The Use of Drugs to Modulate Stress Responses Reduces the Time of Intensive Care Needed by Down Children to Recover after Open-Heart Surgery

Renato Cocchi M.D., Ph.D. (Sociology)
Italian Journal of Intellective Impairment 3 (1): 11-16 (1990)

Reprinted with the permission of Renato Cocchi
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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's syndrome; Open-heart surgery; stress; drug therapy; intensive care.

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; Chromosomeal 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 1: Epidemiological and clinical data of CG (22 Ss)
Ss. no.	Sex	Year of birth	Age (months) at 1^st consultation	Chromosome Diagnosis	Hours in Intens. Care
1	f	1979	103	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 shows the data pertinent to the EG for whom surgical operation was preceded by a period of anti-stress drug therapy.

Table 2: Epidemiological and clinical data of the EG (10 Ss). Surgery performed in years 1983-1989.
Ss. no.	Sex	Year of birth	Age (months) at 1^stconsultation	Chromosome. Diagnosis	Hours in Intens. Care
1	f	1976	71	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; "×" refers to a drug actually taken just before surgery.
Drug /daily dosage (range)	Subject number
Drug /daily dosage (range)	1	2	3	4	5	6	7	8	9	10
L-glutamine 125-500	×	×		×	×	×	×	×	×
Glutamine 45-90 + pemoline 5-10			×						×	×
Pyridoxine	×	×	×	×	×	×	×	×	×	×
5-hydroxytriptophan 25-50	×	×		×	×			×	×	×
Diazepam 1-3	×	×	×	×	×	×	×	×	×	×
Thiamine 125-250	×	×	×	×	×	×	×	×	×	×
Cyanocobalamine 500 mcg	×	×	×	×	×	×		×	×
Carbamazepine 50-200	×		×	×	×	×	×	×
Taurine 500								×
Viloxazine 25-50								×
S-adenisil-l-methionine			×					×
Methiltetrahydrofolate 7.5-15		×	×		×		×	×	×
Oxazepam 3-8					×					×
Alpha-tocopherol 50			×		×
Pyritinol 100			×
L-carnitine 500	×	×			×
Biotin 2.5-5									×
Pantothenate					×

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:

Hereditary factors;
Acquired factors including pathological antecedents in the pre-, peri- and neo-natal period as well as successive periods;
The intensity of the contingent stress;
The particular moment in the individual's biological cycle (these become more rigid as one grows older);
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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