were monitored throughout the study by intermittent arterial line sampling. Potassium was measured using the Ion-Selective Electrode (indirect ISE) method (Hitachi 008AS), and glucose was measured using automated biochemical methods (Hitachi 008AS). The glucose fluctuation was obtained by subtracting the value of the lowest blood glucose concentration from that of the peak concentration. The heart rate (HR) and mean arterial blood pressure (MAP) were also monitored, while the electrocardiograms were continuously monitored. We paid greater attention to such monitoring when abnormally high potassium levels (central serum potassium greater than 7.5 mmol/L) occurred. When this happened, aggressive medical interventions and management were applied without any delay. Furthermore, due to safety concerns, any infant facing such a situation would be excluded from the present study.
2.5. Statistical analysis
Statistical analysis was done using Student's t-test for paired values. Between-groups differences were tested using analysis of variance (ANOVA) and Fisher’s post hoc tests. The results were expressed as mean value ± SEM at a significance level of p < 0.05. In both tables, we used nonparametric statistics (Wilcoxon rank sum test) to test data differences between two groups if the data distribution is not corresponding Gaussian/normal distribution (Kolmogorov–Smirnov test is significantly). Relatively, data in tables with normal distribution will be present as mean value ± SD.
3.1. Comparison of the effects of nebulized salbutamol and glucose-insulin infusion on potassium level, heart rate, and mean arterial pressure
There was no significant difference in the distributions of neonatal birth weights between the nebulized salbutamol and glucose-insulin infusion management groups (Table 1, Student’s t-test: p > 0.05). The mean blood glucose, HR, and MAP levels before treatment of the two groups also showed no significant difference (Table 2, Student’s t-test: p > 0.05). Both interventions were found to significantly reduce the serum potassium levels (Fig. 1 & Table 2; Student’s t-test: Pre-treat vs. 3-h & 72-h, RI + glucose, p < 0.01; Pre-treat vs. 3-h & 72-h, salbutamol, p < 0.01) but not HR or MAP (Table 2, Student’s t-test: Pre-treat vs. 72-h, p > 0.05). However, the effects of these two treatments on serum potassium level, HR, and MAP did not show any significant difference (Figs. 1–3, ANOVA: p > 0.05).
3.2. Nebulized salbutamol alleviates blood glucose fluctuation
Because glucose-insulin infusions can cause either hypoglycemia or hyperglycemia,9,23 we measured the blood glucose fluctuations of both therapeutic groups. There were no significant statistical differences in blood glucose levels over the observation period of each study time points (Fig. 4A or Table 2, ANOVA: p > 0.05). However, the blood glucose fluctuations (indicated by the difference resulting from subtracting the lowest blood glucose concentration from the peak concentration during study period) showed significant differences. The degree of the mean blood glucose fluctuation in the nebulized salbutamol group was significantly lower than that in the glucose-insulin infusion group (42.3 ± 3.70 mg/dL and 105.35 ± 14.05 mg/dL, respectively, p < 0.001, Fig. 4B).
Glucose-insulin infusion has been considered a classic treatment for non-oliguric hyperkalemia in premature infants. However, the potential risks of blood glucose fluctuations are not uncommon in these infants, and such fluctuations will sometimes result in severe sequelae,9,23 The results of the present study indicate that salbutamol is as effective as typical glucose-insulin infusion therapy in lowering the blood potassium level of an infant. No known side effects such as tachycardia or hypertension were observed in either group. In addition, the blood glucose levels, heart rates, and blood pressures of these patients were all within normal limits throughout the study. We also demonstrated that the nebulized salbutamol therapy resulted in less vigorous fluctuations of blood glucose in comparison with the typical glucose-insulin infusion treatment.
Hyperkalemia in premature neonates results from abnormal potassium reabsorption or shifting between the intracellular and the extracellular space.4,24 Therapies for hyperkalemia in neonates include lowering blood potassium levels through the intravenous administration of calcium gluconate, sodium bicarbonate, bolus glucose-insulin infusion, or the administration of a sodium polystyrene sulfonate (Kayexalate®) enema.9,25–27 However, the effectiveness of these treatments has been criticized and doubted in several reports due to their coinciding with various unwanted side effects. For example, the extravasation of intravenous calcium gluconate can lead to regional soft tissue calcification, necrosis, cellulitis, and osteomyelitis, and may even cause compartment syndrome25,28,29; glucose-insulin infusion can cause either hypoglycemia or hyperglycemia9,23; and Kayexalate® enema can lead to stool impaction, rectal perforation, and even necrotizing enterocolitis.30–32
Preterm infants are in danger of abnormal glucose homeostasis. Hyperglycemia is a remarkable risk factor for mortality and morbidity in preterm infants and occurs in 40–80% of ELBW newborns due to the inability of these newborns to inhibit gluconeogenesis in response to a glucose infusion, which leads to insulin resistance.33,34 Moreover, these infants may also develop hypoglycemia due to the limitation of glycogen and fat storage, especially during an exogenous insulin infusion.13 These sequelae will lead to adverse neurodevelopmental outcomes.35 To sum up, glucose-insulin infusions are accompanied by both side effects and potential risk factors. Relatedly, in this study, we detected more severe glucose fluctuations in the glucose-insulin infusion group, in spite of the infusions being administered according to accurate medical guidance. Based on these results of the present study and a recent review article, it can be concluded that nebulized salbutamol should be given higher priority in treating hyperkalemia in premature neonates.36
In 1992, Dilmen et al. conducted the first study in which salbutamol was used as an alternative for treating hyperkalemia in LBW neonates. They also reported that side effects such as tremor and a slight increase in heart rate occurred when glucose-insulin infusion was used as a treatment.20 However, to the best of our knowledge, no study prior to the present one has investigated the differences between nebulized salbutamol and glucose-insulin infusion for the treatment of hyperkalemia in premature infants. Our data demonstrated that the therapeutic effectiveness of both treatments in terms of lowering serum potassium in premature infants was similar. Though no known side effect of salbutamol was observed in our study, some previous studies have claimed that rebound hyperkalemia can occur after dialysis in end-stage renal disease patients.37 However, there are some β2 adrenergic agonistic medications such as procaterol or salmeterol possess higher selectivity react to β2 adrenergic receptor than salbutamol, which may reduce some unwanted side effects resulting from β1 adrenergic receptors.38 In present study we still choose salbutamol as study target owing to the first: it is the earliest β2 adrenergic agonist that being applied in lowering serum potassium.20 Second, the applications of other highly selective β2 adrenergic agnoists are few being reported.39 Third, most documented side effects of salbutamol were little and acceptable.40 Fourth, present study focused on the difference comparison of β2 adrenergic agonist and glucose-insulin therapy but not benefits of β2 adrenergic agonists between. Maybe we can raise another clinical study to compare the efficiency and efficacy of these β2 adrenergic agonists in the future.
Though the present study had a number of potential limitations, including a small sample of participants and some possible biases such as the correlations of the fluid statuses, feeding protocols, and body weights of the infants, it nonetheless provides a prospective, case–control, comparison study of the two treatment groups. Further, more extensive studies are essential in order to gather more evidence to support the effectiveness of salbutamol as an alternative treatment for life-threatening hyperkalemia in premature infants. In addition, the use of more intensive and continuous in-time monitors is also needed to avoid the risk of inconsistent responses.
In conclusion, in comparison with glucose-insulin infusions, the treatment of hyperkalemia in premature infants with nebulized salbutamol can provide a safe and effective clinical option. It can achieve the goals of being less invasive and causing less severe blood glucose fluctuations.
We would like to acknowledge all nursing staffs in neonatal intensive care unit of Cheng Ching General Hospital for their dedication in monitor recording, data collection, and meticulously care of premature infants. This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004).
APPENDIX A. SUPPLEMENTARY DATA
The gender, gestational age and apgar score of individual infant was provided in supplementary information.
Supplementary data related to this article can be found at http://links.lww.com/JCMA/A2.
1. Senterre T, Abu Zahirah I, Pieltain C, de Halleux V, Rigo J. Electrolyte and mineral homeostasis after optimizing early macronutrient intakes in vlbw infants on parenteral nutrition.J Pediatr Gastroenterol Nutr201561491–8
2. Lorenz JM, Kleinman LI, Markarian K. Potassium metabolism in extremely low birth weight infants in the first week of life.J Pediatr199713181–6
3. Gruskay J, Costarino AT, Polin RA, Baumgart S. Nonoliguric hyperkalemia in the premature infant weighing less than 1000 grams.J Pediatr1988113381–6
4. Kwak JR, Gwon M, Lee JH, Park MS, Kim SH. Non-oliguric hyperkalemia in extremely low birth weight infants.Yonsei Med J201354696–701
5. Stefano JL, Norman ME, Morales MC, Goplerud JM, Mishra OP, Delivoria-Papadopoulos M. Decreased erythrocyte na+,k(+)-atpase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalemia.J Pediatr1993122276–84
6. Lehnhardt A, Kemper MJ. Pathogenesis, diagnosis and management of hyperkalemia.Pediatr Nephrol201126377–84
7. Xiong X, Chen D, Zhang J, Mao J, Li J. Nonoliguric hyperkalemia in a late preterm infant with severe birth asphyxia.Transl Pediatr2013248–52
8. Jawa G, Yuen D, Norozi K. The effect of bundle branch block on heart function and cardiac output in premature infant.Pediatr Cardiol2013342099–100
9. Hung KC, Su BH, Lin TW, Peng CT, Tsai CH. Glucose-insulin infusion for the early treatment of non-oliguric hyperkalemia in extremely-low-birth-weight infants.Acta Paediatr Taiwan200142282–6
10. Alexandrou G, Skiold B, Karlen J, Tessma MK, Norman M, Aden U, et al. Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants.Pediatrics2010125e584–e91
11. Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA. Hyperglycemia and morbidity and mortality in extremely low birth weight infants.J Perinatol200626730–6
12. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants.Pediatrics20061181811–8
13. Mitanchez D. Glucose regulation in preterm newborn infants.Horm Res200768265–71
14. Blumberg A, Weidmann P, Shaw S, Gnadinger M. Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure.Am J Med198885507–12
15. Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation.J Allergy Clin Immunol200611718–24
16. Mandelberg A, Krupnik Z, Houri S, Smetana S, Gilad E, Matas Z, et al. Salbutamol
metered-dose inhaler with spacer for hyperkalemia: how fast? how safe?Chest1999115617–22
17. Allon M, Dunlay R, Copkney C. Nebulized albuterol for acute hyperkalemia in patients on hemodialysis.Ann Intern Med1989110426–9
18. Montoliu J, Lens XM, Revert L. Potassium-lowering effect of albuterol for hyperkalemia in renal failure.Arch Intern Med1987147713–7
19. McClure RJ, Prasad VK, Brocklebank JT. Treatment of hyperkalaemia using intravenous and nebulised salbutamol
.Arch Dis Child199470126–8
20. Dilmen U, Toppare M, Senses DA, Kaya IS. Salbutamol
in the treatment of neonatal hyperkalemia.Biol Neonate199262424–6
21. Greenough A, Emery EF, Brooker R, Gamsu HR. Salbutamol
infusion to treat neonatal hyperkalaemia.J Perinat Med199220437–41
22. Liou HH, Chiang SS, Wu SC, Huang TP, Campese VM, Smogorzewski M, et al. Hypokalemic effects of intravenous infusion or nebulization of salbutamol
in patients with chronic renal failure: comparative study.Am J Kidney Dis199423266–71
23. Rozance PJ, Hay WW. Hypoglycemia in newborn infants: features associated with adverse outcomes.Biol Neonate20069074–86
24. Suarez-Rivera M, Bonilla-Felix M. Fluid and electrolyte disorders in the newborn: sodium and potassium.Curr Pediatr Rev201410115–22
25. Radovanovic MR, Milovanovic DR, Ignjatovic-Ristic D, Radovanovic MS. Heroin addict with gangrene of the extremities, rhabdomyolysis and severe hyperkalemia.Vojnosanit Pregl201269908–12
26. Trefz FM, Constable PD, Lorenz I. Effect of intravenous small-volume hypertonic sodium bicarbonate, sodium chloride, and glucose solutions in decreasing plasma potassium concentration in hyperkalemic neonatal calves with diarrhea.J Vet Intern Med201731907–21
27. Lee J, Moffett BS. Treatment of pediatric hyperkalemia with sodium polystyrene sulfonate.Pediatr Nephrol2016312113–7
28. Moss J, Syrengelas A, Antaya R, Lazova R. Calcinosis cutis: a complication of intravenous administration of calcium glucanate.J Cutan Pathol20063360–2
29. Khanagavi J, Gupta T, Aronow WS, Shah T, Garg J, Ahn C, et al. Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes.Arch Med Sci201410251–7
30. Rugolotto S, Gruber M, Solano PD, Chini L, Gobbo S, Pecori S. Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonate (kayexalate): clinical and histopathologic findings.J Perinatol200727247–9
31. Grammatikopoulos T, Greenough A, Pallidis C, Davenport M. Benefits and risks of calcium resonium therapy in hyperkalaemic preterm infants.Acta Paediatr200392118–20
32. Capitanini A, Bozzoli L, Rollo S, Pirolo B, Giannese D, Zullo C, et al. [the presence of crystals of sodium polystyrene sulfonate in the colonic wall: innocent bystander or pathogenic factor?]G Ital Nefrol201633
33. Ng SM, May JE, Emmerson AJ. Continuous insulin infusion in hyperglycaemic extremely-low- birth-weight neonates.Biol Neonate200587269–72
34. van der Lugt NM, Smits-Wintjens VE, van Zwieten PH, Walther FJ. Short and long term outcome of neonatal hyperglycemia in very preterm infants: a retrospective follow-up study.BMC Pediatr20101052
35. Duvanel CB, Fawer CL, Cotting J, Hohlfeld P, Matthieu JM. Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants.J Pediatr1999134492–8
36. Bonilla-Felix M. Potassium regulation in the neonate.Pediatr Nephrol2017322037–49
37. Allon M, Shanklin N. Effect of albuterol treatment on subsequent dialytic potassium removal.Am J Kidney Dis199526607–13
38. Baker JG. The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors.Br J Pharmacol20101601048–61
39. Bennett JA, Tattersfield AE. Time course and relative dose potency of systemic effects from salmeterol and salbutamol
in healthy subjects.Thorax199752458–64
40. Helfrich E, de Vries TW, van Roon EN. Salbutamol
for hyperkalaemia in children.Acta Paediatr2001901213–6