In: Magnes Res 1991 Sep-Dec;4(3-4):137-52
Magnesium and thermoregulation. I. Newborn and infant. Is
sudden infant death syndrome a magnesium-dependent disease of the
transition from chemical to physical thermoregulation?
J. Durlach1, V. Durlach2, Y.
Rayssiguier3, D. Ricquier4, M.
Goubern5, R. Bertin5, M. Bara6,
A. Guiet-Bara6, G. Olive, R7.
Mettey8
1SDRM, Hôpital St. Vincent-de-Paul, Paris,
France; 2Clinique Médicale U52, Reims, France;
3Laboratoire des Maladies Métaboliques, INRA
Theix, France; 4CNRS UPR 1511, Meudon-Bellevue,
France; 5Adaptation Energétique à
l'Environment, EPHE, Paris, France; 6Laboratoire de
Biologie de la Reproduction, Université P. M. Curie,
Paris, France; 7Hôpital St. Vincent-de-Paul,
Paris, France; 8Hôpital de Poitiers, Serv. de
Réanimation Néo Natale, Poitiers, France
Summary:The sudden infant death
syndrome (SIDS) remains a leading cause of death during the first
year. The common epidemiological and pathological data which
characterize SIDS include the curve for age at death (with 3
months as modal age), the stigmata of early maternal intrauterine
injury, the seasonal predominance in winter, and the absence of
an adequate cause of death at autopsy. Some data characterize
risk factor subgroups: for example low socioeconomic level,
environmental pollution, stress, and mistakes in baby care.
Symptoms before death may be lacking, they may be common and
non-specific, or rarely they may be acute, corresponding to
apparent life-threatening events (ALTE). SIDS may be a
magnesium-dependent disease of the transition from chemical to
physical thermoregulation. This theory originates from a
synthesis of our present knowledge of SIDS, maternal magnesium
status, and thermoregulation in the baby. It is consistent with
all the epidemiological and pathological prerequisites
characterizing SIDS. It eliminates the hiatus between relatively
minor thermal stress and induced lethal thermal stroke. Logical
scepticism about the role of an implausible lethal superacute
magnesium deficiency is no longer justified with regard to well
established chronic marginal magnesium deficiency. Further
experimental and clinical research will be interesting,
i.e. ex vivo studies on brown adipose tissue
(BAT) and magnesium deficiency under various conditions of
thermal exposure. But even now the theory leads to three
therapeutic consequences: (1) the need to define the importance
of magnesium deficiency in diagnosis and treatment of ALTE; (2)
an assessment of the use of new techniques of rewarming
(i.e. extracorporeal circulation) in hypothermia cases
to distinguish cot death from "apparent death"; (3) investigation
of the prevention of SIDS with magnesium through a blinded and
randomized multicentre prospective cooperative study of magnesium
supplementation in pregnant and lactating women, followed not
only in the mother, fetus, and neonate at birth, but also through
the first year of life.
Key words: Apparent
life-threatening events, brown adipose tissue, cold stress, cot
death, heat stroke, magnesium, near-miss sudden infant death
syndrome, sudden infant death syndrome, thermal regulation,
uncoupling protein.
Introduction
The sudden infant death syndrome (SIDS) has been defined since
1970 as the "the sudden death of any infant which is unexpected
by history and in which a thorough postmortem examination fails
to demonstrate an adequate cause of death"4. SIDS or
cot death (crib death) remains a leading cause of infant death
(rate of occurrence between 1.5 and 3 per 1000 live births) and
has generated hundreds of hypothesis. But any viable hypothesis
for the cause of SIDS must take into account its unique
epidemiological features and autopsy findings2-5.
The purpose of this study was:
(1) To delineate the epidemiological and pathological data,
distinguishing between common characteristics concerning the
whole SIDS population and particular data concerning subgroups of
SIDS.
(2) To stress the points which indicate that hypothermia,
hyperthermia, and magnesium deficit may be causes of SIDS.
(3) To suggest, after a study on the relationship between
magnesium and thermoregulation, a new hypothesis on SIDS in
agreement with all these prerequisites. SIDS could be a
magnesium-dependent disease of the transition from chemical to
physical thermoregulation.
(4) To work out further experimental and clinical research
including: a SIDS prevention cooperative study on maternal
physiological magnesium supplementation, a very cautious approach
to the difficult diagnosis of death in hypothermic forms of SIDS,
and lastly the evaluation and control of the magnesium
disturbances in "near-miss SIDS".
Epidemiological and pathological data
Common epidemiological data on SIDS
In all cases of SIDS there is concern with certain
epidemiological data on the characteristics of the death, on the
possibility of intrauterine injury, and on seasonal
factors2-8.
Characteristics of the death
The infants die quickly and silently during their sleep. Death is
also unexpected: at the usual feeding time, the baby is
discovered dead in his cot. But if death occurs during sleep,
there is no significant difference in the time of its occurrence
between 20.00 and 08.00 or 08.00 and 20.00
hours2-10.
The curve for age at death among SIDS victims is unique. In
comparison with the curves for 21 other known causes of infant
mortality, the curve for cot death babies appears significantly
different. This curve is independent from other risk factors
including race, gender, birth weight, seasonality, maternal age,
and month of gestation. Although the aetiology of cot death may
be multifactorial, there is probably an underlying mechanism
related to growth and development in the majority of cases which
makes these particular infants highly susceptible between the
ages of 2 and 4 months, with 3 months as modal
age2-11. The incidence decreases until the age of 6
months and the disease becomes exceptional during the second
semester of life2-11. On the other hand, some SIDS
deaths occur among newborns and comprise as much as 10% of all
neonatal mortality. Neonates present a probably small but
significant segment of the total SIDS population. By the design
of studies, these early neonatal SIDS deaths have been ignored
until now7,12.
Intrauterine injury
Higher incidence rates for SIDS have been observed in infants of
diminished birth weight. Several recent analytical studies, for
example the NICHD cooperative study13, controlling a
variety of potential confounders of birth size, have estimated
the likelihood of SIDS deaths in relation to the four variables
of birth size: birth weight, birth length, head circumference,
and gestational age. SIDS may be closely associated with
symmetrical intrauterine growth retardation because of
reduction in both birth weight and length even after controlling
gestational age and sex of the infant. This suggests that
mechanisms responsible for growth retardation in this situation
begin early in pregnancy. Post-term infants were at lower
risk13-15. The notion of early intrauterine injury as
playing some part in the genesis of SIDS relies also on subtle
morphological differences between SIDS necropsies and controls.
Minor adverse influences during intrauterine development produce
some dysplastic and dysmorphic lesions. The difference between
the numbers of flaws or minor anomalies in SIDS and controls is
impressive. This is another piece of evidence for the emerging
concept ascribing a role in SIDS genesis to difficulties arising
before birth7,16,17. The nature of this intrauterine
risk is speculative. Although the risk of SIDS recurrence in
families is greater than for all children, i.e. 1 in 100
instead of 1 in 500, these infants still have a 99% chance of not
having SIDS. Heritability is not a major factor. The role of
constitutional factors appears of very little
importance3-5,7,8,18. Among the environmental factors,
various pollutants such as maternal smoking in particular and
alcoholism--both factors leading to Pb and Cd exposure--or high
altitude exposure are not commonly found in all SIDS
cases3-5,8,9,19,25. An early and permanent nutritional
factor appears as the most probable hypothesis.
Seasonal factors
All the epidemiological studies on SIDS show that it occurs
predominantly in the winter months. This seasonal factor is
observed in all cases of infantile mortality but not during the
neonatal period. Common respiratory infections are only
represented in about 50% of cases. The seasonal variation of SIDS
is thought to be linked to low temperature, either indirectly
through an increased frequency of infections or directly through
cold stress9-10,26-28.
Common pathological data in SIDS
The single most important finding in the extensive
pathological studies of SIDS remains the absence of an
adequate cause of death at autopsy6,7.
Epidemiological and pathological data peculiar to subgroups
of SIDS
Besides the common characteristics concerning the whole SIDS
population, some features are peculiar to certain subgroups of
SIDS. These are environmental risk factors, symptoms before
death, and post-mortem features. Environmental risk factors are
mainly socioeconomic factors, pollutants, and climatic and local
factors.
Socioeconomic factors
SIDS is more common in the offspring of families of low
socioeconomic status. So called racial susceptibility to SIDS, as
well as low maternal age, could be imputed to these socioeconomic
disadvantages as well to related cultural
factors2-5,7-9.
Environmental pollutants
From epidemiological data, both environmental and social risk
factors are known, but the combination of risk indicators suggest
that exposure to pollution may be important9,21,29.
Among the environmental factors that may participate in
intrauterine growth retardation, we have pointed out the
deleterious influence of maternal smoking which induces passive
cigarette smoking for the baby
postnatally3,9,19,22,25,30. Smoking causes carbon
monoxide pollution31,32 and Cd exposure20.
Alcohol addiction induces its own toxicity9,24 and is
a possible factor in lead exposure9,20,21,23,33.
Maternal substance abuse--and opioid addiction
particularly--increases the risk of SIDS. Moreover endogenous
opiates have been involved in SIDS, but there are also links
between narcotic abuse and socioeconomic
features9,24,32,34-42. Several iatrogenic factors may
be considered, phenothiazines in
particular5,9,42,43.
Climatic and local data
Apart from seasonal influences, some clinical features may
intervene in the genesis of SIDS. Increased altitude predisposes
an infant to SIDS. In the same populations post-neonatal deaths
from all other causes combined were found to decrease with
increasing altitude. Perhaps this is due to in utero
hypoxia, which is capable of inducing an early intrauterine
insult related to SIDS but which does not result in increased
mortality in general44. Ambient temperature may be a
factor either of cold or heat stress. But this climatic factor
seems hierarchically less important than infant care practices in
relation to thermoregulation in babies. An example of this is low
incidence of SIDS in Hong Kong45 which has a hot humid
climate but where most infants sleep supine. This has tended to
confirm the suggestion that the prone position may be an
important risk factor46-48, infants sleeping in
procubitus being more likely to become hyperthermic than those
sleeping in the supine position, other thermoregulation factors
being equal. Overheating and the prone position are independently
associated with an increased risk of SIDS. Heat loss can occur by
convection, radiation, evaporation and
conduction27,83-87. Particular cultural combinations
of infant care practices (sleeping position, clothing, bedding
and room heating) may facilitate a thermal stress in the
aetiology of SIDS. Procubitus, overwrapping, excessive clothing,
and sometimes an unusually warm environment, possibly combined
with mild infection or overlying, could produce heat stroke and
hyperthermic SIDS49-57. Conversely underwrapping,
insufficient clothing, cold environment , or chilly air coming
through an open window could induce cold stroke and hypothermic
SIDS26-28,58-61.
Symptoms before death
From 25 to 50% of SIDS cases are unexpected: no premonitory
symptoms are observed before sudden death. But in 50 to 75% of
cases symptomatology may be present during the days or hours
which precede death. Common symptoms include poor feeding,
irritability, drowsiness, sudden onset of rapid and noisy
breathing, hypothermia or hyperthermia, signs of minimal
respiratory or digestive infections, periodic episodes of pallor
or cyanosis, and excessive sweating which may appear to be the
result of dysautonomic symptoms due to either sympathic or
parasympathic hyperactivity. It seems impossible to consider the
onset of these non-specific and common symptoms as "sinister
symptoms" announcing near sudden death. They may be observed in a
minority of cases (around 30%) in conditions of
stress9,25,62-65. In a very small number of cases, the
symptoms observed before death include acute symptoms which were
so severe that the concept of "near-miss SIDS" was originated to
describe those infants who had been resuscitated. The reason for
including the near-miss cases in the SIDS group are insufficient.
Though the main epidemiological data are common to both groups,
and though subsequent occurrence of sudden death occurs in some
of these infants, the trend is comparatively weak (0.6-4% of
cases); that is to say the risk for SIDS is approximately seven
times higher than for other infants. Near-miss SIDS infants
constitute a mixed population with apparently life-threatening
events (ALTE), among which only a few have a truly unexplained
episode of near death. The label "near-miss" is most of the time
the consequence of a judgment made by anxious parents. Since
cardiac death through ventricular fibrillation is practically
instantaneous, it is far more likely that a mother will observe
her child dying of a respiratory than of a cardiac death. This
will allow her to intervene and to save the infant, creating a
new near-miss. ALTE represent a subgroup at a somewhat higher
risk for SIDS which may provide highly relevant information as to
the role of respiratory abnormalities in the genesis of SIDS
(apnoea theory), but this group may also constitute a source of
quite misleading information if data are uncritically
extrapolated to the entire SIDS
problem3-6,9,25,65,66.
Postmortem features
If the SIDS victim is observed in the room where the death
occurred, it is important, before the body is examined, to note
environmental factors and the types of infant care practices:
ambient temperature, bedding, clothing and sleeping position.
In all cases, before necropsy, inspection shows
pallor--sometimes with an erythematous face--or cyanosis. Weight,
length and head circumference may show growth retardation. It is
of great importance to assess the cooling of the body by taking
deep rectal temperature, taking account of the postmortem delay.
This evaluation is complicated by the fact that body weight,
clothing and ambient temperature must be taken into account, but
it allows discrimination to be made between hypothermia or
hyperthermia at the moment of the death. If delay after death is
less than a day it is possible to take samples for microscopical,
bacteriological or virological and biochemical
studies2,6,7,68-71. There are classically three main
morphological features of the SIDS necropsy: pulmonary
congestion, pulmonary oedema, and thoracic petechiae which
resemble those found in experimental anaphylactic shock. In a
complicated double-blind procedure, a group of three pathologists
established that the two pulmonary characteristics were not
helpful discriminators between SIDS cases and "dead controls".
But thymic petechiae were noted in 52% of cases of cot death. The
long-held notion that thoracic petechiae are distinctive, unique,
and a singular feature of SIDS is only true for about half of cot
death victims, but the other half does not have thymic
petechiae7. To support the "apnoea hypothesis", seven
so called markers of chronic hypoxia have been
described2,68,69 but some of them have not been
confirmed and the others, i.e. brown fat alterations or
brain stem gliosis, may be present for reasons other than
hypoxaemia7. Each SIDS theory emphasizes particular
pathological features which in practice are observed in subgroups
of SIDS. The main observations involve the nervous, respiratory,
cardiac and endocrine systems. Special attention to the brain
stem, hypothalamus, and central and peripheral autonomic nervous
apparatus shows subtle maturational abnormalities. In the
respiratory tract, where minor infection is common, surfactant
may [be] altered. In the myocardium the presence or absence of
abnormalities in the cardiac conduction system have been
reported, as well as in the vascular apparatus (either hypoplasia
or hyperplasia of the glomic tissue in the carotid body) In the
endocrine system increased chromaffin tissue in the adrenal
medulla or Langerhans islet cell hyperplasia of the pancreas may
be observed2,6,7,32,68-73. All these data,
complemented by cautious extrapolation from in vivo
observation of polygraphic and cardiopneumographic patterns in
ALTE, point to two mechanisms of death: respiratory and cardiac.
Through immaturity of the brain stem and possibly an associated
obstructive factor, sudden prolonged spontaneous apnoea induces
hypoxia. SIDS infants then succumb to a more prolonged
irreversible apnoea. Heart rate abnormalities and QT prolongation
measured with Holter recordings may precede instantaneous and
silent death by ventricular fibrillation. Hypotheses of
developmental or dysautonomic abnormalities (either sympathic or
vagal hyperactivity) have been presented, but strangely enough
nothing has been found concerning various electrolytic imbalances
which, however, are well-established causes for these
arrhythmias2,6,7,32,65,68-79.
Dysthermias and magnesium deficiency theories
Among the hypotheses of causes of SIDS it seems important to
group together hypothermic and hyperthermic forms as
"dysthermic", and to reassess what evidence may support the
neglected theory of magnesium deficiency.
Dysthermias and SIDS
The epidemiological and clinical datas which stress the
importance of dysthermic forms of SIDS have been highlighted
above. It seems that postmortem hyperthermias are more frequent
than hypothermic forms80. The curve for age at death
among SIDS cases might be correlated with the time of conversion
from chemical to physical thermogenesis81,82.
Paradoxically, early studies on brown fat in SIDS dealt with
their relationship with hypoxia81,83 or with
dysautonomia84. It seems more logical to consider
their key role in thermal dysregulation. Brown adipose tissue
(BAT) is highly specialized for heat production, its mitochondria
showing a variable degree of uncoupled oxidative phosphorylation
dependent on a 32 Kd mitochondrial protein (UCP). Human UCP gene
is now isolated and is assigned to chromosome 4 in q 31. The
gradual depletion of BAT starts just after the inevitable
exposure to cold at birth and continues during the first year.
Thus its disappearance correlated well with the time of
conversion from chemical to physical thermogenesis. Intrauterine
growth retardation in a premature infant decreases BAT, UCP and
the ability to regulate body temperature when exposed to cold.
BAT heat production is sympathetically regulated by a complex
neurohormonal control system, involving hypothalamus, thyroid,
and adrenal glands. SIDS dysthermias may be the result of an
impaired control of BAT thermoregulatory mechanisms leading to a
modified temperature set-point85.
A few interesting studies on the morphological and chemical
alterations of BAT in SIDS allow us to propose that hypothermic
forms may be induced by functional failure of BAT and
hyperthermic forms by inappropriate functional excess of chemical
thermogenesis. Although immaturity91 or fat
retention2,7,83,92 may appear as stigmata of
hypofunction, fat depletion may correspond either to an
insufficient supply inducing hypothermia or to inappropriate
lipolysis inducing hyperthermia28,93-95. BAT may be
particularly vulnerable to infarction on account of its high
metabolic activity and rich capillary plexus96. Brown
fat also appears to be a favoured substrate for various virus
infections97,99 and a target for maternal
alcoholism98 and maternal magnesium
deficiency99. Thus the hiatus between the factors of
chilling or warming and lethal outcome from cold or heat stroke
could be due to a previous disorder of thermal regulation, and
primarily to a functional alteration of BAT.
Animal experimentation had shown that heat stroke of the same
degree induces sudden death among kittens aged four weeks or less
and only hyperthermia among older kittens100. It is
suggested that hyperthermic SIDS and febrile convulsions may be
equivalent responses to a particular level of heat stress
according to age. Most cot deaths occur before 6 months age and
febrile convulsions after that age101. The dysthermic
theory of SIDS agrees with the conflicting data on the
beneficial102 or deleterious74 influence of
active sleep (or REM sleep) on the aetiopathogenesis of SIDS.
During active sleep, there is an increase in factors which oppose
the development of hyperpyrexia. Thus REM sleep can protect
against the hyperpyretic form of SIDS and be noxious in the case
of the hypothermic form103.
Magnesium deficiency and SIDS
For about 20 years Caddell has been accumulating evidence on
the aetiopathogenic role of acute magnesium deficiency in
SIDS104-110. Acute experimental and clinical magnesium
deficiency may induce a pattern of pseudo-anaphylactic shock. The
clinical and pathological anatomical characteristics are those of
vagal shock and seem analogous to lesions observed in SIDS,
especially those relating to the respiratory and cardiac
apparatus. It is interesting to note that the usual absence of
any allergen, which is the traditional argument against an
immunologic theory, loses its value when it is no longer a
question of a true anaphylactic shock but rather of a
pseudoallergic anaphylactoid shock due to magnesium deficit, such
as can be observed in anaesthesiology or in certain cases of
sudden death in adults111. The high metabolism of
early baby growth can increase magnesium needs. The lower the
weight and age of the animal at the onset of magnesium deficiency
the shorter the life and the more abrupt the death105.
Clinically neonatal and postneonatal hypomagnesaemia is
frequent112 and the parenteral magnesium retention
test shows that more than 50% of infants and postpartum women at
risk have increased retention. A retrospective study of magnesium
therapy in 200 premature neonates with apnoea neonatorum seems to
indicate that magnesium supplementation is associated with a
reduction in respiratory problems, i.e. apnoea and
respiratory distress syndrome, in this population. But this study
has been criticized. It was retrospective, not blinded, and not
randomized. Magnesium therapy was either intramuscular or oral.
The criteria by which private physicians decided on the dose of
magnesium and the other confounding variables for apnoea and
prematurity were not known. Lastly the urine response to a
parenteral magnesium load is discussed as though it were an
accurate index of magnesium status in
children113,114.
There is only slight epidemiological support for the above
thesis. Thus a direct correlation between soft water and SIDS and
an inverse correlation between the magnesium concentration in
drinking water and SIDS have been shown in one
study115. There are some data concerning sudden death
in adults, but two major factors may intervene in the
relationship between water hardness and sudden cardiac death:
magnesium concentration and corrosivity. It is necessary to
appreciate the importance of this latter116, which may
be in opposition to the findings of Caddell, who extrapolated
analogically--as was also done later117--from
experiments carried out in weanling rather than newborn rats with
superacute (magnesium intake: 3 ppm) or acute (magnesium intake:
50 ppm) magnesium deficiency, to neonates and infants who are
much younger and who are never subject to such drastic reductions
in magnesium intake. An animal model of cot death should be
related to the early mortality rate of the offspring, which in
rats is the first week mortality. Experimental studies of
magnesium deficiency during pregnancy have mainly studied its
teratogenic effects together with problems of parturition and
delayed postpartum uterine involution118. In contrast
to the usual priorities for other essential nutrients such as
potassium suggested by the term "fetal parasitism", the fetus is
more severely affected than the mother during maternal magnesium
deficit119,120. Very few animal studies have concerned
the effect of maternal magnesium intake on the viability of the
offspring. If some of the live offspring are eaten by the mother
the remainder of the litter die spontaneously. Maternal magnesium
deficiency has a marked effect on viability. Maternal magnesium
deficit affects the condition of the offspring more severely than
that of the mother. The reverse is observed during
lactation99,120. Further research is needed on the
effect of chronic suboptimal maternal magnesium
intake121 on the mortality rate and the quality of the
offspring over the duration of pregnancy and lactation.
Postmortem diagnosis of alterations in magnesium status is
difficult105,111,116K. Plasma magnesium may sharply
increase after stress, for example in ALTE122, and
after death, even with magnesium deficiency. Magnesium deficiency
has no significant effect on liver magnesium, particularly in the
fetus and neonate111,123. Sudden death of adults is
accompanied by a significant fall in myocardial magnesium levels.
The myocardium seems more vulnerable than skeletal muscle to
magnesium loss111,116,124,125. As in adults and
because of the heterogeneity of the myocardium116 it
seems advisable to section the apex of left ventricle when
investigating myocardial magnesium content. Bone is the best
tissue for determining whether or not a young mammal has adequate
stores. But the irregular distribution of magnesium within a
single bone warrants the study of one entire bone, such as the
sternum105. Magnesium levels in the vitreous humor are
rarely depressed, so their measurement does not provide valid
data on which to base the evaluation of magnesium status. Normal
vitreous magnesium is not incompatible with an aetiopathogenic
role of magnesium in SIDS105,111. Thus measurements of
myocardial magnesium and bone magnesium should be routine in
SIDS. But these only constitute two items in the overall
magnesium status and are not specific investigations of the whole
magnesium pool.
The best tool to diagnose experimental or clinical magnesium
deficiency is an oral magnesium loading test. At physiological
dose level, oral magnesium supplementation is totally devoid of
the pharmacodynamic effect of parenteral magnesium. Correction of
symptoms constitutes the best proof that they were due to
magnesium deficiency111,126. If maternal magnesium
deficiency is the cause of newborn and infant magnesium
deficiency, maternal magnesium supplementation should be the key
to establishing the magnesium theory. Indirect support for these
data is given in a large scale prospective follow-up study of
7870 pregnancies over the period from 1964-1970 in which 20
German centres participated. Among 500 variables evaluated it
turned out that women with stomach complaints taking
magnesium-containing antacids had a surprisingly low rate of
early and late abortions and their babies showed low perinatal
mortality127. Several prospective double blind studies
in Germany and in Hungary on the effect of magnesium
supplementation during pregnancy were focused on the consequences
of maternal magnesium deficiency on the mother and on the baby at
birth. Among the positive effects of maternal magnesium
supplementation, six significant results concerned risk factors
for SIDS: a longer gestational age, greater birth weight,
crown-heel length, and head circumference, APGAR scores less
often below 8, and a reduction in the incidence of intrauterine
growth retardation. It now appears worthwhile to study the
effects of maternal magnesium supplementation during the first
year of development of the infant128-131. Cooperative,
prospective, blinded, randomized, preventive studies of maternal
supplementation should also include a follow up of neonates and
infants. Other studies should concern ALTE, all the more so since
polygraph studies allow observation of correlations between
magnesium and episodes of sleep apnoea132.
In place of an inexplicable superacute severe magnesium
deficiency as a possible, but unlikely, cause of SIDS, these new
data allow the substitution of the well-established condition of
chronic maternal magnesium deficiency, which may be palliated by
simple oral physiological magnesium supplementation.
Link between magnesium status and thermal regulation
Magnesium and warm regulation
Artificial hyperthermia in man induces negative magnesium
balance133 and conversely hypermagnesaemia brings
about hypothermia111,134. Body temperature may be
regulated through adaptative variations in
magnesaemia134. Magnesium activates heat defences.
Antihyperthermic magnesium effects might be due to a central
sedative action of magnesium on the hypothalamus134 or
to a peripheral mechanism,29 reduction of muscular
excitability--a factor of physical
thermoregulation111,135,136--and of chemical
catecholaminergic stimulation of chemical thermoregulation. Acute
magnesium deficiency should induce an increase in energy
expenditure which may partly depend on central and peripheral
neuromuscular hyperexcitability111,135,136. Since the
increase in basal metabolism does not seem to be due to an
increase in thyroid function137, it could result from
a catecholamine activation of BAT111,138. Failure of
these central and peripheral antipyretic magnesium effects may
favour hyperthermia. Magnesium deficit may well constitute a
major element in the aetiopathogenesis of various types of
malignant hyperthermia (malignant neuroleptic syndrome, malignant
anaesthetic hyperthermia, and heat stroke). It might also play a
role in cases of hyperthermic SIDS111.
Magnesium and cold regulation
The magnesium requirement in a cold environment is markedly
increased139,140. Cold exposure induces an adaptive
rise in serum magnesium. The increase follows a linear
relationship to fall in rectal temperature. When the regulation
of temperature is poorly developed and particularly at a very
young age i.e. puppies vs dogs), the rise in
serum magnesium is greatest141. This increase in serum
magnesium during efficient adaptation to cold may be due to
mobilization of labile magnesium from its stores, mainly
bone140. Hypothermic peripheral tissues such as skin
could be a source of a transient rise in serum magnesium, but
this has only been shown in the turtle, a poikilothermic animal.
Dietary intake increases by as much as 60% during cold weather
and there may be hypersecretion of adrenaline during cold
exposure, but these mechanisms do not occur during
hibernation111,141,144.
Various points of similarity between the hypothermic form of
SIDS and hibernation have been emphasized61, but
hibernation is life-protecting while SIDS is a lethal event. This
discrepancy could be explained by a difference in magnesium
status: in hibernation, adaptative hypermagnesaemia is a
prominent feature, but this is impossible in the face of the
chronic magnesium deficiency which may lead to SIDS.
Failure of the adaptational mobilization of magnesium may be
observed during cold stress. For example, in fasted sheep severe
cold exposure induces hypo- rather than
hypermagnesaemia145,146. The incidence of acute
clinical hypomagnesaemia in cattle is sometimes associated with
the transference of the animal onto early spring and late autumn
pastures, when the cattle are subject to sudden extremes in
temperature. Several mechanisms intervene:
(1) Low magnesium intake, since in fed sheep a cold stress
capable of causing hypomagnesaemia in fasted sheep induces no
variations in magnesaemia146;
(2) Intense hyperadrenalinaemia which induces
hypomagnesaemia--and not hypermagnesaemia usually caused by
moderate adrenaline hypersecretion--through stimulation
of lipolysis;
(3) magnesium chelation by non-esterified free fatty acids;
(4) uptake in adipocytes111,145,146; and
(5) a reduction in the ability of the liver to catabolize
citrates during cold stroke may induce magnesium deficit due to
an excess of endogenous citrates111,147.
The mechanisms of the beneficial effects of hypermagnesaemia
in cold adaptation may come from cytoprotective properties and
activation of thermogenesis, mainly chemical, in babies. The well
known cytoprotective properties of magnesium are linked to its
stabilizing effects on cellular and subcellular membranes, along
with its metabolic inhibiting, antihypoxic, and cryoprotective
functions111. That is why it is used as an element in
solutions need[ed] for perfusing organs destined for transplant
surgery and sometimes in open-heart surgery111.
Too few studies have investigated the role of magnesium in BAT
physiology. More than 15 years have elapsed since studies were
carried out by two groups on some consequences of acute in
vivo magnesium deficiency on BAT in adult rats.
Mitochondrial swelling and increased adenosine 3',5'
monophosphate (cAMP) concentration were observed and appeared to
be due to hypersecretion of noradrenaline and
adrenaline148,149. The first studies on the
relationship between chronic magnesium deficiency and cold stress
were carried out in Canada. In adult rats with chronic magnesium
deficiency cold stress enhances the development of focal
myocardial necrosis, while magnesium supplements are
protective150,152.
Heroux et al. published a seminal paper on the long
term effect of suboptimal dietary magnesium on Mg and Ca contents
of organs, on cold tolerance, and on life span in
rats153. Within the first 69 days typical signs of
magnesium deficiency were evident in rats acclimatized to 28°
C and 6° C. Severe reduction in magnesium content was
observed except in brown fat, heart, thymus, and duodenum. It is
very interesting that in magnesium deficiency there exist complex
homeostatic mechanisms to maintain normal--and even
increased--concentrations of magnesium in the tissues during
magnesium deficit, which are of vital
importance111,154. Between 69 and 517 days the rats
had apparently become adapted to the low magnesium diet, with the
same relative stability of magnesium content in BAT and an
increase in its CA concentration. But the tolerance to severe
cold stress at -20° gradually decreased with the duration of
magnesium deficiency. Three days after the onset of the stress,
all rats acclimatized to 28° showed an increase in the
magnesium content of brown fat. In contrast all groups
acclimatized to 6° showed a significant decrease in the
magnesium content of brown fat after the severe stress. All
magnesium-deficient groups acclimatized to 28° showed a
degree of hypothermia which gradually increased with the duration
of magnesium deficiency. There was a definitely decreasing trend
in cold resistance. After cold acclimatization at 6°, the
resistance to cold stress was better. Longevity was reduced by
chronic marginal magnesium deficiency. At 69 days, there was a
higher incidence of lesions and more severe lesions in the heart
of magnesium-deficient rat after cold stress. But after
adaptation to the magnesium-deficient diet (at 240 and 517 days)
the cold stress increased the degree of hypothermia in older
rats, but not the incidence of the heart lesions. Reduction in
longevity might first depend on deleterious effects on the heart,
and then on inadequate thermal regulation153.
Only one study99 concerns BAT in the offspring of
magnesium-deficient dams. Newborn rats from dams which had
received a magnesium-deficient diet from days 5-12 of pregnancy
showed a high death rate. Histological examination showed
swelling of the mitochondria and a loss of lipid inclusions in
BAT. A link is proposed between the high death rate and the
alterations in BAT, since this tissue plays an important role in
temperature regulation, especially after birth99.
Sadly the numerous subsequent investigations on the consequences
of maternal magnesium deficiency and on the relationship between
magnesium and lipid metabolism carried out in that laboratory
have no longer concerned BAT123,138,155,157.
Various in vitro biochemical data may provide new
insights on the link between magnesium and BAT functions.
Mg2+ may intervene at each step of chemical
thermogenesis: membranous lipoprotein lipase, which induces the
capture by adipocytes of circulating triglycerides; microsomal
and mitochondrial forms of several enzymes of glycerolipid
synthesis; and enzymes which play a role in the lipolytic events
following the binding of noradrenaline to the cell membrane
receptor (adenylate cyclase, protein kinase, triglyceride lipase,
and phosphodiesterase in membranes, cytosol, microsomes, and
mitochondria particularly)86,158-161. Uncoupling
protein (UCP), which occurs exclusively in BAT mitochondria,
conducts protons and dissipates energy, thereby producing heat.
The H+ uniport through UCP is inhibited by purine
nucleotides and activated by fatty acids. The link between
magnesium and nucleotide binding is controversial. It has been
claimed to be absent162 or present. Mg2+
appears to be a negative modulator of purine nucleotide
inhibition of H+ (and Cl-) transport
through UCP163. Mg2+ in BAT of
cold-acclimatized hamsters decreases the affinity and the maximum
number of available adenosine binding sites164, while
in BAT of cold-stressed hamsters it has no effect on the affinity
but increases the number of GDP sites165. The binding
of GDP to untreated mitochondria may represent thermogenic
activity at the time of death whereas after treatment with
Mg2+ it may more closely reflect total thermogenic
capacity of the mitochondrion166. UCP belongs to the
family of mitochondrial ion carriers and the effect on the
transport of ions other than H+ should receive
consideration. For example according to the Mg2+
carrier-brake hypothesis the Mg-regulated
K+-H+ antiporter is the homeostatic
mechanism which prevents mitochondrial swelling and lysis. A
physiological consequence of respiration-linked proton ejection
is the establishment of a large electrochemical cation uptake by
mitochondria and subsequently the uptake of salts and water.
Matrix Mg2+ determines the amount of matrix
K+ at which the K+ cycle is in a steady
state and thus determines matrix volume. BAT mitochondrial volume
homeostatis seems regulated by matrix
Mg2+.167-169 Lastly the synthesis of UCP
may be affected by magnesium deficiency, which plays an important
role in protein synthesis111.
To sum up, magnesium status intervenes through different
mechanisms in the regulation of both warm and cold exposure.
Conversely chronic magnesium deficiency may favour both cold and
heat stroke.
SIDS: A magnesium-dependent disease of the transition from
chemical to physical thermoregulation
This new theory considers SIDS as a magnesium-dependent
disease of the transition from chemical to physical
thermoregulation. It originates from a synthesis of our present
knowledge on SIDS, maternal magnesium status, and the
relationship between magnesium and thermoregulation in the
baby.
The new theory and the necessary prerequisites for causation
of SIDS
First of all this hypothesis on SIDS agrees perfectly with all
the necessary epidemiological and pathological prerequisites
which characterize SIDS.
The curve for age at death corresponds to the transition
between chemical and physical thermoregulation81,82.
Chronic marginal maternal magnesium intake, present in all social
classes but more frequent in lower socioeconomic groups,
constitutes a well known experimental and clinical factor in
reduction of gestational age, symmetrical growth retardation with
decreased birth weight, birth length, and head circumference, and
a significant increase in Apgar score128-131. All
accessory factors such as stress, alcohol addiction, CD and lead
exposures, may induce secondary magnesium deficit111.
Symptoms before death may be exactly those of marginal magnesium
deficiency, either totally latent, or symptomatic with signs
analogous to "sinister symptoms" and also manifested in
ALTE(111). Dysautonomic symptoms are most often amphotonic with
either vagal or sympathetic predominance111,154,170.
Sleep disorganization is very well known during primary chronic
magnesium deficit in the adult111,154,171,172 and is
also observed in the infant132. Lengthening of the
corrected QT interval may constitute a classical stigma of
chronic magnesium deficit111,173-176.
Hypothermia and hyperthermia theories on SIDS could separately
explain the hypothermic and hyperthermic clinical forms of SIDS,
but the considerable hiatus between such commonplace elements as
inappropriate baby caring or climatic factors conducive of
dysthermia (even when combined) and the lethal event make it
difficult to retain these hypotheses. The large gap between the
magnesium intake of the babies and the occurrence of a superacute
lethal form of magnesium deficiency makes one question the
mechanism of Caddell's theory on SIDS. But all these
discrepancies are resolved by the magnesium-dependent
dysthermoregulation theory. Chronic maternal magnesium deficiency
as early as the beginning of the pregnancy and sometimes during
lactation constitutes a too often neglected nutritional factor in
early intrauterine injury and in symmetrical growth retardation
particularly99,118-121,123,126-131,155-157. Among its
possible noxious consequences it may induce alterations in
thermoregulation, and particularly on BAT in the newborn and
infant99,158-169. This theory rules out the hiatus
between the banality of thermal stress and induced lethal thermal
stroke. In winter, chilly air from an open window, underwrapping
and under-clothing26-28,58-61 may induce hypothermic
SIDS because of a magnesium-dependent failure of cold regulation.
Conversely, and still in winter, a "common cold" overwrapping,
over-clothing, and a prone sleeping position49-57 may
induce hyperthermic SIDS because of a magnesium-dependent failure
in heat regulation. Scepticism about the role of an implausible
lethal superacute magnesium deficiency is logical. But it is out
of place with regard to the well established condition of chronic
marginal magnesium deficiency in humans, and particularly in
pregnant women. In developed countries, recommended daily dietary
amounts of magnesium have been set at 6 mg/kg. d. This intake
prevents negative magnesium balance177,178 and chronic
magnesium deficiency, though with a usual intake around 4 mg/kg.
d121,126 chronic deficiency is relatively common. In
general, some differences exist between the various nutritionists
regarding the special requirements of women during pregnancy:
either 1 x RDA (minimum requirement, with an "adaptive"
mechanism) or optimal requirement (for example 1.5 or more x
RDA). Present knowledge on the experimental and clinical
consequences of marginal magnesium deficiency on the mother and
fetus99,118-121,123,126-131,155-157 together with the
absence of toxicity of physiological oral magnesium intake ( less
2 RDA)111,126,177,178, leads to the conclusion that a
daily supplement of 300 mg in pregnant women is highly
recommendable.
New trends in experimental and clinical
research
Experimental research
This new theory on SIDS should generate further experimental
and clinical research. A large gap exists between the classical
but scanty in vivo data on the importance of magnesium
in thermoregulation and the highly elaborate in vitro
biochemical and molecular studies, particularly on BAT function.
Ex vivo data on BAT from magnesium-deficient animals
might bring further information on the relationship between
magnesium and thermal regulation. Magnesium-deficient animals
should be studied at thermoneutrality, in cold and warm
environments, under cold and heat stress, and with or without
cold and warm acclimatization. These animal models might indicate
the most important targets of magnesium-dependence, allowing us
to distinguish labile from stable alterations according to
postmortem delay, particularly on BAT. After these preliminary
studies, the effect of marginal maternal magnesium deficiency in
rats appears to be the cornerstone of the hypothesis. It seems
possible to obtain, by inducing marginal magnesium deficiency of
dams throughout pregnancy and lactation, newborn rats without
malformations but with a high rate of mortality. BAT from these
newborns will be studied morphologically--by light and electron
microscopy complemented by tissue cartography from a nuclear
microprobe--and biochemically. Sympathetic stimulation of BAT may
also be studied.
It will be of great interest to use modern biochemical and
molecular techniques to investigate current indices of chemical
thermogenesis in BAT sections from newborn rats born after
chronic magnesium deficiency. Validation of these data should be
made in relation to any postmortem delay87-96,179.
Since the human amnion constitutes a valuable and
sophisticated model for studying the electrophysiological and
ultrastructural membranous effects of magnesium and of several
pollutants180-184, it seems of interest to use this
technique to study ex vivo the effect of marginal
magnesium deficiency during pregnancy on rat amnion. It would
also be of interest to determine some markers of marginal
maternal magnesium deficiency on this amniotic membrane. The same
processes could also be applied to maternal exposure to
pollutants.
Clinical research on SIDS
The magnesium-dependent dysthermoregulation theory requires
extreme caution when assessing a dead baby's core temperature. It
seems important in this respect not only to measure deep rectal
temperature using a low reading thermometer, but also to evaluate
oesophageal temperature, which may be considered as the reference
body core temperature. Peritympanic temperature seems very close
to oesophageal temperature and is much easier to
measure185. The importance of this type of evaluation
is first of all to discriminate between hypothermic and
hyperthermic forms71,80, and then to make a rapid
diagnosis of death in cases of hypothermia. Studies on severe
accidental hypothermia have shown that the external appearance of
these patients may be identical to that of cadavers: cold and
pallid skin, cyanotic lips and extremities, mydriasis with loss
of corneal and pupillary reflex, respiratory and cardiac arrest.
Even with profound hypothermia, some of these patients have been
rescued by modern treatments. The only definite criterion for
diagnosis of death in these cases of severe hypothermia is
failure to respond to resuscitation and
rewarming185-189.
Clinical research in ALTE
The magnesium-dependent dysthermoregulation theory demands that
careful investigation into the most accurate criteria for thermal
regulation and magnesium status should be carried out.
Investigations on thermal regulation might include firstly
extremely precise evaluation of body core temperature:
measurement of deep rectal temperature with low reading
thermometers and of peritympanic (or for lack of equipment
sometimes oesophageal) temperature185-189; and
secondly, attempts to investigate basal BAT functions through
non-invasive procedures using thermography, thermometry,
computerized tomography, and cautious administration of
noradrenaline or modifications of ambient
temperature89,190-197. Morphological and biochemical
studies on BAT biopsies could be envisaged.
The investigations on magnesium status will be analogous to
those described in adults and children, with adjustment for age.
Magnesium-dependent symptoms may involve many functions, but
especially the nervous and cardiovascular apparatuses. These
symptoms are without specificity. Specific magnesium
investigations mainly involve free or total magnesium in plasma,
erythrocytes, lymphocytes, and urine, but none of these magnesium
measurements constitute an exploration of the magnesium
pool111,126.
In the final analysis, correction of the clinical
abnormalities with an oral physiological magnesium load is the
best demonstration of the role of magnesium deficiency in the
pathogenesis of a particular clinical disorder111,126.
In case of ALTE, dysthermic, cardiovascular and nervous symptoms
(and particularly lengthening of QTc, sleep disorganization and
apnoeas) should be carefully monitored. The magnesium load should
also initiate continuous physiological magnesium supplements
which might constitute a specific treatment of ALTE due to
chronic magnesium deficiency.
Conclusions
The magnesium-dependent thermal dysregulation theory on SIDS
leads to three therapeutic consequences.
(1) Magnesium therapy may constitute a simple treatment of
ALTE due to chronic marginal magnesium deficiency. Only
systematic research and specific treatment of magnesium
deficiency will reveal the importance of magnesium deficiency in
the pathogenesis of what may perhaps be a heterogeneous
disease.
(2) If some hypothermic cases of cot death are only "apparent
death" it becomes very important to consider the diagnosis of
death with the same caution as exists in the case of known
accidental hypothermia. It seems wise to transfer the baby
rapidly to a well equipped emergency unit where rewarming
extracorporeal circulation using femoro-femoral bypass may be
started. It might be advisable to cautiously add low doses of
magnesium to other helpful treatments such as glucose, naloxone
and thiamine. Heroic measures, including open thoracotomy and
irrigation with warm saline, might be discussed, for example when
there is failure to warm the core temperature at a rate of 1°
C per hour185-189.
(3) The main consequence of the magnesium-dependent thermal
dysregulation theory of SIDS is to develop a simple preventive
treatment for this disease. A multicentre cooperative prospective
study, blinded and randomized, of magnesium supplementation in
pregnant and lactating women should be started. This simple and
cheap supplementation with oral physiological doses of magnesium
(300 mg/day) is ethically justifiable. In most obstetric
departments magnesium supplementation is not systematic.
Therefore randomization would not raise any ethical problem with
regard to the control group. With the supplemented group, the
suggested physiological load (300 mg/day) is without
toxicity111,177,178. Furthermore the beneficial
effects of magnesium supplementation are well established for the
mother, for fetal development, and for the baby at
birth127,131. But follow up of the baby over the first
year must be made in order to discover the results on apnoea
neonatorum, respiratory distress syndrome and SIDS. It will thus
be possible to check the validity of the hypothesis and its
importance. Magnesium-dependent hypothermic and hyperthermic
forms of SIDS may be two subgroups of SIDS or concern the whole
population. Supplementation trials are necessary to answer these
major questions.
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