Cerebral protection during extracorporeal circulation

Resuecitation, 10 (1982) 89-100 Elsevier Scientific Publishers Ireland Ltd.

89

CEREBRAL PRGTECTION DURING EXTRACORPOREAL CIRCULATION

E. MARANA,

F. CAVALIERE,

F. BECCIA,

L. SOLLAZZI

and R. SCHIAVELLO

Zstituto di Anestesiologia e Rianimazione, Univereitci Cattolica de1 Sacro Cuore, Facoltd di Medicina e Chirurgia, Largo A. Gemelli 8, Rome 00168 (Ztaly) (Received

March 22nd, 1982)

SUMMARY

Cerebral damage has been studied in 135 patients with valvular prostheses divided into two groups. One group which was treated with diazepam (1 mg/kg/h body wt) (30 aortic prostheses and 45 mitral prostheses) and another group which was not treated with this drug (30 aortic prostheses and 30 mitral prostheses). The diazepam caused a significant reduction of damage to the central nervous system.

INTRODUCTION

Disorders of the central nervous system have been reported to occur frequently after open-heart surgery. These cerebral dysfunctions may produce a clinical disaster despite an otherwise excellent cardiac repair. These disorders have included acute behavioral changes (Blachy and Starr, 1964; Egerton and Kay, 1964; Kornfeld, Zimberg and Malm, 1965; Haz&n, 1966; Sachdev Carter, Swank and Blachley, 1967; Lee, Brady and Miller, 1971; Dubin, Field and Gastfriend, 1979) as well as clinical signs of both focal and diffuse neurological deficits (Silverstein and Krieger, 1960; Ehrehaft and Claman, 1961; Gilman, 1965; Witoszka, Tamura, Indeglia, Hopkins, Simeone and Providence, 1973). The incidence of these cerebral dysfunctions is directly proportional to the duration of the extracorporeal circulation (Kornfeld et al., 1965; Tufo and Majafi, 1970; Lee et al., 1971; Sveinsson, 1975), to the age (Tufo and Majafi, 1969; Tufo, Ostfield and Shekelle, 1970; Sveinsson, 1975; Kolkka and Hilberman, 1980), to the functional class (Heller, Frank, Malm, Bowman, Harris, Charlton and Kornfeld, 1970; Freyhan, Giannelli and O’Connell, 1971), to the duration of the illness (Matarazzo, Bristow and Reaune, 1963; Kornfeld et al., 1965) and to the presence of hypotension, before, during or after the extracorporeal circulation (Tufo and Majafi, 1969; Tufo et al., 1970; Aguilar, Gerbode and Hill, 0300-9672/82/0000--0000/$02.75

o 1982 Elsevier Scientific

Publishers Ireland Ltd.

90

1971: Stockard, Bickford and Schauble, 1973; Kolkka and Hilberman, 1980). The reported incidence of cerebral complications after open-heart procedures has been variously reported as 44% (Tufo et al., 1970), 31% (Lee et al., 1971), 19% (Brantwaite, 1972; 1973), and 15% (Aberg and Kihlgren, 1974). This apparent reduction in incidence probably reflects an overall improvement in techniques in cardiac surgery, particularly in the use of heart-lung machines which is still being perfected. In spite of this, the frequency of cerebral damage during bypass is still high. Therefore, we have proposed protection of the brain with diazepam to reduce the incidence and the seriousness of cerebral damage in open-heart surgery. Diazepam, like barbiturates, reduces cerebral oxygen consumption and at the same time diminishes the cardiac depressive effect. PATIENTSANDMETHODS

Damage to the central nervous system has been studied in 135 patients with prostheses (60 aortic and 75 mitral valves), who were divided into two groups. One group of patients was treated with diazepam (30 aortic prostheses and 45 mitral prostheses), and another was not given this drug (30 aortic prostheses and 30 mitral prostheses). The patients were premeditated with diazepam (0.2 mg/kg body wt) and their electrocardiographs were monitored. Anaesthesia was started with hypnotic doses of thiopentone (4 mg/kg body wt) and maintained with fentanyl (0.03 mg/kg body wt) and droperidol (0.25 mg/kg body wt); the myorelaxation was then obtained with (+)-tubocurarine (0.5 mg/kg body wt). The patient, connected to an Engstrom 300 respirator, and respired with 50% 02, 50% NzO mixture. The extracorporeal apparatus employed was a roller pump with a Temptrol Q bubble oxygenator. The circuit was primed with Ringer lactate to give haemodilution with an haematocrit of 30%. During the bypass, the blood flow was maintained between 2200 and 2500 ml/m2/min and the internal temperature was lowered to 26-28°C. The PCO, was maintained during all the surgical operation at 30-34 mmHg and the PO, at 100-200 mmHg. At the beginning of the extracorporeal circulation the group of patients to be treated with diazepam were infused with it in a dose of 1 mg/kg/h body wt at a slow infusion rate. At the beginning of the cardiopulmonary bypass methyl-prednisolone (30 mg/kg body wt) and mannitol as 20% solution (0.5 g/kg body wt) were administered to all the patients. The cerebral, neurological and psychiatric conditions of the patients were observed clinically during the postoperative period, and in some cases their electroencephalographs were recorded. The distributions of the neurological deficits and psychiatric disturbances of the patients were assessed relative to their age, the duration of the bypass, the pressure of perfusion, the presence or absence of previous cerebral

DYSFUNCTIONS

Functional

(NYHA)

ClaaS

60

4

B - with diazepam :

A - without diazepam : 35 3 23 3 44 3 56 2 58 3 21 3 41 3 31 2 43 3 39 2

Age

Yes

YeS Yes Yes -

-

Previous cerebral embolus

140

105 125 105 60 120 110 75 120 105 105

Duration of extracorporeal circulation (mi@

under 50

under 50 over 50 under 50 under 50 under 50 under 50 under 50 over 50 under 50 over 50

Pressure of perfusion (mmHg)

In all Tables, the diazepam was given in a dose at 1 mg/kg/h body weight.

NEUROLOGICAL AND NEUROPSYCHOLOGICAL TREATED AND NOT TREATED WlTH DIAZEPAM

TABLE I OF

PATIENTS

WITH

AORTIC

PROSTHESES

Akinetic mutism with disorientation place

to persons, time,

Depression and refusal of food Depression and insomnia Paralysis of the right arm Coma Coma Agitation and insomnia Coma Agitation, insomnia with nightmares Depression, hallucinations and loss of recent memory Coma

Cerebral damage

THE

Yes

diazeparn: 4

B -with 60

Yes -

Previous cerebral embolus

Yes Yes

Functional class (NYHA)

A - without diazepam: 43 3 52 3 4 56 42 3 55 3 67 4

Age

142

110 95 126 104 105 110

Duration of extracorporeal circulation (min)

NEUROLOGICAL AND NEUROPSYCHOLOGICAL TREATED AND NOT TREATED WITH DIAZEPAM

TABLE II

under 50

under 50 over 50 under 50 over 50 under 50 under 50

Pressure of perfusion (mmHg)

DYSFUNCTIONS

OF

PATIENTS

WITH

MITRAL

PROSTHESES

Depression and refusal of food

Paralysis of the left arm and akinetic mutism Depression and disorientation to time and space Coma Depression, anguish and destructive instinct Coma Coma

Cerebral damage

THE

W N

30 30 60 6 54 22 36 22 36 45 15 23 37

Aortic valves Mitral valves Total of csses

Previous cerebral emboli Without previous cerebral emboli

Classes I-II NYHA Classes III-IV NYHA

Duration of ECC over 100 min Duration of ECC under 100 min

Pressure of perfusion over 50 mmHg Pressure of perfusion under 50 mmHg

Age over 50 years Age under 50 years

No. of patients

FREQUENCY AND STATISTICAL SIGNIFICANCE PROSTHESES NOT TREATED WITH DIAZEPAM

TABLE III CEREBRAL

5 4

1 8

7 2

2 7

5 4

5 4 9

Patients with neurological damage

OF

IN

1 6

4 3

6 1

1 6

1 6

5 2 7

Patients with psychological damage

DAMAGE

WITH

26.0 27.0

11.1 73.0

59.0 7.9

13.6 34.2

100.0 18.5

33.3 20.0 26.6

Frequency %

PATIENTS

x2 0.069 N.S.

x= 19.205 P < 0.001

X= 16.208 P < 0.001

x* 2.111 N.S.

x= 14.403 P < 0.001

Significance

VALVULAR

IV

NYHA

NYHA

of perfusion under 60 mmHe

Age over 60 years

Age under 50 years

Pressure

Presstam of perfusion over 60 mmHg

Duration of ECC over 100 min.

Duration of ECC under 100 min.

CIesses III-IV

Chsees I-II

,

without previous cerebral emboIi

Previous cerebral emboIi

Total of cases

OF

CEREBRAL

23 (1) 33 (2)

37 (1) 42 (2)

15 (1) 21 (2)

45 (1) 54 (2)

22 (1) 19 (2)

56 (2)

38 (1)

38 (1) 46 (2)

29 (2)

22 (1)

54 (1) 66 (2)

9 (2)

6 (1)

75 (2)

60 (1)

No. of patients

FREQUENCY AND STATISTICAL SIGNIFICANCE TREATED (1) OR TREATED (2) WITH DIAZEPAM

TABLE

6 2

10 0

11 2

5 0

13 2

3 0

13 2

3 0

10 1

6 1

16 2

Cerebral damages

DAMAGE

BETWEEN

-

-

-

-

26.9 6.1

27.0

73.3 9.5

11.1

59.1 10.9

7.9

34.2 4.3

13.6

18.5 1.5

100 11.1

26.6 2.7

(%)

FrflqWIlCY

PATIENTS

WITH

PROSTHESES

x2 2.913 N.S.

x= 10.690 P < 0.01

x1 12.889 P < 0.001

x* 4.105 N.S.

x2 8.558 P < 0.01

x1 2.424 N.S.

x2 10.641 P < 0.01

x= 2.077 N.S.

x2 8.571 P < 0.01

x2 8.136 P < 0.01

X2 14.603 P < 0.001

Significance of difference

VALVULAR

NOT P

95

emboli, the functional class (NYHA) using the chi-square (x2) test modified for the correction of Yates. We were attempting to evaluate the influence of all the measured variables in the causation of damage to the cerebral nervous system in the group of patients undergoing extracorporeal circulation without cerebral protection with diazepam. The discriminative limits chosen were: 100 min for the duration of extracorporeal circulation, 50 years for the age and 50 mmHg for the perfusion pressure during cardiopulmonary bypass. A level of 0.05 for the P-value was chosen for acceptable significance. Secondly, the two groups treated or not treated with diazepam were compared statistically. In view of the small number of cerebral dysfunctions, the absolute value of significance was limited in respect of the following observations: the group with previous cerebral emboli not treated with diazepam, and the group with previous cerebral emboli either treated or not treated with diazepam during the bypass. RESULTS

The types of cerebral complications found in the 135 patients who underwent open-heart surgery are shown in Tables I and II. The frequency of cerebral damage in the patients with valvular prostheses not treated with diazepam is reported in Table III. A highly significant incidence of cerebral damage was found with previous cerebral emboli, low perfusion pressure and duration of bypass greater than 100 min (P < 0.001). There was no correlation between cerebral damage and age or functional class. The comparison between the two groups of patients, treated or not treated with diazepam, showed (Table IV) a highly significant difference of incidence of cerebral damage with perfusion pressures below 50 mmHg during cardiopulmonary bypass (P < 0.001); there was a significantly different frequency of cerebral complications in the patients of less than the age of 50 years, belonging to functional classes III-IV, with or without cerebral emboli and if the bypass lasted longer than 100 min (P< 0.01). There were no significant differences in respect of other variables considered. DISCUSSION

Damage of the central nervous system, whose etiology is still being discussed, is found with variable frequency in open-heart surgery. Various causes have been considered: -

macroembolization of air or particulate matter from the heart following open-heart repair (Gihnan, 1965; Aguilar et al., 1971; Branthwaite, 1973; Carlson, Land& Landis, Rogoz, Baxter, Patterson, Stenzel and Lillehei, 1973; Salerno, Lince, White, Lynn and Charrette, 1978);

-

microembolization

from pump-bubble

oxygenators

or stored

blood;

96

the material may be air, foreign particles, microaggregates of platelets, leucocytes, fibrin or lipds (Sachdev et al., 1967; Ashmore, Svitek and Ambrose, 1968; Hill, Aguilar, Baranco, de Lanerolle and Gerbode, 1969; Brennan, Patterson and Kessler, 1974; Kritikou and Branthwaite, 1977); -

--

-

inadequate cerebral perfusion due to low perfusion pressures, prolonged cardiopulmonary bypass or cerebral vascular disease (Gilman, 1965; Brierley, 1967; Sachdev et al., 1967; Lee, Miller, Rowe, Hairston and Brady, 1969; Aberg and Kihlgren, 1974; Kritikou and Branthwaite, 1977); inadequate capillary bed perfusion inherent in non-pulsatile perfusion procedures (Sanderson, Wright and Sims, 1972; Aberg and Kihlgren, 1974; Kritikou and Branthwaite, 1977; Taylor, Wright, Bain, Caves and Beastall, 1978); hypothermia (Bjork and Hultquist, 1960; Egerton and Kay, 1964);

Cerebral dysfunctions have included psychiatric complications (Blachley and Starr, 1964; Egerton and Kay, 1964; Kornfeld et al., 1965; Hazan, 1966; Sachdev et al., 1967; Lee et al., 1971; Dubin et al., 1979), as well as clinical signs of both focal and diffuse neurological deficit (Silverstein and Krieger, 1960; Ehrehaft and Claman, 1961; Gilman, 1965; Witoszka et al., 1973). Many publications have rejected the classification of neurological disorders as “organic” or “non-organic”, even if the nature of these behavioral changes and their relationship to neuroanatomical damage have not been clearly defined (Tufo and Majafii 1969; Tufo et al., 1970). On the other hand, while the neurological deficits are easily classifiable and correlate with specific and topographically localized cerebral damage, the psychiatric symptoms are not only difficult to attribute to particular diagnoses but also to correlate with localized anatomic cerebral damage (Tufo and Majafi, 1969; Tufo et al., 1970; Dubin et al., 1979). One of the most important problems in the study of psychiatric complications is the lack of agreement on diagnostic terms. After a cardiac operation various psychiatric symptoms have been described : transitory psychosis, delirious states, confusion, depressive reactions, emotional alterations, schizophrenic reactions, hysteric syndromes, akinetic mutism, anxiety reactions, hallucinations, akinetic conditions called “catastrophic reactions” (Bass and Longmore, 1969; Quinlan, Kimball and Osborne, 1974; Dubin et al., 1979). Our patients who underwent open-heart surgery suffered from different psychiatric complications (Tables I and II). The frequency of cerebral damage in the group of patients without diazepam (26.6%) was of the same order as that reported by Lee et al. (1971) (35%), by Tufo et al. (1970) (40%), by Javid, Tufo, Najafi, Dye, Hunter and Julian (1969) (35%) and by Gilman (1965) (34%). Even the incidence of psychiatric damage (11.6%) was similar to that reported by Prank, Heller, Kornfeld and Malm (1972) (10%) and by Lee et al. (1969; 1971) (14%).

97

The reported higher incidence of cerebral dysfunction in patients of more than 50 years of age (Tufo et al., 1970; Branthwaite, 1973; Kolkka and Hilberman, 1980), and when the pressure of perfusion is less than 50 mmHg or the duration of the bypass is greater than 100 min (Lee et al., 1971; Witoszka et al., 1973) induced us to subdivide the groups of patients using these criteria. In agreement with the literature, we found a greater incidence of cerebral damage in the group of patients not treated with diazepam’when the bypass lasted more than 100 min, in patients with a history of previous cerebral emboli or in presence of a perfusion pressure below 50 mmHg during the extracorporeal circulation (Lee et al., 1971; Frank et al., 1972; Branthwaite, 1973; Aberg and Kihlgren, 1974). In agreement with Matarazzo, Bristow and Reaune (1963), we did not find a difference of incidence of cerebral damage related to age, which was, however, found by Tufo et al. (1969, 1970), Dublin et al. (1979) Sveinsson (1975), and Kolkka and Hilberman (1980). The diazepam was chosen as a cerebral protective open-heart surgery since it reduces uptake of oxygen by the brain (Cotev and Shalit, 1975), while only causing slight cardiocirculatory depression (Jackson, Dhadphale, Callaghan and Alseri, 1978). It inhibits glycolysis and reduces glucose utilization in the cerebral cortex, as do the barbiturates (Cotev and Shalit, 1975; Carlsson and Chapman, 1981). Particularly if it is administered with NzO it causes a considerable reduction in cerebral metabolism comparable to that observed with barbiturates (Cotev and Shalit, 1975; Carlsson, Hagerdal, Korasik and Siesjo, 1976). However, it depresses the myocardial contractility and lowers the arterial pressure less than do barbiturates (Stella, Tori and Castiglioni, 1979). In view of such dangers, barbiturates must be used with extreme caution. Diazepam can cause a mild dilatation of the coronary arteries (Abel, Reis and Staroscik, 1970) and an increase of the myocardial contractility (Dalen, Evans and Banas, 1969; Prindle, Gold and Cardon, 1970). Therefore, its use is also indicated in patients with reduced coronary reserve. Diazepam reduced the incidence of cerebral damage. Such a protective effect on the brain is seen, particularly when the perfusion pressure was less than 50 mmHg during the bypass. It would, also, have a protective action in the presence or absence of previous cerebral emboli, when the bypass lasted longer than 100 min, in the patients belonging to a functional classes III and IV, or who were less than 50 years of age. In the patients who were more than 50 years old, the treatment markedly decreased the incidence of cerebral damage from 26% to 6% even although this difference was not statistically significant. The reported data support the idea that diazepam protects the brains of patients undergoing open-heart surgery. In conclusion, the small effect of diazepam on the cardiocirculatory system and its cerebral protective action - similar to that exerted by barbiturates - suggest that it could be very useful in open-heart surgery.

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100 Steen, P.A. (1980) Barbiturate protection against ischemic brain damage. Stand. J. Clin. Lab. Invest., 40,205-207,. Stella, L., Tori, G. and Castiglioni, C.L. (1979) The relative potencies of thiopentone, Ketamine, propanidid, alphaxalone and diazepam. A statistical study in man. Br. J. Anaesth., 51,119-122. Stockard, J.J., Bickford, R.B. and Schauble, J:F. (1973) PressuredependelW cerebral ischemia during cardiopulmonary bypass. Neurology, 23, 521-529. Sveinsson, I.S. (1975) Postoperative psychosis after open heart surgery. J. Thorac. Cardiovast. Surg., 70,717-726. Taylor, K.M., Wright, G.S., Bain, W.H., Caves, P.K. and Beastall, G.S. (1978) Comparative studies of pulsatile and non-pulsatile flow during cardiopulmonary bypass, III&esponse of anterior pituitary gland to thyrotropin-releasing hormone. J. Thorac. Cardiovasc. surg. 75,579+x4. Tufo, H.M. and Majafi, H. (1969) Neurological abnormalities following open-heart surgery. J. Thorac. Cardiovasc. Surg., 58,502-509. Tufo, H.M., Ostfeld, A.M. and Shekelle, R. (1970) Central system dysfunction following open-heart surgery. JAMA 212, 8,1333-1340. Witoszka, M.M., Tamura, H., Indeglia, R., Hopkins, R.W., Simeone, F.A. and Providence, R.I. (1973) Klectroencephalographic changes and cerebral complications in openheart surgery. J. Thorac. Cardiovasc. Surg., 66,855~863.