thehematokrit rectal temperature alvar visiograph supra .8" beckman micro-hematokrit centrifuge...

J. clin. Path., 23, Suppl. (Roy. Coll. Path.), 4, 202-212

The function of the central nervous system afterhaemorrhage

ARISZTID G. B. KOVACHFrom the Experimental Research Department, Semmelweis University Medical School, Budapest,Hungary

In the first description of the characteristicsymptoms following severe physical trauma,Ambroise Pare in 1575 mentioned that thefeatures of this condition are: flaccid, atonicmusculature, cold sweat, feeble, quick pulse,unresponsiveness, and general indifference. De-fects in nervous function are evident- from thisdescription. In 1889, Crile (Crile and Lower,1899) suggested from experimental results thatthe central nervous system played an importantrole in the development of shock. He thoughtthat impulses originating from the injured areasinhibited the medullary vasomotor centres, thusreducing blood pressure and, if lasting longenough, resulting in a definite impaiirment ofthe circulation. Opinions in the literature dis-agree on the role of somatic and visceralnociceptive afferent impulses in the developmentof irreversible shock (Slome and O'Shaughnessy,1938; Overman and Wang, 1947; Arshawskaya,1950; Guthrie, 1957; Popov, 1959). Later, othertheories gained dominance and the interest in thenervous changes in shock gradually disappeared.But the regulatory adjustments needed to pre-serve physiological homeostasis depend on thenervous system so that when a progressivedeterioration in homeostatic adjustment developsin response to haemorrhage nervous functionmust be affected.

This report is concerned principally withinvestigations carried out in our Institute inBudapest, where one of the chief subjects ofinvestigation has been the functional andmetabolic changes in the central nervous systemand the significance of altered regulatory pro-cesses in the development of haemorrhagilc shock.

Biochemical Changes in Brain Tissue afterTrauma to the Body

In our earlier investigations on rats in traumaticshock (Kovach, Bagdy, Balazs, Antoni, Gergely,Menyhart, Iranyi, and Kovach, 1952) it wasfound that the adenosine triphosphate (ATP)and creatine phosphate (CrP) concentrationsdecreased significantly only in the terminal stages.These findings were contrary to those of McShan,Potter, Goldman, Shipley, and Meyer (1945) butwere confirmed by Stoner and Threlfall (1954).Like the last named authors, we have found thatsevere adynamia and impaired reflexes can beobserved in shock while the energy-rich P contentof the brain is still normal (Fonyo, Kovaich, andKovach, 1957; Kovach, Fonyo, and Kovach,1959a). However, normal concentrations ofATP and CrP do not necessarily imply that therate of oxidative phosphorylation is normal. Theactual energy-rich P content depends on theequilibrium between synthesis and utilization.We could demonstrate that the rate of synthesisof energy-rich P in the brain was decreaseddespite normal concentrations. If the concen-tration of CrP was reduced by bitemporalelectrical stimulation, its rate of resynthesis inthe injured rats was very much slower than innormal rats (Kovach, Fony6, and Kovach,1958b). It was also found that the incorporationof 32p into the energy-rich P compounds wassignificantly lower in shock than under normalconditions (Kovach and Fonyo, 1965).The acetylcholine content of the brain was

found to increase considerably after trauma(Kovach, Fonyo, and Halmagyi, 1958a).

copyright. on January 27, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.s3-4.1.202 on 1 January 1970. Dow

nloaded from

http://jcp.bmj.com/

The function of the central nervous system after haemorrhage

More recent investigations have shown thatthere is a significant increase in the potassiumcontent of the brain after trauma (Kovach,Kellner, and Maklari, 1965a). This is of interestas we had previously found that an increase inthe potassium concentration altered the P meta-bolism of the brain in vitro (Fonyo, Kovach,Maklari, Leszkovszky, and Meszatros, 1958).

Perfusion of the Isolated Head

Studying the metabolism of the brain in vivo intourniquet and haemorrhagic shock, Kovach,Roheim, Iranyi, Kiss, and Antal (1958d) observedthe effect of perfusion of the isolated head. Thecirculation to the head of the dog was isolatedfrom the trunk and the head was perfused with

Parameters measured simultaneously in standardized hemorr-mmHg hagic shock150~100

50

B. B.it1. R. 23 4

Systolic and diastolic art. pressure

Right atrial pressure

Heart frequencyECG II.

Cardiac outputC.o. head and forelimbs-flowC. o. splanchnic -flowC. o. pelvic and rearlimbs-flowVentillationElectrocorticogramHemoglobinHematokritRectal temperature

ALVAR VISIOGRAPH SUPRA .8"BECKMAN micro-hematokrit

centrifuge

Tissue oxygen tensionmeasurment

CortexHypothalamus

POLAROGRAPHIC PRINCIPLEKUTESZ 4-channel instrumentBECKMAN physiological gas

analyzer Mod. 160

Blood-flow measurmentCortexHypotholamus

HENSEL PRINCIPLEby heoted thermo coupleHARTMANN AND BRAUN

A, FLUVOGRAP.H

Bleeding by the LAMSON technique(ENGELKING -WILLIG)

Fig. 1 Summary of the experimental protocol inhaemorrhagic shock experiments on dogs illustratingthe two periods of haemorrhagic hypotension referredSO in the text as BI and BII and the typical changesin blood pressure after reinfusion at R.

blood from donor dogs. Only the spinal cord andthe vagosympathetic trunk remained intact be-tween the head and the body of the acceptor dog(Kovach, 1954). The purpose was to determinewhether a normal supply of blood to the headwould modify the course of shock. Tourniquetshock was induced by ligating both hind limbsat the inguinal level for five hours. Haemor-rhagic shock was induced by a modified Wiggersmethod, ie, maintaining the blood pressure at55 mm Hg for 60 minutes, then at 35 mrn Hg foranother 60 minutes (Wiggers, 1950).

Perfusion of the isolated head lengthened thesurvival time in both tourniquet and haemor-rhagic shock. The survival time was, in bothcases, significantly longer. Intracarotid perfusion,without isolation of the head, with 50 ml blood/min during the hypovolaemic period alsolengthened the survival time of animals inhaemorrhagic shock, and, in 50% of cases resultedin a complete survival despite the fact that anequal quantity of blood was continuously with-drawn from the jugular vein and femoral artery(Kovach et al, 1958d). Perfusion of the isolatedhead during the hypotensive period of haemor-rhagic shock also completely restored renalfunction compared with the control shockanimals which had anuria (Kovach, Roheim,Iranyi, and Kovach, 1958e).

Electrocorticogram (ECoG)

Because of all the tissues in the mammalian bodythe nervous tissue is the least capable of with-standing lack of oxygen, and because it is knownthat hypoxia changes the electrical activity of thecentral nervous system (van Liere and Stickney,1963), we also studied the effect of haemorrhagicand ischaemic shock on the spontaneous cerebro-cortical electrical activity (ECoG).

In the following experiments for inducinghaemorrhagic shock a modified Lamson tech-nique (Engelking and Willig, 1958) was used(Fig. 1). As a standard procedure, the dog, underchloralose anaesthesia, was kept on stabilizedmean arterial blood pressure levels of 55 and 35mm Hg respectively (BI and BIT). Each periodwas maintained for 90 minutes. After theoligaemic period all the blood remaining in thebottle was reinfused. Blood coagulation wasprevented with heparin (5 mg/kg). The arterialand right atrial pressures, the ECG in standardlead II, respiration, and the ECoG on four leadswas recorded on an eight-channel Alvar Viso-graph Supra. The cardiac output and the head-forelimb, the splanchnic, and the pelvic-hindlimb blood flow were measured by the thermo-dilution method as modified in our laboratory(Fronek and Ganz, 1960; Kovach and Mitsanyi,1964). Physiological saline at room temperaturewas injected into the aorta at three different

203copyright.

on January 27, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.s3-4.1.202 on 1 January 1970. D

ownloaded from

http://jcp.bmj.com/

Arisztid G. B. Kovach

points: in the ascending aorta, at the level of thediaphragm, and below the renal arteries. Thethermistor was inserted to the bifurcation of theaorta through a branch of the femoral artery.The dilution curves were calculated with the aidof a Fischer cardiac output computer (FischerA.G., Gottingen). The respiratory rate wasmeasured with a thermistor in the trachealcannula. The haemoglobin content and haemato-crit value (microhaematocrit) of arterial blood,and in some cases of venous blood, was measuredevery 15 minutes.In both haemorrhagic and tourniquet shock, sig-

nificant changes were found in the ECoG (Kovachand Fonyo, 1960). Activity was impaired at 55mm Hg blood pressure and after a period of 30min at 35 mm Hg activity ceased and only iso-electric readings were recorded. When theanimals were reinfused the ECoG activity did notreturn although the blood pressure remainedwithin the normal range for a considerable time.In some cases further blood transfusion wasgiven without improvement in the ECoG. Indogs so bled that the BII period was notlonger than 35 minutes (Fig. 1) the ECoGreturned almost completely to normal 30-90 minafter reinfusion.

'1.110 . Control

Dibenzyline i.v.100 Dibenzyline i.c.

100 .

90.

80 XP

70

60.

50 d

40-

30

20-

10-

0 c 30V60s90' sdol0o3'do'so ~~~~3Y6~Y 9Y 12(1BI.o Bli.-->after R

Fig. 2 The changes in the electrocorticogram duringand after haemorrhagic hypotension in untreatedcontrol dogs and dogs pretreated with phenoxy-benzamine (Dibenzyline), either S mg/kg i.v. or0.5 mg/kg i.c. Average starting wave amplitudeexpressed as 100%.

Phenoxybenzamine, 5 mg/kg intravenously or0.5 mg/kg intracarotid before bleeding, protectedagainst the impairment of activity. The ECoGchanges in different phases of shock after haemor-rhage are summarized in Figure 2. The averagewave amplitude analyses are expressed aspercentages, the starting wave amplitudes beingtaken as 100%. The same pretreatment withphenoxybenzamine lengthened the survival timeand increased the survival rate of dogs in haemor-rhagic shock (Menyhart, Kovach, Kiss, Erdelyi,and Kovach, 1954; Kovach et al, 1958d). Therecovery of the hypoxic ECoG changes dependedlargely on the available oxygen, the blood flowthrough the brain, and the duration of hypoxia.The loss of ECoG activity could be explained bythe fact that during oligaemia the brain lactic acidincreases and the extracellular potassium con-centration rises to levels at which brain metab-olism is depressed (Kovach and Fonyo, 1960).

Spontaneous Activity in the Hypothalamus

Subsequently we investigated the spontaneousbioelectrical activity in the hypothalamus and inthe reticular formation in dogs anaesthetizedwith chloralose (Kovach, Fedina, Mitsanyi,Naszlady, and Biro, 1962). The spontaneouselectrical activity in these regions disappearedafter bleeding at the same time and in the sameway as the ECoG.

Cerebral Blood Flow

It has been shown that when the cortical bloodflow increases, the mean frequencies in electro-cortical activity also increase and vice versa(Lee, Tindall, Greenfield, and Odom, 1966;Baldy-Moulinier and Ingvar, 1968). The questionarises whether a decrease in cerebral blood flowfollowed by cerebral hypoxia could impair thecerebral bioelectrical activity. Jourdan, Collet,and Masbarnard (1950) studied the changes inthe calibre of the cerebrocortical vessels througha window but did not find alterations afterhaemorrhage. Kovach, Roheim, Iranyi, Cserhati,Gosztonyi, and Kovach (1959b) found that inischaemic limb shock the mean blood flowthrough the head measured with a rotameterdecreased 20-25% but this change alone could notbe responsible for the severe cerebral hypoxiaand neural impairment because this degree ofrestriction in the blood flow did not affect theECoG when tested in separate experiments.

Total cerebral blood flow measurements can-not give information about changes in regionalflow so that in our next experiments cerebro-cortical and hypothalamic blood flow wasmeasured. Two methods were used on dogs in

204copyright.


http://jcp.bmj.com

/J C


ownloaded from

http://jcp.bmj.com/


chloralose anaesthesia. One method was thatdescribed by Hensel and Ruef (1959) based onthe measurement of the thermal conductivity ofthe tissues. Continuous recording was carriedout with a direct writing two-channel device(Fluvograph, Hartmann and Braun, Frankfurt).The probes were made according to Betz et al(1961) and were inserted into the cortex or

Hypothalamus

*1.

120.100-80.60-4020j0.

hypothalamus with a stereotactic apparatus.Blood flow records were evaluated in terms of

relative (percentage) thermal conductivity. Thedifference between the thermal conductivity( JA) at the beginning of the experiment and afterdeath is referred to as 100% (Kovach, Mitsanyi,and Stekiel, 1965b).The H2 washout method described by Aukland,

140120.10080

/' 60-40-20.O0

Myocardium

.,I -- ~ m-A,%,* ^_- __

p'-rc~mc

, ",q,

Kidney

MM~~ ~R

JN%8 "8y %, 100.

80160-

20-O0

10

5.,

0

E

15 5 min

afterR

30 60

B I.

Adipose

C Bl. Bll.- control

x---x DBZ pretreated

Fig. 3 Bloodflow through various organs and tissuesduring and after haemorrhagic hypotension in dogsmeasured by the H, electrode method except in thecase ofadipose tissue where flow was measured bythe method of Rosell (1966). The initial flow measuredby the H, electrode is expressed as 100 %. Theinterrupted lines show the changes in dogs pretreatedwith phenoxybenzamine (Dibenzline) 5 mg/kg i.v.

Liver12010080604020j0.

r015 5min

ofterR

°%N,,0~mM

30 60 9aBll.

Muscle

90

a

9 94- 40~~~

120.100-80-

*/. 60-4020-0.

15 30

Bi.60 9C 60 9030

B 11. R

Xa T4

2 aT -1

WOM - --- __+

205

- -.c.m

m Cow~Me- we q 1%*MW~mw~mm.d



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


Bower, and Berliner (1964) was also adapted forthe measurement of local blood flow. Two orthree platinum electrodes, 0.5 mm in diameter,were introduced by a stereotactic apparatus intothe cerebral cortex and hypothalamus (nucleusventromedialis). The electrodes were insulatedwith Insl-X (Insl-X Products Corp. Yonkers,N.Y.) leaving 0-8 mm bare at the tip. Theindifferent electrode of the circuit was a calomelelectrode introduced under the skin of the leg viaa polyethylene tubing KCl-agar bridge. Apositive polarizing potential of 250 mV wassupplied to the measuring electrodes. Hydrogensaturation of the tissues was attained by inhalingthe gas. The exponential desaturation curveswere recorded on a Kipp BD-3 micrograph andtransferred to semi-logarithmic paper; the slopeof the line thus obtained is proportional to bloodflow which can be calculated in ml/min/g accord-ing to the method of Kety (1960).

In the bleeding period I the cerebral corticalblood flow remained unchanged when examinedby both methods. In the BII period it fell to70 to 80% of the original flow level. The bloodflow changes were different in the hypothalamicregion where the flow fell to 65% in the BIperiod and to 40% of the original value in theBII period (Fig. 3). In Fig. 3 we can comparethese blood flow changes with those in othertissues. It is clear that the hypothalamus is notso well protected against a fall in blood pressureafter haemorrhage as the cortex. It is interestingto note that there is no difference in cerebral andhypothalamic blood flow between the control andgroups pretreated with phenoxybenzamine afterhaemorrhage (Kovach et al, 1965b). This findingis especially interesting, because as was shown

CControlDibenzylinetreated

.U1.

_ af ter R.

Fig. 4 The changes in pO2 in the hypothalamusduring and after haemorrhagic hypotension inuntreated control dogs and dogs pretreated withphenoxybenzamine (Dibenzyline) S mg/kg i.v.(interrupted line). The initial p02 is expressed as 100%.

earlier, such pretreatment protects against theECoG changes in shock. H2 desaturationmeasurements also showed a fall in blood flowlike that described with the heat clearancemethod. These results would suggest that thehypothalamic blood flow autoregulation differsfrom that in other parts of the brain. Thequestion arises whether or not we are dealingwith a defensive or protective mechanism.

Cerebral Oxygen Tension

Because we could not find any difference in bloodflow changes between the controls and groupspretreated with phenoxybenzamine after haemor-rhage, the question arose as to whether there weredifferences in regional oxygen utilization in thebrain. The 02 tension in the hypothalamus wasmeasured polarographically with platinum micro-electrodes (Beckman). We found a continuousand progressive decrease in PO2 during the BIand BIT periods to below 20% of the initial value(Fig. 4). After reinfusion, the hypothalamic P02did not rise and remained at this low level despitea significant elevation in local blood flow. Theseresults suggest that oxygen utilization is in-creased in the hypothalamus after bleeding(Kovach et al, 1965b). An elevated cerebral 02consumption after limb ischaemia was describedin earlier papers (Kovafch, Menyhafrt, Erdelyi,Molnar, and Kovach, 1958c). In-vitro studies alsoshowed that O2 uptake by brain slices from ratsin shock was significantly higher than by brainslices from normal rats (Kovach, Fonyo, Vittay,and Pogaftsa, 1957).

In the group treated with phenoxybenzaminethe PO2 in the hypothalamus showed a smallerfall during the hypotensive period and returnedto normal after reinfusion (Fig. 4).

Cerebral A-V Oxygen Difference

Figure 5 shows the arteriovenous 02 differences in16 control and 11 dogs treated with phenoxy-benzamine in haemorrhagic shock. The sagittalvein was cannulated and blood samples weretaken every 15-20 minutes. The arteriovenous02 difference rose very considerably afterhaemorrhage in the untreated dogs. The A-V02difference remained high after reinfusion. Pre-treatment with phenoxybenzamine had a definiteeffect, for in these animals the A-V02 differencedid not change after haemorrhage.From the present results we can conclude that

the cerebral hypothalamic 02 utilization in-creases considerably during haemorrhage so thatthe reduction in blood flow can result in severelocal hypoxia. The increased total cerebral 02utilization is maintained after reinfusion while

10090-80

c 700c 60t 50c 40-> 30o 20

10;0

mnn.

206copyright.


http://jcp.bmj.com

/J C


ownloaded from

http://jcp.bmj.com/


A-V 021-51 Art.-vena sagittalis A-V 02

hypoxia, leads to functional impairment in thecentral regulatory functions. In this respect, theearly impairment of hypothalamic function isespecially important.

Cerebral Hypercapnia

---rT ---1t-

C. Dib. 30 90' 30' 90' 30' 60' 90'B 1. B 11. after R

Fig. 5 The arteriovenous (sagittal vein) 0ences during and after haemorrhagic hypot,untreated control dogs and dogs pretreatedphenoxybenzamine (Dibenzyline) S mg/kg j(interrupted line). A-V 02 differences exprtpercentages.

the blood flow is normal. Phenoxyprevented the increase in cerebralsumption, and, consequently, the pCreduced during bleeding. After reinihypothalamic PO2 became normal itreated with phenoxybenzamine. Thithat the protective effect of pretreatphenoxybenzamine may be relatedmetabolic effect.What are the causes of the increase

uptake in shock?The increase in O2 uptake might

catecholamines inasmuch as King, So]Wechsler (1952) have shown thatincreases 02 consumption in humatissue in vivo. This possibility is undthe fact that pretreatment withbenzamine reduced the elevated 02 co

of the brain in shock in the present exOther humoral factors may also playThe significance of an increasec

afferent nervous impulses has to beconsideration. Partial transection of tpathways in the spinal cord (Swingle, F

Kleinberg, Drill, and Eversole, 1942), 1

of the sinus or Hering nerve (MWinternitz, 1945), and vagal transecticand Kovach, 1961) all had a favourab]shock. On the basis of these results,suggested that after haemorrhage or trcatecholamine secretion and nociceplincrease the metabolism of the centrsystem, which, together with the lh

It is known that characteristic changes in acid-base balance have been demonstrated in thecourse of haemorrhagic shock (Root, Allison,Cole, Holmes, Walcott, and Gregersen, 1947;Darby and Watts, 1964; Baubkus and Kirchheim,1966).

Dibenzyline Comparison of thepH, bicarbonate, and pCO2pretreated in carotid and sagittal venous blood suggests

that the central nervous system must be involvedin the disturbance of acid-base balance. It was

0' striking to find that a significant increase inpCO2 in the blood of the sagittal vein developsduring bleeding while the bicarbonate level

2 differ- declines in the same manner as in arterial blood.lension in This causes a substantial fall in pH, largelywith through the increase in pCO2. Acidity thus

L.v. increases in the blood perfusing the brain. Toessed as the changes in the CO2 of the

brain tissue in haemorrhagic shock we performedexperiments on dogs anaesthetized with chloral-ose. Both controls and animals treated with

'benzamine phenoxybenzamine were used. Blood samples02 con- were taken from the carotid artery and from the

)2 was less sagittal vein before bleeding, at the end of thefusion, the BII period, one hour after reinfusion, and in thein animals terminal phase of shock. After each bloodis suggests sampling 10 animals were decapitated by a singletment with blow. The skull was opened immediately, theto a local brain was immersed in paraffin and specimens

were excised from the frontal and occipitalin cerebral cortex, thalamus, hypothalamus, pons, and

medulla oblongata. The samples were pulverizedbe due to in liquid nitrogen and their CO2 content waskoloff, and estimated by the method of Anrep, Ayadi, andadrenaline Talaat (1936).n cerebral The CO2 content in cerebral tissue obtainedlerlined by from six different parts of the brain rangedphenoxy- between 15 and 20 mmol per kg wet weight

nsumption before bleeding. At the end of the BII period,periments. the figures had risen to 40 mmol in the hypothal-a part. amus and to 30.5 mmol in the frontal cortex,1 flow of whereas the values found in the thalamus (20.4taken into mmol) and other regions were not significantlyhe afferent raised. Reinfusion was followed by a reduction of(emington, hypercapnia in the hypothalamus and the frontaltransection cortex. With increasing severity of shock thelylon and CO2 content of cerebral tissue increased sig-:n (Erdelyi nificantly again. The values as percentages of thele effect on prebleeding values are presented in Fig. 6,it can be (Maklari and Kovach, 1966 and 1968).auma both Brain CO2 values in dogs pretreated withtor stimuli phenoxybenzamine before bleeding were higheral nervous than in the controls. Levels of over 20 mmol perocal tissue kg wet weight were found in the frontal cortex

* Control

207

--i



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


(23.1 mmol) and in the hypothalamus (26.3mmol). Unlike the untreated animals the CO2content of the cerebral tissue diminished but thereduction was not significant. No tissue hyper-capnia was found after reinfusion either (Fig. 6).From these results it may be inferred that

haemorrhage affects the different parts of thecentral nervous system to different degrees.These results also suggest that the reduction inblood flow and the increase in 02 requirementsduring the hypotensive phase leads not only tohypoxia, but also to metabolic changes in thehypothalamus and frontal cerebral cortex asreflected by tissue hypercapnia and increasingacidosis. None of the dogs pretreated withphenoxybenzamine presented any of the signs ofthe severe acidosis found in the untreated dogsduring haemorrhage. The pCO2 of the sagittalvenous blood remained constant. This differencebetween the pretreated and the control animals isemphasized by the fact that as shown above thefall in blood flow during bleeding was the samein both groups. Infusion of buffer solutions hasa similar effect (Fig. 7) to phenoxybenzamine,protecting the brain from hypercapnia in theBIT period (Maklari, Kovach, and Nyary, 1970).We thought that phenoxybenzamine could exert

Co230.

300,

a direct influence on tissue metabolism, reducingthe brain damage (Kovach, Menyhart, Erdelyi,Molnar, Kiss, Kovafch, and Bodolay-Varga,1961). To investigate the possible metabolic roleof pretreatment with phenoxybenzamine, westudied the effect of phenoxybenzamine onisolated rat liverand brain mitochondria (Kovafch,Koltay, and Kovach, 1970). It was found thatphenoxybenzamine in concentrations of 2.5,ug/ml medium and above reduced the metabolicactivity of the rat liver mitochondria so thatstate IV and state III respiration and thedinitrophenol-activated respiration were reduced(Fig. 8). A dose response effect is demonstratedin Figure 9. These results indicate thatphenoxybenzamine has metabolic actions inaddition to those of a-receptor blockadewhich might be concerned in the effect of pre-treatment with phenoxybenzamine on the effectsof haemorrhage.

Hypothalamic Stimulation

That the cardiovascular mechanisms controlledby the hypothalamus are greatly affected by

a- before haemorrhageb=end of -"- E.C n lh after retransfusiond = 2h3r-e.- _1

controtn m dib. pretreated

.t ~~tlb

ab c d a b c d a b c d a b c d a b c d1 2 3 4 5

a b cd6

Fig. 6 The changes in the CO2 content of thecerebral tissues at the six sites indicated in thediagram during and after haemorrhagic hypotensionin untreated control dogs and dogs pretreated withphenoxybenzamine (Dib) 5 mg/kg i.v. The initialC02 content is expressed as 100%.

208

2'i1'I

1

3 4 56



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


NORMAL AT THE END OF HAEMORRHAGE

30204

0-

30120]

OCCIPITAL CORTEX

m20. THALAMUS

21°D EnHHYOTALMUIiHYPOTHALAMUS401

20

10

30 PONS20_10.i L n

20 MEDULLA OBLONGATA

10. [ nn0- ~ 1 2 3 41untreated 2: duringB7continuousty adm.THAM buffer sol.

3:during B., conbnuously odm. bicorbonate solution4 bicarbonate inf. in the last period of B.

Fig. 7 The changes in the CO2 content of six partsof the brain ofdogs in haemorrhagic hypotensionand being treated with different buffers.

2911

DNPT 17940 jM

Fig. 8 The polarographic measurement of therespiration offour samples of rat liver mitochondriashowing the inhibitory effect ofphenoxybenzamine(PBZ) on state IV respiration and later, in the case

of the higher dose, on the responses to the addition ofadenosine diphosphate (ADP) and dinitrophenol(DNP). The phenoxybenzamine was dissolved in 50%ethanol and the lack of effect of the addition ofappropriate volumes of the solvent is shown by thetracings on the left. Tracings to be readfrom leftto right. Mitochondria added at M.

c

(D0

~0E0ac

260240220200' \180 \160140 \

120 \100\80 \60- \ Uncoupled20 ~ St.Il.o- . . , St. IV.0 5 10 25 50,ug PBZ/m(

Fig. 9 Effect ofphenoxybenzamine (PBZ) on the02 uptake of rat liver mitochondria in differentmetabolic states.

haemorrhage is also shown by the followingresults. In 17 dogs in chloralose anaesthesia we

studied the effect of stimulation of the hypothal-amus and reticular formation during the course

of haemorrhagic shock and after reinfusion.Stimulating electrodes were inserted eitherimmediately or one week before the bleeding,using sterotactic apparatus. Before bleedingstimulation produced a marked cardiovasculareffect (Fig. 10) which was abolished duringbleeding and the stimulating voltage had to beincreased to get a response in the BI period. Thethreshold level rose. In the BII period hypo-thalamic stimulation was without effect. In some

cases reinfusion produced a short-lasting recoverybut later the response to hypothalamic stimulationdisappeared (Kovach et al, 1962). To be sure thatperipheral disturbances were not responsible forthese results we stimulated the medulla directlyand obtained blood pressure responses (Fig. 11).

Evoked Responses in the Hypothalamus

Hypothalamic neural impairment could also bedemonstrated by studying the evoked responses(Kovach, Dora, and Nyary, 1970). Theseexperiments were carried out on dogs anaes-thetized with chloralose. Electrodes were insertedwith a stereotactic device into the fornix and thenucleus ventromedialis. The first electrode wasused for stimulation, the second for recording theevoked response. In Fig. 12 we can see thecontrol evoked response. After bleeding theanimals to 55 mm Hg for 30 minutes the evokedresponse changed, the positive wave disappearing.Reinfusion of the shed blood did not fully restorethe response. Bleeding the dog again to 55 mmHg and holding the blood pressure at this level

0)

-EE

2039

lm 31o7

75 juM 1 119PBZ

DP 291162 m

DNP40.uM 6,2



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


mmHg EXP. N°56 l8kgd(nembutal)dog ( Form. ret. tegm. stim.-~~~~~~.20befor B.l17"5 to

'fto

100 42V 2msec 30 c/secI 50 stimulation2240cc C.o. 2740cc C.o. 2130cc1230 Head 1400 Head 1090640' Abd. 900" Abd. 650"370 Hind 440 " Hind 390'mm Hg qu. qu. ,

.21 during B.l 1821

50° t 2V 22msec 30 c/sec2V ~s timulation1300cc C.o. 1270cc C.o. 156Occ500 oHead 440 Ha 610 '480" Abd. 370' Abd 650'320" Hind Ad 300

qu. Hqu.mmHg

. 100 after R. 19"°

150t4V 4msec 40csec4 9 t80c sec t8V t10v

2200cc Co. 2200cc stimulation850" Head 850"800" Abd. 780'550" Hind 570

qu.

Fig. 10 The effect of stimulation of the reticular formation of a dog under nembutal anaesthesia on the bloodpressure before, during, and after haemorrhage. The figures below the tracings give the total cardiac output(ml/min) and the volumes going to the head and forelimbs, the splanchnic region, and the hindquarters (see text).

H EXP. NO 56 (Medulla obl. stim.) R. +500cc saline 2053

1o LM!8V4msec 40c/sec I

s t i m ul a t o n2290cc Co. 3820cc C.o. 2860cc490 ' Head 1040" Head 8201400 a Abd. 1760 * Abd. 1120400" Hind 1020 after fi 2110 Hind 920

qu ~~~~~~~qu.mm Hg

10js5o'~'~ ~ 12V 4msec

0 7630cc C.o. 7630cc stimulation4850' Head 4230"19BO Abd. 1700'800R Hind 1700'

qu.after R 2239

mmHg s 4

150 s ~~~~~~~~~~~~~~aso 12V 4msec 40c/sec %52° s t i m uu a tio n exitus 23°2570cc C.o. 2480cc 2760cc C.o. 2600cc1130" Head 1280 , 1410 " Head 1400"920" Abd. 600". 870' Abd. 800'520' Hind 600s* 480' Hind 400

qu. qu.

Fig. 11 The effect of stimulation of the medulla oblongata ofa dog under chloralose anaesthesia on the bloodpressure during and after haemorrhage. The figures below the tracings give the total cardiac output(ml/min), and the volumes going to the head andforelimbs, the splanchnic region, and the hindquarters (see text).

210copyright.


http://jcp.bmj.com

/J C


ownloaded from

http://jcp.bmj.com/

The function of the central nervous system after haemorrhage 211

CONTROL BLEEDING I 30 2REINFUSION 3'

200 100 200

ARTESSURE MAA

fmHg o0 °

EEG 2000_lsec lsec lsec

EVOKEDSE 40,uV]

l0msec l0msec 10msec

60'AFTER REINFUSION BLEEDING 11 30' REINFUSION 60'200 10

ART. 10-5PRESSURE°00mmHg 0 0 O

EEG 40

lsec lsec ,sec

40,uV ];;_EVOKED 4~.VRESPONSE

10msec 10msec lUsec

Fig. 12 The effect of haemorrhage on the evokedresponse in the ventromedial nucleus of the hypo-thalamus following stimulation of the fornix in a dogunder chloralose anaesthesia.

for 30 min led to complete disappearance of theevoked response. The electrocortical activity, asseen in the right lower record of Fig. 12, was stillnormal. These results would suggest that evokedresponses in the hypothalamus are impairedbefore the spontaneous cortical activity, and thatthe hypothalamus is extremely sensitive tobleeding.

Conclusions

In summary, we can conclude that the centralnervous functions are seriously affected instandardized haemorrhagic shock.The impairment of the central nervous system

is not equal in all regions. The hypothalamic andperhaps the frontal cortex are specially sensitive.Blood flow autoregulation seems less well

developed in the hypothalamus, which is perhapsmore vulnerable than other regions.

Cerebral, cortical, and the hypothalamic 02utilization is raised in shock. This, together withthe fall in blood flow, increases the degree of localhypoxia. In addition to the loss of circulatorycontrol shown in these experiments the hypothal-amic impairment can involve other regulatorymechanisms such as those for temperature

regulation and neurohormonal secretion. Theresults are of interest in relation to the changesin thermoregulation after trauma described byDr Stoner in his paper (pp. 47-55).The protective action of phenoxybenzamine in

haemorrhagic shock may be due to the met-abolic as well as the pharmacological effectsof the drug.

References

Anrep, G. V., Ayadi, M. S., and Talaat, M. (1936). A method fordetermination of carbon dioxide applicable to blood andtissues. J. Physiol. (Lond), 86, 153-161.

Arshavskaya, E. J. (1950). On the mechanism of origin ofexp_rimental shock in the presence of nociceptive irritationin different age p.,riods. (Russian.) Fiziol. Zh (Mosk.), 36,333-341.

Aukland, K., Bower, B. F., and Berliner, R. W. (1964). Measure-ment of local blood flow with hydrogen gas. Circulat.Res., 14, 166-187.

Baldy-Moulinier, M., and Ingvar, D. H. (1968). EEG frequencycontent related to regional blood flow of cerebral cortexin cat. Exp. Brain Res., 5, 55-60.

Baubkus, H., and Kirchheim, H. (1966). Saure-basen Verander-ungen im hamorrhagischen Schock. (Abstr.) Actaphysiol. Acad. Sci. hung., 29, 342.

Betz, E., Braasch, D., and Hensel, H. (1961). Die Wirkung von2,6-bis-(diaethanolamino)-4,8-dipiperidino-pyrimido (5,4-d)-pyrimidin auf die Durchblutung von Myocard, Gehirn,Niere, Leber, Haut und Muskulatur. Arzneimittel-Forsch.,11, 333-336.

Betz, E., and Hensel, H. (1961). Lokale Registrierung der Gehirndurchblutung an wachen, frei beweglichen Tieren. Natur-wissenschaften, 48, 527-528.



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

Arisztid G. B. Kovach 212

Crile, G. W. (1899). An Experimental Research into SurgicalShock. Lippincott, Philadelphia.

Darby, T. D., and Watts, D. T. (1964). Acidosis and bloodepinephrine levels in hemorrhagic hypotension. Amer. J.Physiol., 206, 1281-1284.

Engelking, R., and Willig, F. (1958). tYber eine Methode zurKonstanthaltung des Blutdruckes im Tierexperiment.Pfliigers Arch. ges. Physiol., 267, 306-312.

Erdelyi, A., and Kovach, A. G. B. (1961). Quoted by Kov-ch,A. G. B. Importance of nervous and metabolic changes inthe development of irreversibility in experimental shock.Fed. Proc., 20, Suppl. 9, 122-137 (on p. 125).

Fony6, A., Kovach, A. G. B., and Kovich, E. (1957). Functionalstate and cerebral, acid-soluble phosphorus fractions intraumatic shock of rats. (Hungarian.) Kiserl. Orvostud., 9,206-211.

Fony6, A., Kovich, A. G. B. Maklari, E., Leszkovszky, G.,and Meszaros, J. (1958). The effect of potassium ions andglutamate on the incorporation of P23 into nucleotides andphosphocreatine in brain slices. Acta physiol. Acad. Sci.hung., 14, 305-307.

Fron6k, A., and Ganz, W. (1960). Measurement of flow in singleblood vessels including cardiac output by local thermo-dilution. Circulat. Res., 8, 175-182.

Guthrie, C. C. (1917). Experimental shock. J. Amer. med. Ass.,69, 1394-1398.

Hensel, H., Ruef, J., and Golenhofen, K. (1959). FortlaufendeRegistrierung der Muskeldurchblutung am Menschen miteiner Calorimetersonde. Pflugers Arch. ges. Physiol., 259,267-280.

Jourdan, F., Collet A., and Masbernard, A. (1950). Les reactionsarterielles chr6brales du cours du choc traumatique. C.R.Soc. Biol. (Paris), 144, 1507-1509.

Kety, S. S. (1960). Theory of blood-tissue exchange and itsapplication to measurement of blood flow. Meth. Med.Res., 8, 223-227.

King, B. D., Sokoloff, L., and Wechsler, R. L. (1952). The effectsof l-epinephrine and l-norepinephrine upon cerebralcirculation and metabolism in man. J. clin. Invest., 31,273-279.

Koltay, E., Kov-ch, A. G. B., and Kovach, E. (1970). Effect ofethyl-diphenyl propenylamine and phenoxybenzamine onrespiration of isolated rat liver mitochondria. Abstracts,34th Annual Conference of the Hungarian PhysiologicalSociety, Debrecen 1968, edited by K. Lissak, p. 166.Akademia Kia6, Budapest.

Kovach, A. G. B. (1954). Kiserleti Orvostudomdny VizsgdliModszerei, vol. I. Akademiai Kiad6, Budapest.

Kovach, A. G. B., Bagdy, D., Balazs, R., Antoni, F., Gergely, J.,Menyhart, J., Iranyi, M., and Kovhch, E. (1952). Traumaticshock and adenosine triphosphate. Acta physiol. Acad.Sci. hung., 3, 331-344.

Kovach, A. G. B., D6ra, E., and Nyary, I. Unpublished.Kovach, A. G. B., Fedina, L., Mitsanyi, A., Naszlady, A., and

Bir6, Z. (1962). Neurophysiological and circulatorychangesin hemorrhagic shock. In Proceedings of the 22nd Inter-national Congress of Physiological Sciences, Leyden, 1962,vol. 2 (Excerpta Med. Int. Congr. Ser., 48) p. 678.

Kovach, A. G. B., and Fonyo, A. (1960). Metabolic responses toinjury in cerebral tissue. In The Biochemical Response toInjury, edited by H. B. Stoner and C. J. Threlfall, pp. 129-160. Oxford, Blackwell.

Kovach, A. G. B., and Fony6, A. (1965). Incorporation of 32Pinto the rat's brain during traumatic shock. Acta physiol.Acad. Sci. hung., 27, 27-31.

Kovach, A. G. B., Fony6, A., and Halmagyi, M. (1957). Acetyl-choline content of the brain in traumatic shock. Actaphysiol. Acad. Sci. hung., 13, 1-4.

Kovach, A. G. B., Fony6, A., and Kovah, E. (1958). Creatininephosphate resynthesis after electric stimulation of thebrain of rats in shock. Acta physiol. Acad. Sci. hung., 14,309-310.

Kovach, A. G. B., Fony6, A., and Kovach, E. (1959a). Cerebralphosphate metabolism in traumatic shock. Acta physiol.Acad. Sci. hung., 16,157-164.

Kovach, A. G. B., Fony6, A., Vittay, T., and Pogatsa, G. (1957).Oxygen and glucose consumption and hexokinase activityin vitro of brain tissue of rats in traumatic shock. Actaphysiol. Acad. Sci. hung., 11, 173-180.

Kovach, A. G. B., Kellner, M., and Maklari, E. (1965a).Kaliumtartalom traumas shockos patkanyok versavoj-aban es szoveteiben. Kiserl. Orvostud., 17, 277-281.

Kovach, A. G. B., Koltay, E., and Kovach, E. (1969). Effect ofphenoxybenzamine on mitochondrial respiration. FourthInternational Congress on Pharmacology, Basle, p. 140.

Kovach, A. G. B., Menyhart, J., Erd0yi, A., Molnar, G., Kiss,S., Kovach, E., and Bodolay-Varga, A. (1961). The roleof the sympatho-adrenal system in ischaemic shock. Actaphysiol. Acad. Sci. hung., 19, 199-208.

Kovaich, A. G. B., Menyhart, J., Erd6lyi, A., Molnar, G., andKovach, E. (1957c). The effect of dibenamine given atdifferent stages of ischaemic shock on survival time indogs, and on the oedema of their ligated limbs. Actaphysiol. Acad. Sci. hung., 13, 5-13.

Kovach, A. G. B., and Mitsanyi, A. (1964). Die Wirkung von4,4'- diathylaminoathoxy Hexostrol auf den allgemeinenKreislauf und die Durchblutung des Myocards. Wien.nmed. Wschr., 114, 401-405.

Kovich, A. G. B., Mitsanyi, A., and Stekiel, W. (1965b). Localblood flow and oxygen tension of brain tissue in haemor-rhagic shock. (Abstr.) Acta physiol. Acad. Sci. hung., 26,Suppl. 35-36.

Kovach, A. G. B., Roheim, P. S., Iranyi, M., Cserhati., E.,Gosztonyi, G., and Kovach, E. (1959b). Circulation andmetabolism in the head of the dog in ischaemic shock.Acta physiol. Acad. Sci. hung., 15, 217-229.

Kovach, A. G. B., Roheim, P. S., Iranyi, M., Kiss, S., and Antal,J. (1958d). Effect of the isolated perfusion of the head onthe development of ischaemic and haemorrhagic shock.Acta physiol. Acad. Sci. hung., 14, 231-238.

Kovach, A. G. B., R6heim, P. S., Iranyi, M., and Kovach, E.(1958e). Renal function in haemorrhagic shock, with thehead p_rfused with normal blood. Acta physiol. Acad.Sci. hung., 14, 247-254.

Kovach, A. G. B., Rosell, S., Sindor, P., Koltay, E., Tomka, N.,and Kovach, E. (1970). Blood flow oxygen consumptionand free fatty acid release in subcutaneous adipose tissueduring hemorrhagic shock in control and phenoxybenza-mine-treated dogs. Circulat. Res. In press.

Lee, J. F., Tindall, G. T., Greenfield, J. C., Jr., and Odom, G. L.(1966). Cerebral blood flow in the monkey. J. Nearosarg.,24, 719-726.

McShan, W. H., Potter, V. R., Goldman, A., Shipley, E. G., andMeyer, R. K. (1945). Biological energy transformationsduring shock as shown by blood chemistry. Amer. J.Physiol., 145, 93-106.

Makliri, E., and Kovach, A. G. B. (1966). Carbon dioxidecontent of brain tissue in control and phenoxybenzamine-pretreated experimental hemorrhagic shock. (Abstr.) Actaphysiol. Acad. Sci., hung., 29, 414.

Maklari, E., and Kovach, A. G. B. (1968). Carbon dioxide contentof brain tissue and acid-base balance in hemorrhagicshock after pretreatment with dibenzyline. Acta med.Acad. Sci. hung., 25, 13-22.

Maklari, E., Kovach, A. G. B., and Nyary, I. (1970). Carbondioxide content of brain tissue after infusion of differentbuffer solutions. Acta physiol. Acad. Sci. hung. In press.

Menyhart, J., Kovach, A. G. B., Kiss, S., Erd6lyi, A., and Kovich,E. (1954). Die Wirkung von Dibenamin im ischamischenSchock. Acta physiol. Acad. Sci. hung., 5, Suppl., 32.

Mylon, E., and Winternitz, M. C. (1945). Factors concerned withthe induction of tourniquet shock. Amer. J. Physiol., 144,494-504.

Overman, R. R., and Wang, S. C. (1947). The contributory roleof the afferent nervous factor in experimental shock:sublethal hemorrhage and sciatic nerve stimulation.Amer. J. Physiol.. 148, 289-295.

Popov, L. I. (1959). Shok i krovopotjerya. Tr. Voenno-med. Ord.Lenina Akad. S.M. Airova, 102, 108-144.

Root, W. S., Allison, J. B., Cole, W. H., Holmes, J. H., Walcott,W. W., and Gregersen, M. I. (1947). Disturbances in thechemistry and in the acid-base balance of the blood ofdogs in hemorrhagic and traumatic shock. Amer. J.Physiol., 149, 52-63.

Rosell, S. (1966). Release of free fatty acids from subcutaneousadipose tissue in dogs following sympathetic nervestimulation. Acta physiol. scand., 67, 343-351.

Slome, D., and O'Shaughnessy, L. (1938). The nervous factor intraumatic shock. Brit. J. Surg., 25, 900-909.

Stoner, H. B., and Threlfall, C. J. (1954). The effect of nucleotideand ischaemic shock on the level of energy-rich phosphatesin the tissues. Biochem. J., 58, 115-122.

Swingle, W. W., Remington, J. W., Kleinberg, W., Drill, V. A.,and Eversole, W. J. (1942). An experimental study of thetourniquet as a method for inducing circulatory failure inthe dog. Amer. J. Physiol., 138, 156-165.

Van Liere, E. J., and Stickney, J. C. (1963). Effect of hypoxia onthe nervous system. In Hypoxia, pp. 276-349. Universityof Chicago Press, Chicago.

Wigg-rs, C. J. (1950). Physiology of Shock. Commonwealth Fund,New York.



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

thehematokrit rectal temperature alvar visiograph supra .8" beckman micro-hematokrit centrifuge...

Documents