With respect to van Dommelen et al’s(1) interesting paper we would like
to make the following contribution.
Neonatal hypernatraemic dehydration screening is complicated by an
unclear but possibly rising incidence(2) and the need to avoid undermining
the ‘breast is best’ message whilst recognizing the severity of the
condition. The notoriously variable clinical presentation adds to this
dif...
With respect to van Dommelen et al’s(1) interesting paper we would like
to make the following contribution.
Neonatal hypernatraemic dehydration screening is complicated by an
unclear but possibly rising incidence(2) and the need to avoid undermining
the ‘breast is best’ message whilst recognizing the severity of the
condition. The notoriously variable clinical presentation adds to this
difficulty.
In common with many centres we have seen a number of dehydrated
babies following a period of sub-optimal feeding. A number of these babies
have had severe neurological impairment following thrombotic events
secondary to dehydration. We report four such cases, three breast feed and
one mixed breast / formula fed, who presented to our paediatric unit in
the last 5 years:
Case 1:
A healthy second child, born at term by LSCS for failure to progress,
discharged on day 4 having established breast feeding – 40 minutes every 3
-4 hours. Admitted at 11 days old with a four day history of being floppy,
quiet and one day of recognised poor feeding. Weight not checked since
discharge.
Found to have hypernatraemic dehydration (Na 190, birth wt 3.06kg
admission wt 2.2kg, 28% drop from birth weight). Her dehydration resulted
in acute renal failure requiring peritoneal dialysis and a cranial venous
sinus thrombosis with haemorrhagic venous infarction. No inter-current
infection, inborn error of metabolism, primary renal disorder or
gastrointestinal cause of fluid loss was identified. She is now 5 years
old and has asymmetric spastic quadriplegia and remote symptomatic
epilepsy.
Case 2:
First child, born at 42/40 by LSCS for cephalopelvic disproportion, birth
weight 3.84 kg, apgars 91, 105. Breast feeding was difficult and she was
admitted to NNU on day 4 clinically and biochemically dehydrated and
polycythaemic (Hb 24). Seizures commenced on day 4 and CT suggested a
haemorrhagic venous infarction secondary to sagittal sinus thrombosis.
This has resulted in remote symptomatic epilepsy secondary to a small,
deep, white matter lesion in the right frontal lobe. Her seizures have
improved markedly since receiving epilepsy surgery.
Case 3:
38/40 girl, 2nd child, ventriculomegaly on antenatal U/S, born at home,
birth wt 3.01 kg. Early twitching movements seen by midwife but felt to be
normal. Poor mixed breast / bottle feeding with only ~4oz milk/24 hours
taken in the few days prior to admission. Reviewed by a different midwife
each day & once by GP, feeding and social concerns noted.
Admitted at 7 days old peripherally shut down, hypothermic, having
apnoeic episodes, weight 2.50 kg (16.9% weight loss), polycythaemic (Hb
24), maximum Na 150. Microbiology demonstrated Group B streptococcal
septicaemia and meningitis and her PICU stay was complicated by DIC, a
sagittal sinus thrombosis and haemorrhagic venous infarct. At 4 years old
she has mild cerebral palsy affecting her lower limbs more than upper, is
visually impaired and has mild developmental delay.
Case 4:
Breast fed, term baby girl, first child of a 40 year old mother.
Discharged home one day after delivery. Seen at home by a community
midwife and poor feeding noted. Readmitted at 9 days old moribund with
severe hypernatraemic dehydration (Na 190, weight loss > 12%),
capillary refill time of 6 seconds, absent femoral pulses and unrecordable
blood pressure in the lower limbs. An echo excluded transposition but
demonstrated an IVC thrombosis. A prolonged PICU stay was complicated by
necrotic, perforated gut needing an iliostomy, seizures, acute tubular
necrosis and a cardiac arrest. Long term renal problems are anticipated
and survival is not assured.
We agree with Dr. Modi’s commentary(3) that sensitivity rather than
specificity should be the focus of a screening regime given the severity
of neurological problems that may follow severe dehydration. Any screening
guideline needs to have an evidence base whilst remaining pragmatic and
working within the resources available. The weighing policy advocated by
McKie et al(4) seems to meet these targets and in addition has been shown
not to discourage breast feeding. The intervention points for formula fed
infants are supported by data reported by MacDonald et al(5).
There is more to assessing and supporting breast feeding than merely
weighing babies. In an era of six hour discharges from maternity units and
fragmented, geographically distant families support can be compromised.
Community midwifery services are often stretched and there seems to be
value in a ‘red flag’ marker, in terms of weight loss, to identify those
mother-baby dyads that need additional support beyond that routinely
delivered.
For babies highlighted in this way it would be important to
distinguish, preferably in the community, between the hungry but healthy
baby and the quiet, unwell baby. Management could then proceed as ‘breast
is best’ for the well baby, for the dehydrated – rehydration. Telling the
two apart is the trick.
References
1. Van Dommelen P, van Wouwe JP, Breuning-Boers JM, van Buuren S,
Verkerk PH. Reference chart for relative weight change to detect
hypernatraemic dehydration. Arch Dis Child 2007; 92: 490-494.
2. Harding D, Cairns P, Gupta S et al. Why bother weighing breast fed
babies? Arch Dis Child Fetal Neonatal Ed 2001; 85: F145.
3. Modi N. Avoiding hypernatraemic dehydration in healthy term
infants. Arch Dis Child 2007;92: 474.
4. McKie A, Young D, MacDonald PD, Does monitoring newborn weight
discourage breast feeding? Arch Dis Child 2006; 91: 44-46.
5. MacDonald PD, Ross SR, Grant L, Young D. Neonatal weight loss in
breast and formula fed infants. Arch Dis Child Fetal Neonatal 2003; 88:
F472
Dr. Joe Fawke MBChB MRCPH Clinical Research Fellow & Neonatal
SpR, School of Human Development, University of Nottingham
Dr WP Whitehouse, BSc, FRCP, FRCPCH, Clinical Senior Lecturer in
Paediatric Neurology, School of Human Development, University of
Nottingham, E Floor, East Block, Queen’s Medical Centre, Nottingham NG7
2UH, UK
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2)...
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2). The
inference is that the elevation of blood lactate in septic shock may have
nothing to do with the adequacy of tissue oxygenation. As PDH is also
inactivated by a decline in energy charge, which should be accompanied by
a fall in tissue pH if indeed its stochiometric surrogate, the
inactivation might alternatively be due to a fall in tissue pH. This would
explain why augmenting PDH activity with dichloroacetate (DCA) normalized
lactate levels without influencing oxygen delivery and uptake relations
and did not appear to be of any value in managing septic patients (3).
If PDH is inhibited by a fall in energy charge and/or tissue pH
lactate could be generated and oxidative phosporylation continue if some
of the pyruvate continued to be converted into acetyl-CoA and ATP yield
even be increased by shifting substrate utilization to fatty acids. If so
a sudden fall in tissue pH might be the stimulus for sufficient a reverse
Randle effect, the increased availability of circulating free fatty acids
(FFA) inhibiting the rate of glycolysis in heart and resting skeletal
muscle. An alternative explanation might be that an excess of oxygen
promoted by the sudden inhibition of PDH generates free radicals which
induce a reverse Randle effect.
Untreated faecal peritonitis in pigs caused an increase in PCO(2)-gap
and a drop in gut intramucosal pH (pHi) (4). A blind loop of the small
intestine was constructed in this study for repeated tissue biopsies to
measure intestinal energy-related metabolites and lactate concentration.
The intestinal energy metabolism was not disturbed until the end of the
experimental period when the energy charge decreased and there was a
moderate rise in lactate concentration. This important study is
consistent with the claim (5) that ATP degradation, measured from tissue
metabolities, is a late event relative to the fall in tissue pH.
This suggests that the initial fall in tissue pH might indeed be an
active cytoprotective event induced by reversal of the direction of ATP
synthase activity, apoptosis putatively being a later product of the same
cytoprotective phenomenon (6) as previously mooted. If so the fall in pH
accompanying the subsequent degradation of ATP degradation might be the
only product of unreversed ATP hydrolysis per se if that is indeed
responsible for the fall in pH in these circumstances. Regardless of the
mechanisms involved the importance of these observations in pigs is that
measuring the intramucosal pH should increase the sensitivity and accuracy
of any measure of the magnitude of the energy charge made from ATP
degradation products be they measured by microdialysis or by NMR
spectroscopy. In other words reversible cellular dysfunction might occur
in the absence of ATP degradation.
.
The administration of epinephrine "dramatically decreased microcirculatory
blood flow...visualized in the sublingual mucosa at baseline and 0.5, 1,
and 5 mins of ventricular fibrillation, at 1 and 5 mins of precordial
compression, and at 1 and 5 mins after return of spontaneous circulation"
in rats (7) . The authors interpreted a discrease in their study of
septic shock as evidence of "impaired microcirculatory alteration" . The
reverse might be truer if a fall in pH upregulates oxidative
phosphorylation by increasing the magnitude of the protonmotive force
and/or increasing nutrient energy density by shifting consumption from
glucose to fatty acids, Opie now believeing that in the failing heart both
glucose and fatty acids might be needed for ATP resynthesis (8). The
adverse effects of fatty acids on ischemic-reperfusion injury in the
myocardium might be mediated, at least in part, by oxygen-derived free
radicals(9) whose release appears to be enhanced by inhaling oxygen.
In isolated perfused rat hearts which had undergone 30 min of total
global ischaemia followed by 30 min of reperfusion palmitate increased the
formation of free radicals (ROS) and reperfusion contracture. Furthermore
TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling,
decreased the formation of free radicals by the palmitate and improved
postischemic mechanical dysfunction (10). This can explain why
withholding oxygen or even inhaling CO in low doses can be beneficial in
these circumstances (11).
As a fall in extracellular pH impairs myocardial function (12)
raising the extracellular pH might be expected to improve myocardial
function unless the rate of ATP hydrolysis induced by the increased
workload imposed on a failing heart exceeds its capacity for ATP
resynthesis and causes a further decline in energy charge in accordance
with the Daniel Atkinson's hypothesis. Bicarboinate infusions might,
therefore, either improve myocardial performance by elevating the
extracellular pH and/or decreasing the need for coronary artery perfusion
by shifting substrate utilization to fatty acids. It might,
althernatively, make it worse by down-regulating oxidative phosphorylation
and/or inducing uncoupling by the same means and/or greatly increasing the
need for nutrient delivery. That could explain why sodium bicarbonate
infusion during resuscitation of infants at birth has an equivocal effect
upon outcome (13). Sodium bicarbonate infusions might still be of value in
reversing a chronic metabolic acidosis (14).
Knowing what was happening to the tissue pH could be a great help in
patient anagement.
References:
1. 2. Fang X, Tang W, Sun S, Huang L, Chang YT, Castillo C, Weil MH.
Comparison of buccal microcirculation between septic and hemorrhagic
shock.
Crit Care Med. 2006 Dec;34(12 Suppl):S447-S453.
2. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake
relations and lactate flux in hyperdynamic, endotoxin-treated dogs.
Am Rev Respir Dis. 1992 Feb;145(2 Pt 1):348-54.
3. Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration
in the treatment of endotoxin shock.
Circ Shock. 1990 Mar;30(3):221-8.
4. Ljungdahl M, Rasmussen I, Ronquist G, Haglund U. Intramucosal pH
and pCO(2) do not strictly correlate with intestinal energy metabolism in
experimental peritonitis. Eur Surg Res. 2000;32(3):182-90.
5. Nutrient and energy supply-dependency
Richard G Fiddian-Green (31 October 2003) eLetter re: D F Treacher and R
M Leach
ABC of oxygen: Oxygen transport1. Basic principles
BMJ 1998; 317: 1302-1306
6. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart.
Ann Thorac Surg. 2004 Apr;77(4):1376-83.
7. Fries M, Weil MH, Chang YT, Castillo C, Tang W. Microcirculation
during cardiac arrest and resuscitation. Crit Care Med. 2006 Dec;34(12
Suppl):S454-S457.
8. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE,
Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid
depletion acutely decreases cardiac work and efficiency in cardiomyopathic
heart failure.
Circulation. 2006 Nov 14;114(20):2130-7.
9. Gambert S, Vergely C, Filomenko R, Moreau D, Bettaieb A, Opie LH,
Rochette L. Adverse effects of free fatty acid associated with increased
oxidative stress in postischemic isolated rat hearts.
Mol Cell Biochem. 2006 Feb;283(1-2):147-52.
10. Durante W, Johnson FK, Johnson RA. Role of carbon monoxide in
cardiovascular function.
J Cell Mol Med. 2006 Jul-Sep;10(3):672-86.
11. Opie L. Effect of extracellular pH on function and metabolism of
isolated perfused rat heart.
Am J Physiol. 1965 Dec;209(6):1075-80.
12. Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during
resuscitation of infants at birth.
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004864.
13. Hoste EA, Colpaert K, Vanholder RC, Lameire NH, De Waele JJ, Blot
SI, Colardyn FA. Sodium bicarbonate versus THAM in ICU patients with mild
metabolic acidosis.
J Nephrol. 2005 May-Jun;18(3):303-7.
14. Kutala VK, Khan M, Mandal R, Ganesan LP, Tridandapani S, Kalai T,
Hideg K, Kuppusamy P. Attenuation of myocardial ischemia-reperfusion
injury by trimetazidine derivatives functionalized with antioxidant
properties.
J Pharmacol Exp Ther. 2006 Jun;317(3):921-8.
It is my hypothesis (1985) that the sleep-consciousness cycle is
controlled by interactions of melatonin and DHEA. (It has been
demonstrated that DHEA is involved in melatonin production and melatonin
is involved in DHEA production.) Basically, when melatonin is high, sleep
occurs, when DHEA is high, consciousness occurs. As is well known, quiet
sleep alternates with active sleep. I suggest this cycl...
It is my hypothesis (1985) that the sleep-consciousness cycle is
controlled by interactions of melatonin and DHEA. (It has been
demonstrated that DHEA is involved in melatonin production and melatonin
is involved in DHEA production.) Basically, when melatonin is high, sleep
occurs, when DHEA is high, consciousness occurs. As is well known, quiet
sleep alternates with active sleep. I suggest this cycling is designed to
maintain sufficient levels of DHEA during sleep to maintain brainstem
function during times of sufficiently low DHEA that allow sleep. When
DHEA is very low, quiet sleep occurs, when DHEA is higher, during sleep,
active sleep occurs. Prolactin is known to stimulate DHEA production.
The cycling of quiet sleep and active sleep involves the reduction of
prolactin by melatonin with prolactin rebounding in response to levels of
melatonin. The first sleep is the deepest, I suggest, due to the high
levels of melatonin at this time. As prolactin rebounds, DHEA is produced
which begins to decrease levels of melatonin as sleep progresses. This
gradual reduction of melatonin and increase in prolactin eventually
reaches a level of DHEA which induces consciousness and stops release of
melatonin until DHEA production decreases near nighttime and begins the
cycle again. The connection between melatonin and DHEA is prolactin.
Breast milk contains prolactin. I suggest prolactin occurs in breast
milk to stimulate DHEA. Therefore, prolactin in breast milk would
activate DHEA production, but not sufficient to induce arousal. This
would combine with an infant's DHEA to increase DHEA during active sleep.
It is my hypothesis that sudden infant death syndrome results from
insufficient DHEA during quiet sleep to maintain brainstem function. I
suggest the evolutionary value of prolactin in breast milk is decreased
SIDS.
The authors state that “mercury is toxic to the environment”. But is
it?
Because mercury (Hg) is what humans call an “element”, it cannot be
broken down into something simpler, and leaving aside Hg exportation
effects via human space travel and other unknowns, all of the element
mercury (Hg) that was originally here on this planet is still here, though
in a variety of forms – elemental, ionic, organic.
The authors state that “mercury is toxic to the environment”. But is
it?
Because mercury (Hg) is what humans call an “element”, it cannot be
broken down into something simpler, and leaving aside Hg exportation
effects via human space travel and other unknowns, all of the element
mercury (Hg) that was originally here on this planet is still here, though
in a variety of forms – elemental, ionic, organic.
Presumably, the planet, it’s mercury, and non-human life itself,
proceeded collectively in that which humans call “the environment”, for
millions/billions of years. There always were areas of the planet that
were unsuitable for occupation by many forms of life due to high levels of
naturally occurring mercury. In areas which humans call “mercury mines”,
Hg occurs in combination with sulphur as cinnabar, as well as in the form
which humans call “quicksilver”.
It seems likely that humans will continue to populate, and
industrialize, the entire planet. It will be increasingly difficult to
conceive of any environment other than “man’s environment”, since humans
and human influence will be everywhere. Mercury is toxic, but only to
“man’s environment”.
Retaining the mercury sphygmomanometer seems to be happening de
facto, via the endless debate about electronic device suitability, and
suggests a common sense obligation to a safer, and more consumer friendly
mercury device that has undergone some evolution from it’s unsafe,
unsealed, unlabelled, nineteenth century origins.
Wherever mercury is used in a therapeutic device, the presentation of
the device should reflect the respect for health and safety implied in
the term “health professional”. Accuracy is not the only consideration.
Neville et al reported on a randomized controlled trial of hypotonic
versus isotonic saline for rehydration of children with gastroenteritis.
They found that isotonic saline was superior with regards to correction of
hyponatraemia [1]. The majority of patients in the study received a “rapid
replacement protocol” which entailed the infusion of 40ml/kg of isotonic
saline over 4 hours in the isotonic salin...
Neville et al reported on a randomized controlled trial of hypotonic
versus isotonic saline for rehydration of children with gastroenteritis.
They found that isotonic saline was superior with regards to correction of
hyponatraemia [1]. The majority of patients in the study received a “rapid
replacement protocol” which entailed the infusion of 40ml/kg of isotonic
saline over 4 hours in the isotonic saline arm of the study.
The authors did not report on important known adverse effects associated
with rapid infusion of isotonic saline which have been reported in
previous randomized controlled trials [RCT] of volume support with
isotonic saline versus other fluids.
Rapid isotonic saline infusion predictably results in hyperchloremic
acidosis [2]. The acidosis is due to a reduction in the strong anion gap
by an excessive rise in plasma chloride as well as excessive renal
bicarbonate elimination [2]. In a randomized controlled trial with a mixed
group of patients undergoing major surgery isotonic saline infusion was
compared to Hartmann’s solution with 6% hetastarch with a balanced
electrolyte and glucose solution. Two thirds of patients in the saline
group but none in the balanced fluid group developed postoperative
hyperchloraemic metabolic acidosis [3]. The hyperchloraemic acidosis was
associated with reduced gastric mucosal perfusion on gastric tonometry.
Another double blind randomized controlled trial of isotonic saline versus
lactated Ringer’s in patients undergoing aortic reconstructive surgery
confirmed this result and the acidosis required interventions like
bicarbonate infusion and was associated with the application of more blood
products [4]. Hyperchloremia was found to have profound effects on
eicosanoid release in renal tissue leading to vasoconstriction and a
reduction of the glomerular filtration rate [5].The increased eicosanoid
release may also explain the findings of reduced gastric perfusion in
hyperchloraemia mentioned above [3]. The main adverse effect of saline
induced hyperchloraemic acidosis however may be the action which is taken
to correct the abnormality. Acidosis is often seen as a reflection of poor
organ perfusion and poor myocardial function and a negative base excess
may prompt the application of boluses of more saline containing fluids
exacerbating the acidosis, the use of blood products, escalation of
inotropic support and initiation of ventilatory support [6].
The safety of hyperchloremic acidosis has not been established in
prospective studies and in patients with different types of critical
illness. Particularly in critically ill patients with co-morbidities like
renal disease more physiological electrolyte solutions (e.g. Ringers
lactate solution) may be preferable to isotonic saline and a slow
replacement protocol safer than rapid infusions.
References:
1. Neville KA, Verge CF, Rosenberg AR, O’Meara MW, Walker JL. Isotonic is
better than hypotonic saline for intravenous rehydration of children with
gastroenteritis: a prospective randomised study. Arch Dis Child
2006;91:226-32.
2. Prough DS, Bidani A. Hyperchloremic metabolic acidosis is a
predictable consequence of intraoperative infusion of 0.9% saline.
Anesthesiology 1999;90:1247-49.
3. Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R,
Mythen MG. The effects of balanced versus saline-based hetastarch and
crystalloid solutions on acid-base and electrolyte status and gastric
mucosal perfusion in elderly surgical patients. Anesthesia and analgesia
2001;93:811-6.
4. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson
DR. Normal saline versus lactated Ringer’s solution for intraoperative
fluid management in patients undergoing abdominal aortic aneurysm repair:
an outcome study. Anesthesia and analgesia 2001;93:817-22.
5. Bullivant EMA, Wilcox CS, Welch WJ. Intrarenal vasoconstriction
during hyperchloremia: role of thromboxane. Am J Physiol 1989;256:152-7.
6. Brill SA, Stewart TR, Brundage SI, Schreiber MA. Base deficit does
not predict mortality when secondary to hyperchloremic acidosis. Shock
2002;17: 459-462.
We thank Dr Oudesluys-Murphy for her letter in
response to our article. In essence, two points were
raised.
I. Can one estimate the deficits of Na+ and water if one
applies the formula proposed by Katz [1]]?
This
calculation makes the presumption that one can predict
the change in plasma sodium concentration (PNa)
when water is drawn out of cells by hyperglycaemia.
This assumpti...
We thank Dr Oudesluys-Murphy for her letter in
response to our article. In essence, two points were
raised.
I. Can one estimate the deficits of Na+ and water if one
applies the formula proposed by Katz [1]]?
This
calculation makes the presumption that one can predict
the change in plasma sodium concentration (PNa)
when water is drawn out of cells by hyperglycaemia.
This assumption is not correct for a number of reasons
(for details, see [2]).
A. Glucose must be added as a pure solute. Glucose
will be retained in the ECF compartment (normal 10 L
in a 50-kg person with 30 L of total body water). With
the net retention of 600 mmol of glucose without water
in the ECF compartment, the PGlu will rise by close to
57 mM if we assume that glucose distribution is only in
the ECF compartment because water will shift from
cells to the ECF. In more detail, the total number of
osmoles in the body was 8550 milliosmoles (285 X 30
L) before the addition of glucose and 9150
milliosmoles after the addition of glucose (8550 + 600).
Therefore the new Posm will be 305 mOsm/kg H2O
(9150/30 L). The new ECF volume is equal to the total
ECF osmoles (2850 + 600) divided by the new
osmolality of 305 mOsm/L, or 11.3 L. Therefore 1.3 L of
water will be drawn out of cells due to the high PGlu.
Bottom line: The new PGlu is 57.5 mM, the new PNa is
124 mM, and the new ECFV is 11.3 L.
B. Addition of isosmotic glucose (285 mM) to raise the
PGlu by close to 50 mM with all the same assumptions:
No water is drawn out of or enters cells because an
iso-osmotic solution of glucose was added to the ECF
compartment and all added glucose remains in the
ECF compartment. When 2.3 L of this glucose solution
is in the ECF compartment, the new PGlu is 57 mM, the
new PNa is 114 mM because water was retained in the
ECF compartment without Na+, and the new ECF
volume is 12.3 L.
Bottom line: The new PGlu is 57 mM, the new PNa is
114 mM, and the new ECFV is 12.3 L.
Overall, because the ECF volume was expanded by
different amounts in calculations A and B above yet the
rise in the PGlu was virtually identical, there is no
constant relationship between the PGlu and the ECF
volume. Moreover, there was no change in the content
of Na in the ECF compartment in these two examples.
In contrast, patients presenting with DKA have a
contracted ECF volume and a deficit of Na+ when their
PGlu is 57 mM.
Conclusion: If you do not know what the ECF volume is
in quantitative terms, you cannot deduce the ECF Na+
content from the PGlu. Accordingly, much as we would
like to agree with the suggestion of Dr
Oudesluys-Murphy, the facts do not support that view.
C. Potassium: Part of the deficit of K+ reflects the shift
of K+ out of cells in a 1:1 relationship with a cation (Na+
and H+) of unpredictable amounts. The other major
part of K+ loss from the ICF reflects the catabolic state
(primarily a loss of K+ with organic phosphate (e.g,
from RNA)). Since both of these components are not
known with certainty, one cannot use the relationship
described by Katz [1] to help in this context.
D. Error in the assumption of Katz [1]: The volume of
distribution of glucose is larger than the ECF volume
even if there is a lack of insulin actions. Our reasoning
is that, in cells that do not require insulin for glucose
transport such as liver cells, cells of the proximal
convoluted tubule, and red blood cells, the
concentration of glucose is likely to be equal in their ICF
and ECF compartments.[3]
II. Urea should be included in calculations of effective
osmolality.
Urea is not an effective osmole across cell membranes
when the change in the plasma urea concentration
(Purea) is not abrupt.[4] Given the time course for the
fall in Purea in patients with DKA, we did not include
urea in our calculation of effective osmolality. Therefore
we believe that it is more prudent to keep the PGlu + 2
(PNa + PK) relatively constant in the first 12-18-h of
therapy. We agree that a gradual decline in the effective
Posm should occur with time thereafter.
References
(1) Katz MA. Hyperglycemia-induced hyponatremia:
Calculation of expected serum sodium depression. N
Engl J Med 1973;289:843-4.
(2) Davids MR, Lin S-H, Edoute Y, Cheema-Dhadli S,
Halperin ML. Hyponatraemia and hyperglycaemia
during laproscopic surgery. Quart J Med
2002;95:321-30.
We read with interest the letter discussing bloodless treatment of
infants with haemolytic disease [1], which highlighted the successful use of
erythropoietin and D-penicillamine. We wish to contribute to the
discussion of the use of erythropoietin
with a case report:
Mrs M (G2 P1), a Jehovah’s Witness, presented at 12 weeks with high
avidity anti-D antibodies (9.5 I.U.), and anti-JKa antib...
We read with interest the letter discussing bloodless treatment of
infants with haemolytic disease [1], which highlighted the successful use of
erythropoietin and D-penicillamine. We wish to contribute to the
discussion of the use of erythropoietin
with a case report:
Mrs M (G2 P1), a Jehovah’s Witness, presented at 12 weeks with high
avidity anti-D antibodies (9.5 I.U.), and anti-JKa antibody titres of 1
I.U. The role of blood products was discussed with the parents, who wished
to avoid their use. Other treatment options were discussed, including
iron, erythropoietin and minimal phlebotomy. The anti-D antibody level
peaked at 31 weeks at 14.1 I.U. Baby M was born in good condition at 37+5
weeks. The cord bilirubin (SBR) was high, and the Direct Coombs Test (DCT)
was strongly positive. Phototherapy was started and SBR and haemoglobin
(Hb) were monitored with capillary blood gas analysis, with formal
laboratory samples sent daily, to minimise iatrogenic blood loss.
Folic acid (100mcg od), Sytron (2ml bd) and erythropoietin (750 i.u.
subcut. three times a week) were commenced on day 5. At discharge (day 19)
the Hb reached a nadir of 8.6g/dl with no reticulocytes. By 6 weeks the Hb
was 11.8 g/dl, with a reticulocyte count of 18x 109 and the DCT was still
strongly positive. Erythropoietin was discontinued and the Hb and
reticulocyte count remained stable at 3 months.
The rate of SBR rise in the first 12 hours and high antibody titres would
have made exchange transfusion a reasonable option, although Baby M
remained asymptomatic. However adequate fluids and phototherapy
immediately after birth proved sufficient. Further blood loss was reduced
by minimal phlebotomy, and erythropoiesis maximised with folic acid, iron,
and erythropoietin acting in synergy [2].
Recombinant erythropoietin was ethically acceptable to baby M’s parents
and can reduce transfusions for isoimmune-haemolytic disease (such as ABO
[3] ) and subsequent anaemia. Elevated endogenous erythropoietin might be
expected in rhesus-haemolytic disease, with recombinant erythropoietin
providing little extra erythropoiesis. However erythropoietin levels
analysed in babies with rhesus-haemolytic disease are unexpectedly low,
with associated bone marrow suppression [4]. In this case, while on
erythropoietin, the Hb continued to rise despite a strongly positive DCT,
(still present postnatally at six weeks) and ceased rising off
erythropoietin. In addition the reticulocyte count improved markedly, and
continued to rise off erythropoietin.
A six-week course of erythropoietin costs about £350, which is
similar to transfusion costs. One unit of leucodepleted, irradiated, CMV
negative blood is £113 [5], in addition to the cost of exchange equipment.
Rising transfusion costs and limited blood product reserves make
erythropoietin more cost-effective in rhesus-haemolytic disease. In
addition erythropoietin has few side-effects, while 3% of neonates have
transfusion reactions [2].
Minimal phlebotomy is important in neonatal management to avoid blood
products. Hb and SBR are available by blood gas analysis, and requires
95mcl of blood, compared to 500mcl for serum electrolytes and SBR, and
500mcl for a full blood count. Baby M lost an estimated 24 ml of blood
for tests during his inpatient stay (10.6% of blood volume).
Throughout the antenatal and postnatal period, consistent and regular
communication with the parents maintained a good rapport, and it was
emphasised that all treatment modalities would be explored before
obtaining a specific treatment order for blood products.
We believe that these strategies helped Baby M overcome complicated
maternal antibody isoimmunization without the use of blood products, and
that recombinant erythropoietin is cost-effective, safe and could make up
for a shortfall in endogenous erythropoietin production.
References
(1). Lakatos L Bloodless treatment of infants with haemolytic disease.
Arch Dis Child 2004; 89-1076.
(2). Bader D. Kugelman A.Weinger-Abend M et al The role of high-dose oral
iron supplementation during erythropoietin therapy for anemia of
prematurity. J Perinatology. 21(4):215-20, 2001 Jun.
(3). Lakatos L. Csathy L. Nemes E. “Bloodless” treatment of a Jehovah’s
Witness infant with ABO hemolytic disease. J Perinatology 19(7); 530-2;
1999 Oct-Nov
(4). Thorp JA, O’Connor T, Callenbach J et al. Hyporegenerative anemia
associated with intrauterine transfusion in Rhesus Haemolytic disease. Am
J Obs Gynae 1991; 165(1); 79-81.
(5). Figures from Southampton University Pathology Services.
We read with great interest the article of Perez et al (1) on the
relationship of severity of meningococcal infection with anthropometrical
parameters in children. Patients with severe disease and non-survivors had
higher weight for age z scores than patients with non-severe disease. Body
mass index was significantly higher in those with severe disease.
Binder A et al (2)reported an association of the 4G...
We read with great interest the article of Perez et al (1) on the
relationship of severity of meningococcal infection with anthropometrical
parameters in children. Patients with severe disease and non-survivors had
higher weight for age z scores than patients with non-severe disease. Body
mass index was significantly higher in those with severe disease.
Binder A et al (2)reported an association of the 4G/5G plasminogen
activator inhibitor –1 (PAI-1) gene polymorphism with disseminated
intravascular coagulation in children with meningococcal disease. They
found that DIC was significantly associated with the 4G/4G genotype.
Haralambous et al investigated the association of the 4G/5G PAI-1
polymorphism and outcome in meningococcal disease (3). He found that the
4G/4G genotype was significantly associated with increased mortality.
Logistic regression indicated that the 4G/5G and the 5G/5G genotypes were
associated with a 40% and 91% reduction in the odds of dying respectively,
compared to a 4G/4G genotype.
There is also a strong association of the 4G/5G polymorphism in the PAI-1
gene with obesity. Hoffstedt J et al (4)found that in otherwise healthy
Scandinavian subjects homozygosity for 4G was more common among obese
people, whereas homozygosity for 5G was more common among lean subjects.
The relative risk for being obese was threefold higher for subjects with
the 4G/4G genotype.
These studies clearly establish the association of the 4G/4G genotype with
both the severity of meningococcal disease and obesity. This association
of 4G/4G genotype with both the severity of meningoccal disease and
obesity may explain the higher incidence of severe disease in obese
children.
Future research into the relationship of antropometric measurements and
severity of meningococcal septicemia should include investigation of 4G/5G
PAI-1 gene polymorphisms. Such research may establish whether only obese
children with the 4G/4G genotype are at an increased risk of severe
meningococcal disease.
References:
1. N Perez, L Regairaz, J Bustamante, N Osimani, D Bergna, J Morales,
M R Agosti, S Gonzalez-Ayala, C Peltzer, A Rodrigo.Severity of
meningococcal infections is related to anthropometrical parameters.
Archives of Disease in Childhood 2007;92:790-794.
2. Binder A, Endler G, Müller M, Mannhalter C, Zenz W; for the
Central European Meningococcal Genetic Study Group.4G4G genotype of the
plasminogen activator inhibitor-1 promoter polymorphism associates with
disseminated intravascular coagulation in children with systemic
meningococcemia. J Thromb Haemost. 2007 Aug 3 [Epub ahead of print].
3. Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M.
Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter
polymorphism in susceptibility, severity, and outcome of meningococcal
disease in Caucasian children. Crit Care Med. 2003 Dec;31(12):2788-93.
4. Hoffstedt J, Andersson IL, Persson L, Isaksson B, Arner P. The
common -675 4G/5G polymorphism in the plasminogen activator inhibitor -1
gene is strongly associated with obesity. Diabetologia. 2002 Apr;45(4):584
-7.
Regarding Blair et al evaluation of a paediatric ambulatory care unit
published on line 12 March 2008.
This paper concludes that PACU model is an effective alternative to A&E
services, suggesting that it could work in isolation, so that the
emergency department would be relieved of seeing children.
This is not the case, as PACUs need to be associated with an
emergency department (ED), eithe...
Regarding Blair et al evaluation of a paediatric ambulatory care unit
published on line 12 March 2008.
This paper concludes that PACU model is an effective alternative to A&E
services, suggesting that it could work in isolation, so that the
emergency department would be relieved of seeing children.
This is not the case, as PACUs need to be associated with an
emergency department (ED), either on the same site or in a near by large
hospital; PACUs when ward based, have problems of immediate access and are
rarely designed to receive and manage ambulance admissions. The PACU
described in the survey conducted by Blair et al found this in their own
setting, with only 76% of parents saying access was easy compared with 95%
in the emergency cohort.
Another major difference between a PACU and an ED is the availability
of people trained and skilled at triage and re-triage, i.e. being able to
prioritise large numbers of patients safely.
It is less of a problem when the doctors are able to see and treat
patients immediately when the numbers are small.
The numbers of patients seen on the PACU during the study period was 4,190
annually, the emergency department at the hospital in the study sees 25
000 children per year.
There is no mention of any resuscitation facilities in the ambulatory
setting, or mention of any resuscitation of critical ill patients in the
paper, a concerning omission.
Worryingly, there is no mention of critical incidents or adverse outcomes
in the two units over the same period.
A major limitation of this study is that the data on emergency
patients were collected at night time and the data on PACU patients were
collected from the day. This is a fatal flaw in the study.
The major advantages of the PACU in the study appeared to be a child
friendly environment and paediatric trained staff. It is important to note
that the comparison in this setting was between a PACU and an emergency
department without a separate paediatric area; this has since changed at
the hospital involved in the study, and paediatric emergency medicine is
developing in this context.
The advantages described in this paper of the PACU, in the assessment
of acutely ill children, could be achieved by the creation of a paediatric
ED. This allows the child centred approach to be applied to all attending
paediatric patients, including ill and injured children of all types.
A paediatric ED provides a system with robust triage, resuscitation
facilities and easy access.
The Trust where this study was conducted has realised this and have
since opened a paediatric emergency department which has an integrated
PACU which is functioning well and has taken over the PACU cohort of
patients. The unit described in the paper is now closed.
The paediatric ED now can triage patients (and, if required,
resuscitate them) to a PACU/observation unit when indicated, so avoiding
unwarranted admissions.
The creation of PACUs is not to be perceived as an alternative to
paediatric emergency departments, rather it adds another resource in
providing optimal management of unwell children.
Gammelgaard et al have to be commended for their study which attempts
to throw light on some of the complex issues, ethical and otherwise,
surrounding parental attitudes towards research in children.(1) While
agreeing broadly with the authors' conclusions regarding the feasibility
of setting up a research project which conforms to parental perceptions,
we would like to stress the need for viewing this i...
Gammelgaard et al have to be commended for their study which attempts
to throw light on some of the complex issues, ethical and otherwise,
surrounding parental attitudes towards research in children.(1) While
agreeing broadly with the authors' conclusions regarding the feasibility
of setting up a research project which conforms to parental perceptions,
we would like to stress the need for viewing this in a wider perspective.
The COPSAC study involves follow up of infants who are healthy at the
outset, with a view to early identification of asthma and related allergic
disorders, which are relatively common and usually not life threatening in
the general paediatric population. All the mothers involved had suffered
from similar conditions, thus equipping them with a unique insight into
the disease, as well as a possible 'motive' to allow even invasive testing
for early diagnosis in their children. In contrast, many paediatric
research studies involve children newly diagnosed with severe and often
fatal conditions such as malignancies and immunodeficiencies. Another
major area of research in children is the evaluation of newer therapies by
randomised trials. It is questionable whether parents faced with such
situations can be compared with their counterparts in the COPSAC study.
It may be noted that the 'parent' in this study was almost always the
mother. This possibly is based on the premise that it is more difficult to
recruit fathers and that the mother's opinion on research is
representative. However, previous workers have demonstrated the fallacy
associated with both these assumptions.(2) An ideal study trying to
address parental perceptions on research should hence aim to recruit
comparable proportions of both mothers and fathers across a range of
sociocultural backgrounds.
The 'motivation' of mothers as recorded in this study is based on the
cumulative experiences over a couple of years since the start of the
study. Whether this is consistent with actual feelings and true
motivations at the point of inception of the study is not clear. This
assumes obvious importance when applied to parents approached with consent
for a research study soon after the disclosure of a serious and possibly
lethal diagnosis. The emotional trauma inherent in such situations makes
the dynamics of parental participation in the consenting process
significantly different from the simplistic model of COPSAC study.(3)
It is obvious that parental outlooks are affected by a diverse set of
variables and hence cannot be predicted from such a study with limited
sample size confined to mothers who also had suffered from the same
condition. Recent studies have highlighted issues like parental worries
about possible financial tie-ups between physicians and pharmaceutical
companies.(4) It is also worth pointing out that parents have been known
to give consent for studies involving significant potential risks with no
obvious benefit to their children, when placed in a vulnerable
position.(5)
The authors have rightly concluded that it is possible to implement
invasive research studies on children while achieving an accepable level
of parental satisfaction. However, caution must be applied when
extrapolating this conclusion to all types of paediatric research. The
importance of realising the individualistic nature of each research study
and the variety of factors influencing parental opinion cannot be over-
emphasised.
References:
(1) Gammelgaard A, Knudsen LE, Bisgaard H. Perceptions of parents on
the participation of their infants in clinical research. Arch Dis Child
2006; 91 : 977-980.
(2) Woollett A., White DG, Lyon ML. Studies involving fathers:
Subject refusal, attrition and sampling bias. Current Psychological
Reviews 1982; 2 : 193-212.
(3) Deatrick JA, Angst DB, Moore C. Parents' views of their
children's participation in phase I oncology clinical trials. J Pediatr
Oncol Nurs 2002; 19(4) : 114-121.
(4) Hampson LA, Agrawal M, Joffe S, Gross CP, Verter J, Emanuel EJ.
Patients' views on financial conflicts of interest in cancer research
trials. N Engl J Med 2006; 355(22) : 2330-2337.
(5) Singhal N, Oberle K, Burgess E, Huber-Okrainec J. Parents'
perceptions of research with newborns. J Perinatol 2002; 22 : 57-63.
Dear Editor,
With respect to van Dommelen et al’s(1) interesting paper we would like to make the following contribution.
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Dear Editor,
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Dear Editor
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The authors state that “mercury is toxic to the environment”. But is it?
Because mercury (Hg) is what humans call an “element”, it cannot be broken down into something simpler, and leaving aside Hg exportation effects via human space travel and other unknowns, all of the element mercury (Hg) that was originally here on this planet is still here, though in a variety of forms – elemental, ionic, organic.
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Dear Editor,
Neville et al reported on a randomized controlled trial of hypotonic versus isotonic saline for rehydration of children with gastroenteritis. They found that isotonic saline was superior with regards to correction of hyponatraemia [1]. The majority of patients in the study received a “rapid replacement protocol” which entailed the infusion of 40ml/kg of isotonic saline over 4 hours in the isotonic salin...
Dear Editor
We thank Dr Oudesluys-Murphy for her letter in response to our article. In essence, two points were raised.
I. Can one estimate the deficits of Na+ and water if one applies the formula proposed by Katz [1]]?
This calculation makes the presumption that one can predict the change in plasma sodium concentration (PNa) when water is drawn out of cells by hyperglycaemia. This assumpti...
Dear Editor,
We read with interest the letter discussing bloodless treatment of infants with haemolytic disease [1], which highlighted the successful use of erythropoietin and D-penicillamine. We wish to contribute to the discussion of the use of erythropoietin with a case report:
Mrs M (G2 P1), a Jehovah’s Witness, presented at 12 weeks with high avidity anti-D antibodies (9.5 I.U.), and anti-JKa antib...
Dear Editor,
We read with great interest the article of Perez et al (1) on the relationship of severity of meningococcal infection with anthropometrical parameters in children. Patients with severe disease and non-survivors had higher weight for age z scores than patients with non-severe disease. Body mass index was significantly higher in those with severe disease. Binder A et al (2)reported an association of the 4G...
Dear Sir
Regarding Blair et al evaluation of a paediatric ambulatory care unit published on line 12 March 2008. This paper concludes that PACU model is an effective alternative to A&E services, suggesting that it could work in isolation, so that the emergency department would be relieved of seeing children.
This is not the case, as PACUs need to be associated with an emergency department (ED), eithe...
Dear Editor,
Gammelgaard et al have to be commended for their study which attempts to throw light on some of the complex issues, ethical and otherwise, surrounding parental attitudes towards research in children.(1) While agreeing broadly with the authors' conclusions regarding the feasibility of setting up a research project which conforms to parental perceptions, we would like to stress the need for viewing this i...
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