ELECTROLYTES. See also SWEAT TESTS, IMMUNOGLOBULINS

1951 Kessler WR, Andersen DH. Heat prostration in fibrocystic disease of the pancreas and other condition. Pediatrics 1951; 8:648. [PubMed]
One of the most important papers up to that time from New York. Walter Kessler, the senior resident at the time, and Dorothy Andersen reported 12 children with heat prostration. Ten were admitted during a New York heat wave in 1948 and no less than seven were known to have cystic fibrosis. These were the days before air conditioning was generally available in New York and 1948 was a particularly hot summer. Paul di Sant’Agnese was working with Dorothy Andersen at the time and looking after her patients, and later said that he treated these particular infants as Andersen was away vacationing in Europe when they were admitted! The authors of this present report queried whether the sweat glands, as well as the glands of the pancreas and other organs, were inadequate in function or alternatively whether a low grade infection lowered the margin of tolerance to increased temperatures.
At the time of this report there was no explanation as to why infants with CF were particularly susceptible to heat prostration and salt depletion – fortunately Paul di Sant’Agnese decided to find out! This was the first report that children with CF were particularly susceptible to heat. It was this original incident that eventually led Paul di Sant’Agnese to search for the reason for salt depletion in many of these CF infants and eventually to his recognising the abnormally high sweat sodium and chloride, and to a lesser extent potassium. This was undoubtedly the first and most important major advance in the understanding of the causation of CF up to that time (see di Sant’Agnese et al, 1953 below).

1956 Rendle-Short J. Fibrocystic disease of the pancreas presenting with acute salt depletion. Arch Dis Child 1956; 31:28-30. [PubMed]
Referred to as a case of pseudo-Bartter syndrome by Devlin et al. 1989 below<

1958 di Sant’Agnese PA, Grossman H, Darling RC, Denning CR. Saliva, tears and duodenal contents in cystic fibrosis of the pancreas. Pediatrics 1958; 22:507-514 [PubMed]
Higher mean values of sodium and chloride but similar potassium levels were present in saliva of people with CF than in controls, as previous studies had shown. Also electrolytes were increased in the tears of people with CF but there was considerable overlap with normals in both tears and saliva. The concentrations of ions were similar in duodenal contents of CF and controls and not related to variations in proteolytic activity. At this stage di Sant’Agnese noted that three abnormalities in CF need explanation – an abnormality of mucus secretion, high electrolyte concentrations in sweat saliva and tears and an increased rate of secretion in parotid glands (also Lawson 1956 above; Barbero & Chernick, 1958 below).

1958 Barbero GJ, Chernick W. Function of the salivary gland in cystic fibrosis of the pancreas. Pediatrics 1958; 22: 945-952. [PubMed]
Children with CF had greater unstimulated salivary flow and the concentration of sodium and chloride was elevated compared with controls as had been shown by others. Response to mecholyl injection greater but potassium did not differ between CF and controls. This suggested an increased parasympathomimetic sensitivity in cystic fibrosis.

1959 Douglas WAC. Acute salt depletion in fibrocystic disease of the pancreas. Med J Australia 1959; 46:962-963. [PubMed]
The Australian climate provides the requisite conditions for acute salt depletion but up to this time no cases of this complication in people with CF had been reported from there. These are the first two children to be reported from Queensland – a girl aged four years who quickly recovered with intravenous (IV) fluids and a girl aged 10 months admitted in a collapsed state but who also recovered with IV fluids. Climate temperature was over 100°F in both instances. Both were discharged on a 4 g salt supplement daily. “The association of pink lips with peripheral circulatory collapse is most unusual” – a sign also noted by Rendle-Short (1956 above). The normal daily sodium chloride requirement is approximately half a gramme per year of age per day up to a total of 5 grammes (4 grammes= a level teaspoonful). In warm conditions this daily salt supplement is recommended.

1959 Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959; 24:739-45. [PubMed]
The first of a number of studies in CF examining the composition of secretions in the airways although airway secretions had been studied in other conditions – the authors reviewed the literature. CF secretions, obtained via a bronchoscope, contained twice the organic material found in non-CF bronchiectasis and this was related to their increased viscosity. The amounts of nitrogen, carbohydrate, hexosamine and lipids were similar but the DNA content was higher. “The fluid component is related to the percentage of sodium and chloride ions in the secretions – the lowest levels being in the CF secretions”.
These are very pertinent observations in view of the present “low salt” theory caused by the excessive absorption of sodium and reduced secretion of chloride into the airways as a result of defective or absent CFTR. The depletion of the airway surface liquid is now regarded as being of major importance in the pathogenesis of the lung disease. The authors with a very accurate prediction prophetically observed at the end of their paper “an alteration in the ionic concentration may be responsible for the peculiar characteristics observed in the tracheobronchial secretions of patients with cystic fibrosis”!! Also the increased amount of DNA present in CF sputum was relevant when the effect of enzymes was investigated (Chernick et al, 1961 below) - eventually leading to the development of the most effective mucolytic rhDNase in the Nineties.

1963 Lobeck CC, McSherry NR. Response of sweat electrolyte concentrations to 9 alpha-fluorohydrocortisone in patients with cystic fibrosis and their families. J Pediatr 1963; 62: 393-398. [PubMed]
Patients with CF failed to show a significant decrease in their sweat electrolytes after administration of oral 9-alpha fluorohydrocortisone (3.0 mg per square meter for two days). Parents, siblings of people with CF and controls all had a significant decrease in the concentration of their sweat electrolytes after this challenge – for example the fall in chloride in parents was - 40.8%, in controls - 43.6%, in siblings -35.6%, but people with CF only had -1.1% reduction in their sweat chloride level.

This was a practically useful paper when there was a problem with diagnosis and there was a marginal sweat test result -– particularly pre-1989 before genetic mutations could be determined. We used the test on a number of occasions and found it to be helpful when the diagnosis was in doubt and the sweat test result borderline with chloride values of around 50 – 70 meq/l. Margaret Hodson also found the fludrocortisone suppression test useful in adults with marginal sweat test results (Hodson ME et al. BMJ 1983; 286:1381-1383). [PubMed]

1965 Kopito L, Mahmodian A, Townley RRW, Khaw KT, Shwachman H. Studies in cystic fibrosis: analysis of nail clippings for sodium and potassium. N Engl J Med 1965; 272:504-509. [PubMed]
Abnormal electrolyte content of nails was suggested as a possible diagnostic help but the test never became popular as there was overlap between CF and non-CF and it was difficult to perform. (also Leonard PJ, Morris WP. Arch Dis Child 1972; 47:495-498)

1971 Gottlieb RP. Metabolic alkalosis in cystic fibrosis. J Pediatr 1971; 79:930-936. [PubMed]
An early example of metabolic alkalosis in an infant with cystic fibrosis. This came to be recognised as a mode of presentation eventually known as Pseudo-Bartter’s syndrome. There were subsequently isolated case reports in children with CF and an estimate of incidence in infants with CF by Beckerman & Taussig (1979 below).

1979 Beckerman RC, Taussig LM. Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis. Pediatrics 1979; 63:580-583. [PubMed]
In Tucson Arizona five of 11 infants with CF diagnosed in the first year between 1972 to 1977 were seen with hypokalemia, hypochloremia and metabolic alkalosis unassociated with marked dehydration, hyperpyrexia or major pulmonary or gastrointestinal symptoms. Chronic loss of sweat electrolytes together with mild gastrointestinal or respiratory disturbance may predispose. The lack of shock and hyperpyrexia differentiates the clinical state from the heat prostration syndrome described by Kessler & Andersen in 1951 (above).
This complication came to be known as Pseudo-Bartter’s syndrome. Of course occasionally infants with this clinical picture may not have CF but actually do have true Bartter’s syndrome as did an affected infant we reported in the previous year (Littlewood J M, Lee M R, Meadow S R. Treatment of Bartter's syndrome in early childhood with prostaglandin synthetase inhibitors. Arch Dis Child 1978; 53:43-48). [PubMed]. Both these situations will be diagnosed if the precaution is taken to perform serum electrolytes on any infant, CF or non-CF, who has a significant degree of “failure to thrive”.

1981 Laughlin JJ, Brady MS, Eigen H. Changing feeding trends as a cause of electrolyte depletion in infants with cystic fibrosis. Pediatrics 1981; 68:203-207. [PubMed]
Five infants with CF had eight episodes of hypoelectrolytemia - six of these were not associated with high environmental temperature and were considered possibly related to the current trends in reducing the salt in infant formula feeds. The salt content of infant formula feeds had been reduced in view of the reports of hypernatraemic dehydration which occurred in some infants on formula milk. But just as the incidence of hypernatraemic dehydration diminished in non-CF infants diminished when the salt content of infant feeds was reduced, so some infants with CF were adversely affected by the reduction in their dietary salt.

1989 Devlin J, Beckett NS, David TJ. Elevated sweat potassium, hyperaldosteronism and pseudo-Bartter’s syndrome: a spectrum of disorders associated with cystic fibrosis. J R Soc Med 1989; 82 (Suppl 16):38-43. [PubMed]
Three infants with “pseudo-Bartter’s syndrome” (the term first used by these authors) and two further with related electrolyte disturbances with low potassium and sodium and alkalosis. They emphasise the importance of measuring the serum electrolytes at diagnosis and when unwell. They mention the first report in CF was by Rendle Short J (Arch Dis Child 1956; 31:28-30.above). [PubMed]
Bartter’s syndrome was described by Fred Bartter in 1962 (Bartter FC et al. Hyperplasia of the juxtamedullary complex with hyperaldosteronism and hypokalemia alkalosis. Am J Med 1962; 33:811-128). In 1978 we described successful treatment of a non-CF infant with Bartter’s syndrome using indomethacin (Littlewood JM, et al. Treatment of Bartter’s syndrome in early childhood with prostaglandin synthetase inhibitors. Arch Dis Child 1978; 53:43-48.). [PubMed] Of course, children with CF require only salt replacement and an adequate sodium intake to remain well.

1990 Kennedy JD, Dinwiddie R, Daman-Willems C, Dillon MJ, Matthews DJ. Pseudo-Bartter's syndrome in cystic fibrosis. Arch Dis Child `1990; 65:786-787. [PubMed]
A further seven cases of Pseudo-bartter's syndrome are described from Great Ormond Street, London. Chronic salt depletion was associated with severe failure to thrive which was soon reversed when the salt deficit was corrected.

Dr Bob Dinwiddie, the senior author, was consultant Respiratory Paediatrician at the Hospital for Sick Children, Great Ormond Street in London where he succeeded Dr Archie Norman as Director of the CF Unit. He was heavily involved in CF care and respiratory paediatrics both nationally and internationally until his retirement in 2000s.

2009  Coates AJ, Crofton PM, Marshall T. Evaluation of salt supplementation in CF infants. J Cyst Fibros 2009; 8:382-385. [PubMed]
CF infants may be at increased risk of sodium depletion which may lead to impaired growth. The objective of this study was to evaluate their sodium supplementation requirements. Ten CF infants had serial measurements of weight and plasma/urine sodium and creatinine. Sodium supplementation was adjusted with the aim of maintaining fractional excretion (FENa) between 0.5% and 1.5% and urinary sodium > 10 mmol/L. The urine sodium:creatinine (UNa:Cr) ratio strongly correlated with FENa [UNa:Cr (mmol/mmol)=35.0 x FENa (r=0.99)]. The FENa target range corresponded to UNa:Cr 17-52 mmol/mmol. All infants required sodium supplementation to achieve UNa:Cr > 17 mmol/mmol. Sodium supplement requirements (mean+/-SD) at ages 0-3, 3-6, 6-9 and 9-12 months were 1.9+/-0.5, 1.8+/-0.8, 1.9+/-0.9 and 0.8+/-0.4 mmol/kg/d. No infant required calorie supplementation to achieve expected weight gain. The authors concluded that using current UK CF Trust and European CFS guidelines many cases of sodium depletion may be overlooked. Some infants require more than the recommended 1-2 mmol/kg/d. The UNa:Cr ratio is a useful non-invasive measure to monitor sodium supplementation.

This is a particularly useful paper as most infants are diagnosed after neonatal screening and the advice in the UK and European CF Society consensus documents suggested that routine sodium supplementation was unnecessary.