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Management of the severely malnourished child: perspective from developing countries

BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7381.146 (Published 18 January 2003) Cite this as: BMJ 2003;326:146

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Hypophosphataemia and the feeding of malnourished children

The hypothesis that hypophosphataemia causes a depletion in energy
rich phosphates in malnourished children cannot be sustained (1,2).

In the burns literature hypophosphataemia is common and has been
comprehensively investigated. The nadir appears on the second to fifth
days after the burn injury (3,4). Its appearance does not correlate with
measurable changes in body phosphate balance even though there are a
number of changes that may increase phosphate losses in urine. This is not
surprising for energy rich phosphates make up a small part of total body
phosphate which is mostly within bone. Furthermore ATP hydrolysis
generates the Pi it needs for replenishing ATP stores by resynthesis by
oxidative phosphorylation.

The development of hypophosphataemia in previously well nourished
burns patients coincides with the completion of fluid resuscitation and
the commencement of nutritional support. It is accompanied by a rise in
intracellular stores of Pi, ATP and Glucose-6-phosphate. It is believed
to be the result of insulin released in response to the nutrients and its
effect upon glucose influx into cells and hence upon the rate of ATP
resynthesis. (ATP synthesis is driven by the protonmotive force created
by the pH gradient across the mitochondrial membrane and is triggered by
and depends upon the availability of ADP, Pi and protons within the
cytosol). The hypophosphataemia would appear, therefore, to be the
consequence of a shift from extracellular to intracellular fluids induced
by nutrients.

As observed in the electronic response to this article, the
hypophosphataemia in malnourished patients is rarely apparent until
feeding is commenced (2). There is no evidence I can find to suggest that
hypophosphataemia per se causes organ dysfunctions or failures in the
absence of enteral or intravenous nutrition. Moreover it is well
established that feeding has to be introduced slowly to malnourished
patients if complications are to be avoided. If enteral feeding is
commenced prematurely, as in often the case in premature infants, or is
given too rapidly, as may occur in burns patients, diarrhoea and on
occasions even intestinal necrosis may be induced.

The release of energy by ATP hydrolysis is demand driven. That is to
say it is initiated by the need to replenish ATP stores used to perform
some form of metabolic activity. In the case of feeding it will be the
absorption and/or metabolism of the nutrients. If, however, the ability to
replenish ATP stores in a timely manner is compromised then those
enzymatic processes that consume ATP are down regulated and those that
replenish ATP stores are up-regulated (5). The net effect is to compromise
those metabolic processes which ATP supports and prime ATP re-synthesis
by oxidative phosphorylation to use the oxygen and/or nutrient efficiently
when it becomes available.

The ability to replenish ATP stores in a timely manner is most
commonly compromised by hypovolaemia, occlusive vascular diseases and what
now appears to be an uncoupling of oxidative phopshorylation caused by the
release of cytokines, notably TNF alpha. The uncoupling appears to be the
result of an inappropriate opening of the permeability transition pores on
the mitochondrial membrane.
The effects of the cytokines may persist long after hypovolaemia has been
reversed. This is important for the intramucosal pH may fall to
abnormally low levels, indicative of tissue dysoxia, when the demand for
energy from ATP hydrolysis exceeds the capacity for replenishment in a
timely manner by ATP resynthesis by oxidative phosphorylation (6). Not
only may this impair nutrient digestion and absorption but if severe
and/or prolonged may cause mucosal injury and even transmural necrosis
(7,8).

By promoting the generation of free radicals, the translocation of
toxins and further cytokine release (9) this may induce or compound the
severity of the uncoupled oxidative phosphorylation. Malnourished
children will have a gut mucosal barrier impaired not only by their
malnutrition but also by the intestinal parasites and recurrent bouts of
diarrhoea to which they are often exposed. Malnourished children may,
therefore, be far more likely to develop uncoupling of their mitochondrial
oxidative phosphorylation than a patient who was well nourished before
sustaining burn injuries. Malnourished children are, therefore, more
likely to develop an inadequacy of oxidative phosphorylation in gut mucosa
when feeding is instituted. The same mechanisms are almost certainly
operative in the pathogenesis of necrotising entrocolitis.

In summary hypophosphataemia is not usually the product of body
phosphate depletion per se. It is most commonly seen after the
commencement of enteral or intravenous feeding and appears to be the
result of accelerated demand for cytosolic Pi. This is in turn caused by
an accelerated demand for ATP resynthesis induced by the need to meet the
sudden demand for metabolic energy from ATP hydrolysis imposed by the
exposure to nutrients. This may cause an energy deficit or failure to
replenish ATP stores ina timely manner.

Early clinical signs of an impairment of mitochondrial oxidative
phosphorylation in the gut might include anorexia, oesophageal reflux,
dysphagia and diarrhoea. Late signs include blood-stained stools, sepsis,
and peritonitis. In the majority of cases, however, the effects are
manifest as remote organ dysfunctions and failures and ultimately
nosocomial infections from gut organisms. In many cases if not the
majority of cases the organ dysfunctions develop without conventional
clinical evidence of antecedent gut involvement (10,11).

1. Maharaj K Bhan, Nita Bhandari, and Rajiv Bahl Management of the
severely malnourished child: perspective from developing countries BMJ
2003; 326: 146-151

2. Hypophosphataemia in children with protein-energy malnutrition Jose C
Cabrera-Abreu, et al. bmj.com, 31 Jan 2003

3. Ozingo DW, Mason AD Jr. Hypophosphatemia. In: Total burn Care. Herndon
D, Ed. WB Saunders, London, 2002. Chapter 24, pp 309-315

4. Saffle JR, Hildreth M. Metabolic support of the burned patient. In:
Total burn Care. Herndon D, Ed. WB Saunders, London, 2002. Chapter 20, pp
271-287.

5. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003

6. Fiddian-Green RG, Stanley JC, Nostrant T, Phillips D. Chronic gastric
ischemia. A cause of abdominal pain or bleeding identified from the
presence of gastric mucosal acidosis.
J Cardiovasc Surg (Torino). 1989 Sep-Oct;30(5):852-9.

7. Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler
M, Wheeler HB, Baker S. Prediction of the development of sigmoid ischemia
on the day of aortic operations. Indirect measurements of intramural pH in
the colon.
Arch Surg. 1986 Jun;121(6):654-60.

8. Schiedler MG, Cutler BS, Fiddian-Green RG. Sigmoid intramural pH for
prediction of ischemic colitis during aortic surgery. A comparison with
risk factors and inferior mesenteric artery stump pressures. Arch Surg.
1987 Aug;122(8):881-6.

9. Nielsen VG, Tan S, Baird MS, McCammon AT, Parks DA. Gastric
intramucosal pH and multiple organ injury: impact of ischemia-reperfusion
and xanthine oxidase.
Crit Care Med. 1996 Aug;24(8):1339-44.

10. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid
-base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.

11. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.

Competing interests:  
None declared

Competing interests: No competing interests

04 February 2003
Richard G Fiddian-Green
None
None