Neuroendocrine and metabolic effects of general Anaesthesia during spontaneous breathing

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NEUROENDOCRINE AND METABOLIC EFFECTS OF GENERAL
ANAESTHESIA DURING SPONTANEOUS BREATHING, CONTROLLED
BREATHING, MILD HYPOXIA, AND MILD HYPERCARBIA e
N~.r.TA B. ,NIKBOD ,.D.M RETEP H. ,SELYB ,.B.M DNA NHOJ F. ,ELLIVEN Jl% .D.M
Vision is as necessary an element in scientific achievement as is the carefully controlled
experiment.
-Ernest Gellhorn, 1953
EMOS FO TIIE ENIRCODNEORUEN SECNATSBUS that play a prominent role in the
central nervous system are found in the peripheral circulation. Their exact func-
tions are not entirely clear, but it appears evident that alterations in their con-
centration in the circulating blood are associated with profound overt mental and
physical changes, as well as possibly initiating sudden serious disturbances of
TM
pulmonary ventilation, myocardial contractility, microcireulatory homeostasis,
gastrointestinal and renal function, and carbohydrate metabolism. 9-~ These in
turn may lead to the development of a shock-like state and death.
The purpose of this study was to make a precise systematic inquh T into the
effects of general anaesthetics as administered in clinical practice on the circu-
lating blood level of four biogenic amines and to attempt to interrelate these with
any changes that might appear in the mean arterial blood pressure, urine out-put,
haematocrit, blood water, blood sugar, serum potassium, serum inorganic
phosphorus, pyruvate, lactate, oxygen tension, acid-base balance, and serum
transaminases (SGOT and SGPT).
SLAIRETAM nNA SDOHTEM
Serial crossover tests were carried out in four consecutive sets of experiments
in 10 to 15 trained, large (20 to 30 kg.) male dogs. Each animal received a
general anaesthetic at one- to two-week intervals without prior administration of
premedicant drugs or antisialogogues. After an overnight fast, a dog was weighed,
then an intravenous infusion of 0.9 per cent saline was started in a forepaw vein
after drawing a blood sample for estimation of blood sugar, serum potassium,
serum inorganic phosphorus, SCOT, SGPT, whole blood histamine, and serotonin
and plasma catecholamines (epinephrine and norepinephrine). Anaesthesia was
then induced with 20 mg./kg, thiopenta (2.S$ solution), and the dog was
intubated with a large cuffed tube that was attached to a gas machine which
delivered NsO ~ ~O (except with cyclopropane, when N20 was not used). A gas
flow was used sufllcient to provide a minute ventilation of 350 to 400 ml./kg.
eFrom the Anesthesiology Laboratory, State University of New York, Upstate Medical
Center, Syracuse, New York, U.S.A. Supported by grants-in-aid from Abbott Laboratories,
Ayerst Laboratories, McNeil Laboratories, E. .R Squibb & Son, and .S.H.P.S.U grant ,40-20450 .5
Presented at the Annual Meeting of the Canadian Anaesthetists Society in Chadottetown,
Prince Edward Island, June 24, 1965.
031
Can. Anaes. Soc. J., vo. 13, no. 2, March, 1966
DOBKIN, et a~.: NEUROEN~2BINE AND ~ETABOLIC EFFECTS 131
(checked with a Wright Bespirometer). An E.C.G. (lead 2) was attached, and
a urinary catheter was inserted into the bladder for drainage. Gravity collection
of urine was arranged using a calibrated trap bottle. A 19-gauge needle was
inserted into the femoral artery and attached to a damped aneroid manometer
for measurement of mean arterial blood pressure. When the above arrangements
were completed, an arterial blood sample was drawn anaerobically for measure-
ment of pH, Paco2, Pao2 and haematocrit, and free-flowing arterial blood was
collected for measurement of whole blood lactate, pyruvate, and blood-water
content. The infusion saline was given in an amount suf~cient to replace the
blood volume removed for the laboratory tests, except with thiopental and
Innovar anaesthesia in which tests an additional 001 to 051 ml. was administered.
During the experiments, the dogs were maintained under moderately deep
anaesthesia for 90 minutes with the anaesthetics shown in Table I. Under the
TABLE I
AGENTS USED FOR MAINTENANCE OF DEEP ANAESTHESIA FOR 90 MINUTES FOLLOWING
INDUCTION WITH 20 mg./kg. THIOPENTAL
Chloroform 1.5% + 50% N20 + 50% 02 (GUV)
enaporpolcyC 30% + 70% 02 knirbdieH( )elcric
lyhteiD Ether 6--8% + 50% NsO -{- 50~ Os (EMO)
Fluroxene 4.8-6% -{- 50% N~O -{- 50% 02 )cetoulF(
enahtolaH 3% -- 50% NsO -{- 50~ Oz )cetoulF(
rehtE-enahtolaH eportoezA 3.7% -{- 50% NsO -}- 50% Ot )cetoulF(
ravonnI 1 8/.lm .gk ni 002 .lm 0.9% enilaS . .V deretsinimda( ni eno )ruoh + 50%
NzO -{- %05 Os
enarulfyxohteM 1.5% -- 50% NsO + 50% 02 )cetneP(
latnepoihT 03 ,gk/.gm ni 002 .lm 0.9% enilaS .I .V deretsinimda( ni eno )ruoh %50%
O~N + 50~ 2O
enhyhterolhcirT 1,5% -- 50% N20 + 50% Os )cetirT(
first condition (106 experiments), the animals were allowed to breathe
spontaneously except with chloroform, cyclopropane, and lnnovar, with which
respiration was assisted or controlled as required (ff it was apparent that
a dog was becoming virtually apnoeic). In the remaining three conditions,
pulmonary ventilation was controlled by a respirator with a minute volume of
350 to 400 ml./kg., using 50 per cent N20 -{- 50 per cent 02 (127 experiments);
85 per cent N20 -{- 51 per cent 02 (mild hypoxia-136 experiments) and 50 per
cent N20 -}- 47.5 per cent 02 -{- 2.5 per cent 2OC (mild hypercarbia-95 experi-
ments) respectively.
At the end of the 90 minutes of anaesthesia, arterial and venous blood samples
were drawn again for the analyses noted above. Anaesthetics were then discon-
tinued and the dog was venRlated with 001 per cent oxygen until it recovered
consciousness. The animal was then kept under direct surveillance until it was
able to ambulate. During each experiment, recordings of the E.C.G., the reading
of mean arterial blood pressure, and the volume of urinary drainage were taken
every 01 minutes. Notes were kept of clinical events during anaesthesia and
recovery.
231 "N...AZD&.N.=~C ,.~..~.,S~Ul~'.l:~'t~' "~",_TCOS ,OtJ"r~.,
Between experiments the dogs were cared for in "dog runs" and in cages where
they received a routine diet with meat (high protein) supplements. A few of the
animals developed urinary infection from repeated catheterization and were
treated with appropriate antibiotics. On occasion, a parenteral infusion of five per
cent dextrose in water was administered for a day or two following a test ff an
animal did not take food or did not recover completely from a test.
LABORATORY ~FRUD~(ORP
Arterial blood samples were analyzed for pH, ,2OOaP and Pie2 on an Epsco
Medical Blood Parameter Analyzer using a constant temperature bath (87 ~ C.),
a Metrohm pH electrode, Clark electrode for Pie= and Severinghaus =ecaP elec-
trode. ~1 Oxygen saturation was derived from the Rahn and Feun chart, using the
direct measurements of Pete= and .2o~g n Plasma bicarbonate was derived from
a line chart based upon the Henderson-Hasselbach equation. Haematocrit was
measured by the Natelson micromethod. 21 Duplicate enzymatic analyses of
pyruvic and lactic acids in whole arter/al blood were carried out by a modification
of the spectrophotometric methods d Biicher (1963) and Hohorst (1963) respec-
tively and expressed as mM/L. of blood water, 41'sl Whole blood water was
determined by weighing the arterial blood sample before and after drying in an
oven and cooling in a desiccator. SGOT and SGFT were measured by the colori-
metric method of Reitman and Franke (1957). 61 Blood sugar and serum inorganic
phosphorus were measured on an auto-analyser using methods of Hoffman (1937)
and of Fiske and Subbarow (1925) respectively. 71.61 Serum potassium was
measured on a flame photometer. Duplicate whole blood histamine and serotonin
estimations were made by the method of Noah and Brand (1063) adapted to the
Turner fluorometer, ~2-sl Duplicate assays of plasma eatecholamines were made
fluorometrically by modification of the trihydroxindole methods of Cohen and
Goldenberg (1957) and Price and Price 22.'2.)7591(
Laboratory estimations were analysed statistically for at least ten experiments
with each anaesthetic administered under each of the four conditions described
above.
STL',tS._~ ~
During the experiments there was a moderate to marked reduction (> 10~) in
the mean arterial blood pressure with Innovar, halothane, halothane-ether
azeotrope, and methoxyflurane. Cyclopropane, diethyl ether, thiopental and
fluroxene usually caused a slight or moderate elevation of the mean arterial blood
pressure, whereas the changes with trichlorethylene and chloroform were variable,
but without excessive elevation or depression. Mean heart rate increased
appreciably with diethyl ether (~20~g) and slightly (<5~g) with thiopental and
fluroxene. There was a marked decrease in the mean heart rate with Innovar
(~50~), cyclopropane (,--30g), halothane (--,g0~), halothane-ether azeotrope
,)g~51-.,( and methoxyilurane (N20~), and a slight decrease (<55) with chloro-
form and trichlorethylene (see Table II).
A variety of persistent ventricular arrhythmias appeared in most of the experi-
~ data ton nwohs were deleted ot evresnoc ecaps dna will be dehsinruf no .tseuqer
,NIKBOD el: a/,: NEUIIO~ DNA METABOLIC Eru 133
TABLE II
YRAMMUS FO SEGNAHC NI TRAEH ETAR DNA NAEM LAIRETRA DOOLB ERUSSERP EUD OT LARENEG
AISEHTSEANA
Mean arterial
Number of Heart rate/rain, blood pressure (ram. Hg)
experiments start end start end
Thiopental 50 751 161 134 681
Innovar 54 ~61 84 131 95
Diethyl Ether 48 981 981 130 241
Cyclopropane 22 182 114 721 731
Chloroform 47 781 154 531 140
Trlchlorethylene 47 751 150 831 130
Fluroxene 47 162 661 731 143
Halothane 47 561 831 831 121
Halothane-Ether Azeotrope 47 162 341 841 130
Methoxyflurane 48 851 134 131 90
ments when the dogs were allowed to breathe spontaneously except with diethyl
ether and thiopental. During the remaining experiments, in which pulmonary
ventilation was controlled, ventricnlar arrhythmias only occurred occasionally
and were evanescent. Except when thiopental was used throughout, a marked
suppression of urine excretion occurred during virtually every experiment, which
became apparent usually aher 01 to 20 minutes of anaesthesia. SCOT and SGPT
estimations were within normal limits in all of the experiments.
suoenatnopS noitaripseR 601( )stnemirepxE
The data are summarized in Table III and Figures ,1 2, and .3
All the dogs had a slight respiratory acidosis following induction of anaes-
thesia with thiopental. During the maintenance period of anaesthesia the pH
decreased appreciably following the addition of thiopental, diethyl ether, cydo-
propane, chloroform, halothane-ether azeotrope and methoxytturane; ~ocaP rose
fiuther, except with Innovar, diethyl ether, trichlorethylene, flurexene, and halo-
thane; plasma bicarbonate decreased appreciably with diethyl ether only;
haematocrit rose significantly with diethyl ether, chloroform, and trichlorethylene;
blood sugar rose significantly (>205) with Innovar, diethyl ether, and chloro-
form; serum potassium fell slightly with all agents (5 to 195); serum inorganic
phosphorus rose with all agents (7 to 575); whole blood lactate and pyruvate
rose with all agents except halothane; diethyl ether and fluroxene mused a striking
rise. L/P ratio was increased appreciably by diethyl ether only (1145) and excess
lactate was slight with thiopental and fluroxene and marked (>2 mM/L. ) with
lyhteid ether. Histamine increased during diethyl ether anaesthesia ylno (475);
serotonin was increased (>255) by Irmovar, chloroform, and fluroxene; epine-
phrine rose (>505) with thiopental and diethyl ether; norepinephrine rose
(>505) with thiopental and diethyl ether, and total catecholamines increased
(>255) with thiopental and diethyl ether only. Whole blood water decreased
appreciably with diethyl ether and trichlorethylene.
+17 -8 +8
+5 +4 -16
-33 -19
E + NE +3 +21 -7 +5 -14 +T
-35 -19
NE
+16 0 -14 -8 -21 -10 +II -14
E
S +35 -17 +28 -37 +25 -15 -18 +7
H -17 -5 -5 -25 -29 -58 +16 -36
ANAESTHESIA XL ,45 .28 .08 29 (cid:12)9 .17 46 (cid:12)9 0 0 ,16
L/P +10 +11 +26 +25 .,, +29 +22
GENERAL
+34 +38
OF
Py +33 +3? +5 +51 -27 +47 +7
RESPIRATION "
EFFECTS +i8 +60 +14 +29 +78 -5 +12 +29
III L +55
+25 +7 +51 +32 +42 +44 +30 +57
P
TABLE
K -5 -19 -13 -6 .,..,o@@ -9 -11 -10 -8
NEUROENDOCRINE
AND DOGS EACE)--$PONTANEOUS B.S. +20 | +9 ~ | +16 +20 +17 +14
e
(10
Hct. +7 0 +17 +20 +7 -2 0 -2
$1
METABOLIC
OF -0. 6 -0.4 e -0. 8 0 -3. 3 1.0 +0, 5 I. $ +I. 4
- -
HCO]
SUMMARY pCO 2 +8 0 "Q +21 -11 - 5 +11 +14 +22
05 01 08 02 0 02 07 06
pH -. -. 8 -. -. -. -. -.
Ether
Azeotrope
Thiopental Innovar Dietllyl Cyclopropane Chloroform Trichlorethylene Fluroxene Halothane liE Methoxyflurane
ESAB-DICA ECNALAB ESAB-DICA ECNALAB
25 25
20 20
p;OCH p;OCH
IM/L. eMIL.
51 Thiopental- SR 15 Innovar - Sit .....
7.2 7.3 7.4 7.5 7.6 7.2 7.3 7.4 7.5 7.6
.Hp .Hp
"7"- ~... / /
25 ,"2
d,i x
O2 C2
acO;p / p~'OCH - -A/
IM/L. uMIL,
51 -- "e yl Ether - SR IS -- y clo p opane- SR
2.7 3.7 4,7 5.7 6.7 7.2 7.3 7.4 7.5 B.7
.Hp .Hp
25 2~
O2 C2
/ /
p;OCH pSOCH
uM/L. ~llro/fforL - S~ uM/L.
Trichlorethylene - SR
IS 51
7.2 ,~.? 7.4 7.3 7.6 2.7 3.7 4.7 5.7 6.7
.Hp .Hp
9~"~'~0~,1/ I /
25 25 "~ Z ~P"
p;Oc. O2 O2
p;OCH i/
IM/L. ~l:rc xe~ e _ IM/L
15-- SR/~_ 51 -- Halothane - SR-
2.7 3.7 4.7 5.7 6.7 2.7 3.7 4.7 5.7 6.7
.Hp .Hp
/ /
25
l t~l ,
O2 p;oce 20
HcO;p
IM/L. IMIL. enarulfyxohteM'-
IS .~ I /I IB - SR"
Halothane-Ether 3.7 - SB 6.7
7.e 7'.3" 7.4 2.7 3.7 4.7 5.7 6.7
.Hp .Hp
Ficva~ 1. Acid-base balance-spntaneous respiration.
olin
80 40 o
SR I 1 TL~Or t 1-,o :
- (cid:12)9 9"o
e o u o 6'o Mine.
-
'li/ in Time-Mine. .~'I ~ in Time
tALOTHANE-ETHER , 0.2 3 "Pyr. "O I~ To., O:

o
I
L~I,
.o 60 rilIo 40 ,o / ~176
t
;o (cid:12)9 9"o
5 0 e'o (cid:12)9 s'o Mine. -
5'o Time-Mine. '~ 3'o Time
~ ., (cid:12)9 6
0.1 (cid:12)9 io,--Lo o 0 ~ respiration.
4o, 3 LOCI.
S .o 6 t 20 ,o
(cid:12)9 so
6o 6'o 9'0 ratio---spontaneous
40 - Mins.
.
io
, 3o Time-Mini. Time
, o i
, o o.,
5 ,.o, 3 I I 0 T 3" . "' ,-
4"
0
'~
~.o -40 ~'PO 80 ,o ,o Lactate-pyruvate-L/P
* SR (cid:12)9 ;o 2.
ETHER I ~I / /A ~'o 6'o Time-Mine. S 60 . t ~e. 5'o 6'o y'o Time -Mine. Fz~nm~
5, DIETHYL ~ .0.2 / 3'' Pyr. ' '0.1 m~ I,. ~A F o ~ 0.2 Pyr. o . l , ~ 0 ] ~
LOci. LOCI.
fOliO
(cid:12)9 eo (cid:12)9 60 L/prolio -40 (cid:12)9 20 5 80 60 ,o
t.o
9'o 90
SR
-
io -Mini. /" . 60 *Mine.
e 3'o Time ..30 Time
I[ I 'TH|OPENTAI. 4T0"2 3' ' Pl*r.i,~,mm~I (cid:12)9 'O.I j 0 5 ii 0.2 ~~~ I.,, I 0 / .o
LOci. mM/t (cid:12)9 ./,~ot ,-.
' '
w a O - $R ;o - SR ,'o
6'o i s'o
~'o
A O- IALOTHANE-ETHER ; ,'o _ L C~ METHOXYFLURANE
1000 IO0 IO I O. IO' 0.0 I 1000 I00 I0 I 0.10 o.o, ;
~o O 5R ;o
IO - SR E -
~o ~'o
Io ~'o
L C~ FLUROXENE O HALOTHAN ;
Iooc lOG I0 I 0,I0 o.o, ; I000. ,oo! lob' o.,o[ o.o,[
S!
,o I - ;o
J I 0
~o ,'o
3'0 ~'o
-- - CHLOROFORM-SR - | 0 RICHLORETHYI.ENE ~ amines--spontaneous respiration.
I000 I00 IO I 0.I0 o.o, ~ I000 I00 I0 I o.lo o.o,
Biogenic
3.
L ;o - SR ,'o
J
O
ETHER - SR :o 6'o FZCUBE
I 3'0
: ~r ......---- DIETHYL ~ ~o i I1 C CYCLOPROPANE ;
1000 I00 IO I 0.10 o.o, I000 I00 I0 I o.lo o.oi
- SR ;o | A - SR | 90
-L 6'o 60
H liE BINS.
5HT 30 30
-- THIOPENTAL i i L _ 0 ]NNOVAR i
I000 I00 I0 ~tlL ' 0,I0 o.o, o 1000 IO0 I0 I 0.10 0.0 i
831 NAIDANAC 'STSITEHTSEANA YTEICOS LANt:IUOJ
To summarize: Induction of anaesthesia with thiopental caused a mild respira-
tory acidosis. Spontaneous breathing during relatively deep general anaesthesia
augmented the respiratory acidosis with thiopental, cyclopropane, chloroform,
halothane-ether azeotrope and methoxyflurane. Innovar (briefly) and chloroform
(consistently) caused periods of apnoea in dogs if breathing was not augmented
arti~cialy. Diethyl ether produced the most striking metabolic changes: acidosis,
hyperglycaemia, haemoconcentration, and lactic and pyruvic acid accumulation
with marked rise in L/P ratio and excess lactate. Diothyl ether and thiopental
increased circulating plasma catecholamine's; whole blood histamine increased
with ether, and serotonin increased during Innovar anaesthesia.
dellortnoC noitaripseR 721( )stnemirepxE
The data are summarized in Table IV and Figures ,4 ,5 and .6
A mild respiratory alkalosis (mean control pH 7.46; mean control gaco~ 27)
was produced following induction of anaesthesia with thiopental by mechanically
controlling each dog's minute pulmonary ventilation at 053 to 400 ml./kg. During
maintenance of anaesthesia the following changes occurred: pH decreased with
diethy ether only; Pac% remained consistently reduced in these tests; plasma
bicarbonate was reduced by diethy ether only; haematocrit rose significantly
with diethyl ether only; blood sugar rose (>205) with Innovar, diethyl ether,
cyclopropane, and chloroform, serum potassium decreased in all tests (9 to ,)53,.P
serum inorganic phosphorus rose during diethyl ether (305) and cyclopropane
(185) anaesthesia only. Whole blood lactate rose with all agents, especially with
diethyl ether and fluroxene, while whole blood pyruvate rose with all agents
except thiopental. L/P ratio increased strikingly with. diethyl ether only (1525),
while excess lactate occurred appreciably with diethyl ether and fluroxene. Hista-
mine levels did not increase appreciably with any anaesthetic; serotonin levels
rose slightly with diethyl ether, fluroxene, and halothane, but the variation
among individuals was great. Epinephrine increased appreciably with thiopental,
Innovar, chloroform, cyclopropane, and trichlorethylene ( > 2,55); norepinephrine
increased slightly (18 to 34~) with all anaesthetics except chloroform and
methoxyflurane, and total catecholamines increased appreciably with thiopental,
diethyl ether, cyclopropane, and trichlorethylene. Blood water decreased (>35)
with diethyl ether only.
To summarize: The metabolic changes were less obvious during controlled
respiration; however, diethyl ether caused metabolic changes during controlled
respiration that were similar to those with spontaneous respiration except for the
rise in histamine and catecholamines. Thiopental consistently increased epine-
phrine levels appreciably. Cyclopropane increased epinephrine less with spon-
taneous breathing than with controlled breathing, probably owing to the deeper
anaesthesia produced by intermittent positive pressure.
Mild Hypoxia (with dellortnoC ;noitaripseR 631 )stnemirepxE
Data are summarized in Table V and Figures ,7 ,8 and .9
All the dogs had a mild hypoxia after induction of anaesthesia with thiopental
since their breathing was controlled with 15 per cent oxygen and 85 per cent
nitrous oxide (mean control: pH 7.45; P, 2oo N ;82 ~ouP < 75 ram.).
+1 +I~ +24 -15
Q
+18 -1 +24 "+23 -16
~
0
+25 (~ +33 G +22 +12
-40
-10 -28 +16 -6 -21 -33 +42 +22 -25 -32
-49 +8 -23 -11 -45 +22 -41 -6 +11 -7
XL .33 .49 .65 .70 .21
ANAESTHESIA
~A L/P +31 +38 +2? +47 +8
GENERAL
OF +30
~A Py -10 +10 +14 +41 +49 +57
RESPIRATION +22 +~
EFFECTS ~A +17 +5 ~ +48 +94 0 +~
1V L
G
~/~ P -2 +30 +18 +4 -23 -6 -2 0
TABLE
K -11 -9 - 17 -10 -20 -13 -15
NEUROENDOCRINE EACH)--CoNTROLLED ~A -15
AND DoGs ~A B.S. +6 +7 +8 +11 +20 +20
(10
Het. +2 +9 +10 +5 +8 -2
-
METABOLIC 3
OF (cid:12)9
HC(Y +0.8 ~2 -2.8 -2.2 -0.4 -2.0 -0.6
2
SUMMARY pCO 0 +7 -7 - 3 -6 "- 13 -4 -7 - 12
- 3
pH -. O1 0 ~ +. 02 +. 01 +. 01 +. 03 0 +. 02 +. 03
Ether
Azeotrope
Thiopental hmovar Diethyl Cyclopropane Chloroform Trichlorethylene Fluroxene Halothane HE Methoxyflurane