By
Renato COCCHI MD, neurologist and medical psychologist.
Abstract
The time that 10 Down children, all
pre-treated with individualized drug therapies, spent in intensive care after
undergoing open-heart surgery was compared to the time taken by 22 Down
children operated on before such treatment.The therapies are mainly antistress
but also aim at compensating for probable deficits of physiological substances.
Compared to the control group, the
index group spent average 74.11 hour less, with 99% CI from 66.44 to 87.74
hours; "t" = 3.30 with 30 df and p < .01. The results, of wide
spread interest, require further investigation as it is possible to establish
beyond doubt whether the two samples are random.
Key words: Down' syndrome ; open-heart
surgery; stress; drug therapy; intensive care.
Drug modulation of stress reactions
Down syndrome
Mental retardation
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An evaluation of stress reactions is
becoming more and more indispensable in understanding the individuality of
human responses to any illness.Down' syndrome, however, constitutes a
large-scale natural scientific experiment which can throw to light on the
etiology and of illnesses which are common to non-Downs (Scoggin and Patterson,
1982).
While the research carried out on
Alzheimer's disease has become very impressive (see: Cordella and Cocchi,
1987), for my own part I have investigated into childhood psychoses, which
affect about 10% of Down children (Cocchi, 1989a), susceptibility to upper
respiratory tract infections (Cocchi, 1987b; Cocchi and Bonaduce 1988a; Cocchi
1990b), intolerance to environmental temperature (Cocchi 1989b), prevalence of
cerebral palsy due to prematurity, low birthweight or both (Cocchi, 1987c), the
link between squint and cerebral palsy trough prematurity, low birthweight or
both (Cocchi and Branchesi, 1989).
In my working I start from the
hypothesis (supported by basic research of others and verified ex-juvantibus by
my own therapeutic work) that most of the symptoms present in Down' syndrome
are not directly dependent on the trisomy 21.
They are instead caused by the
internal biological stress derived from the 50% acceleration (the so-called
"dosage effect") of all the metabolisms whose enzymes have control
genes in the chromosome 21 (Cocchi 1987a).
A drug therapy able to modulate stress
responses should act, as it indeed does, favorably in various ways. The results
of my work along these lines have either already been published or are in the
press both in Italy and abroad (Cocchi 1987b; Cocchi & Lamma, 1988; Cocchi,
1990).
Between 20 and 25 % of Down's
subject suffer from a cardiac defect requirIng rectification through
open-heart surgery which, in itself, causes considerable stress. It is feasible
to suppose that if the Down child had been treated with an anti-stress drug
therapy, also the post-operational intensive care period would have been
reduced.
This was the indication given by the
parents' reports as for children operated on before the drug therapy or after
it had been started. I did in fact write about the reduced post-operational
period spent in intensive care by Down children pre-treated with anti-stress
drug therapy. Not only is this what is actually happening, to the amazement of
some heart surgeons, but I had always assured the parents that this would be
the case (Cocchi, 1987a). I stated then that I was collecting data on the
subject for quantitative research and this paper shows the first results of
this work.
Material and method
Among the Down subjects examined
personally by the author between January 1979 and December 1989, constituting a
non-selected consecutive series of 450 individual, 52 of them (11.56 %) had
undergone open-heart surgery in order to rectify a cardiac defect.
I managed to gain information as to the
length of time spent in intensive care after the operation for 35 of these subjects
while details of the other 17 are unavailable due to their not returning for
re-examination since I started my investigation.
The following information on these 35
subjects was collected:sex; year of birth; age (in months) at first
examination; chromosomal diagnosis; time period (in hours) spent in intensive
care after surgery. For 10 of these, constituting the Experimental Group (EG) I
also noted all the drugs administered, their daily dosages, as well as all the
drugs currently.taken just before the surgical operation. The drug therapy had
firstly been selected on an approximate basis and adapted to the symptoms of
stress evident in that particular child while using low dosages of each single
drug.
The Control Group (CG) consists of 25
children, also having undergone open-heart surgery but who had not previously
been subjected to such therapy.
The days and hours spent in intensive
care were used as a means of comparison. All the subjects were operated on in
Italy, specifically Rome, Genoa, Florence, Massa, Bergamo, Padua and Bologna.
For the statistical analysis, 2 cases
(with respectively 48 and 120 hours of intensive care) were eliminated from the
CG because they were born before the eldest of the EGG and another one was
eliminated from the same group, because the time spent in intensive care (29
days) was abnormally high compared to all the rest. Confidence intervals were
determined and the significance was calculated by using "t" test for
independent samples, on the assumption that the general population is of normal
distribution.
Results
Table 1 shows epidemiological and
clinical data referring to the CG subjects operated on before having been
examined and put under drug therapy. Table 2 shows the data pertinent to the EG
for whom surgical operation was preceded by a period of anti-stress drug
therapy.
Table 1: Epidemiological
and clinical data of CG (22 Ss)
|
Ss. no. |
Sex |
Year of birth |
Age at 1st consultation |
Chromosom. Diagnosis |
Hours in Intens. Care |
|
1 |
f |
1979 |
103 months |
Mosaicism |
72 |
|
2 |
m |
1979 |
65 " |
t(21-21) |
72 |
|
3 |
f |
1980 |
106 " |
Trisomy 21 |
96 |
|
4 |
f |
1981 |
43 " |
Trisomy 21 |
48 |
|
5 |
f |
1981 |
51 " |
Trisomy 21 |
72 |
|
6 |
m |
1981 |
17 " |
Trisomy 21 |
240 |
|
7 |
f |
1981 |
58 " |
Trisomy 21 |
168 |
|
8 |
f |
1981 |
74 " |
Trisomy 21 |
96 |
|
9 |
f |
1981 |
47 " |
t(14-21) |
192 |
|
10 |
m |
1981 |
25 " |
Trisomy 21 |
144 |
|
11 |
m |
1982 |
13 " |
Trisomy 21 |
96 |
|
12 |
f |
1982 |
48 " |
Trisomy 21 |
48 |
|
13 |
m |
1982 |
33 " |
Trisomy 21 |
27 |
|
14 |
m |
1983 |
31 " |
Trisomy 21 |
72 |
|
15 |
m |
1983 |
29 " |
Trisomy 21 |
168 |
|
16 |
m |
1984 |
16 " |
Mosaicism |
192 |
|
17 |
m |
1984 |
50 " |
Trisomy 21 |
48 |
|
18 |
f |
1984 |
54 " |
Trisomy 21 |
72 |
|
19 |
f |
1984 |
37 " |
Trisomy 21 |
288 |
|
20 |
f |
1986 |
11 " |
Trisomy 21 |
48 (*) |
|
21 |
f |
1986 |
12 " |
Mosaicism |
120 |
|
22 |
f |
1987 |
14 " |
Trisomy 21 |
72 |
|
Average + SD |
42.59 + 30.36 |
|
111.41 + 69.56 |
||
(*).Palliative operation
Table 2: Epidemiological and clinical data of the EG (10 Ss). Surgery
performed in years 1983-1989.
|
Ss. no. |
Sex |
Year of birth |
Age at 1st consultation |
Chromosom. Diagnosis |
Hours in Intens. Care |
|
1 |
f |
1976 |
71 months |
Trisomy 21 |
24 |
|
2 |
m |
1977 |
94 " |
Trisomy 21 |
21 |
|
3 |
m |
1981 |
60 " |
Trisomy 21 |
24 |
|
4 |
f |
1981 |
27 " |
Trisomy 21 |
72 |
|
5 |
f |
1981 |
17 " |
Trisomy 21 |
31 (*) |
|
6 |
f |
1981 |
13 " |
Trisomy 21 |
36 |
|
7 |
f |
1981 |
15 " |
Trisomy 21 |
48 |
|
8 |
f |
1983 |
34 " |
Trisomy 21 |
24 (**) |
|
9 |
f |
1984 |
14 " |
Trisomy 21 |
45 |
|
10 |
m |
1985 |
12 " |
Trisomy 21 |
48 |
|
Average + SD |
34.70 + 30.03 |
|
37.30 + 16.08 |
||
(*) operated on twice in the same day,
(**) palliative operation
Table 3 shows all the drugs
used on each child of the EG and the drugs actually taken just before surgery;
daily dosage of each drug is in mg, if not otherwise noted.
Table 3: drugs used in IG
Ss and daily doses; "X" refers to a drug actually taken just before
surgery.
|
Drug /daily dosage in mg (range) |
Subject number |
|||||||||
|
|
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
|
L-glutamine 125-500 |
X |
X |
|
X |
X |
X |
X |
X |
X |
|
|
Glutamine 45-90 + pemoline 5-10 |
|
|
x |
|
|
|
|
|
x |
X |
|
Pyridoxine 125-150 |
X |
X |
X |
X |
X |
X |
X |
X |
X |
X |
|
5-hydroxytriptophan 25-50 |
X |
X |
|
X |
x |
|
|
x |
X |
X |
|
Diazepam 1-3 |
X |
X |
X |
X |
X |
X |
X |
X |
X |
X |
|
Thiamine 125-250 |
X |
X |
X |
X |
X |
X |
X |
X |
x |
X |
|
Cyanocobalamine 500 mcg |
X |
X |
X |
X |
X |
X |
|
X |
X |
|
|
Carbamazepine 50-200 |
X |
|
X |
X |
x |
X |
X |
X |
|
|
|
Taurine 500 |
|
|
|
|
|
|
|
X |
|
|
|
Viloxazine 25-50 |
|
|
|
|
|
|
|
x |
|
|
|
S-adenisil-l-methionine 100-200 |
|
|
X |
|
|
|
|
X |
|
|
|
Methiltetrahydrofolate 7.5-15 |
|
x |
X |
|
X |
|
X |
x |
X |
|
|
Oxazepam 3-8 |
|
|
|
|
x |
|
|
|
|
X |
|
Alpha-tocopherol 50 |
|
|
x |
|
X |
|
|
|
|
|
|
Pyritinol 100 |
|
|
X |
|
|
|
|
|
|
|
|
L-carnitine 500 |
X |
X |
|
|
X |
|
|
|
|
|
|
Biotin 2.5-5 |
|
|
|
|
|
|
|
|
X |
|
|
Pantothenate |
|
|
|
|
X |
|
|
|
|
|
Statistics: Difference: 74.11 hours; 99 %
CI from 66.44 to 81.7 hours; t = 3.30 with 30 df
and p < .01.
On average therefore, the 22 non-treated
children spent 4.64 days in intensive care (ranging from 27 to 288 hours),
while the 10 pre~treated children spent an average of 1.5 days in intensive
care over a range of 21 to 72 hours (one female S. undergoing open-heart
surgery in Padua twice in 24 hours was in intensive care for only 31 hours
afterwards).
Discussion.
Despite the possibility of a
methodological error (the two groups may not necessarily be random samples) the
above results are nonetheless of extreme interest.
In trying to verify any probable
causality of the samples I attempted the analysis of the "runs" but I
found that the outcome changed depending on the parameter used in ordering the
subjects, with scores ranging from 10 to 99 % causality I did not find any
ordering criteria which could be justifiable by itself.
Even after the admission of this
warranted caution, it must be said that the results for the two groups too
different and once again those of the EG point clearly towards an attenuation
of the stress responses, as was the case in previous research (Cocchi, 1987a;
Lamma and Cocchi, 1988; Cocchi, 1990a).
The area in which the results were
obtained - open-heart surgery on Down subjects - is far too important not to go
deeper into and I therefore here and now declare myself willing to collaborate
with any Children's' Heart Surgery Center interested in verifying these
results.
The stress responses are always the same
though they may on the whole be explicit in different body areas, depending on
the individual. As a matter of fact, they are independent of the type of stress
(physical, chemical, biological, or psychological) and are governed by:
l. Hereditary factors; 2. Acquired factors including pathological
antecedents in the pre-, peri- and neo-natal period as well as successive
periods; 3. The intensity of the contingent stress; 4. The particular moment in
the individual's biological cycle (these become more rigid as one grows older);
5. The moment of the daily cycle (they tend to intensify during
nocturnal sleep).
These stressing components are capable of
building one upon the other (an individual who is already stressed is less able
to support further stress).
Of the drugs used, glutamine and
pyridoxine act to favor the synthesis of GABA (Ward, Thanki & Bradford,
1983; Ebadi, 1981). Benzodiazepines sensitizes the type A post-synaptic
GABAergic receptor (Schoch et al., 1985; Sanger, 1985; Chan and Farb, 1985).
The carbamazepine, which acts on the calcium ion channel, almost certainly
desensitizes the type B post-synaptic GABAergic receptor (Crowder and Bradford,
1987).
The other drugs used, having been administered for presumed deficits, either
dietary or from hyper-consumption due to the Down's syndrome itself, may also
effect their own anti-stress action as regulators of a homeostasis upset by
their lack.
Conclusion
The modulation of stress responses seems
to significantly reduce the amount of time that Down children spend in
intensive care after undergoing open-heart surgery for the correction of a
cardiac malformation.
If the above findings are confirmed by
further research, this will lead us to at least two implications:
The first is that stress responses can be
modulated for anyone having to undergo to a major surgical operation, with the
exception of very aged persons . (*). The second is a further confirmation that
pharmacological modulation of stress responses, to be effective should be
adapted to the individual.
(*) I made the last successful attempt in one 70 year relative, undergoing urinary tract surgery in February 1990.
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Author's address: dr Renato COCCHI, via
Rabbeno, 3
42100 Reggio Emilia (Italy).
renatococchi@libero.it
Italian translation
Drug modulation of stress reactions
Down syndrome
Mental retardation
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