ken, Japan 755. Address ... its centre on a line drawn between the external au ditory meatuses and 1.5 cm ..... The authors wish to thank Mr. David Myers for.
1:195-201 © 1981 Raven Press. New York
Journal of Cerebral Blood Flow and Metabolism
CO2 Responses of the Cerebral Circulation During Drug-Induced Hypotension in the Cat
P. Gregory, T. Ishikawa, and D. G. McDowall Department of Anaesthesia. University of Leeds, Leeds, United Kingdom
Summary: Concern has often been expressed that hypocapnia produced by
controlled hyperventilation might further reduce cerebral perfusion during
drug-induced hypotension. In the present studies. hypotension was induced in cats with either practolol/trimetaphan (five experiments) or practolol/ nitroprusside (five experiments) together with controlled haemorrhage. Arte
rial Pco2 was altered between 17 and 51 mm Hg by varying inspired CO2 during
constant-volume ventilation, first during control conditions of light halothane/ nitrous oxide anaesthesia and then during hypotension to mean blood pressure
of 36-37 mm Hg. Cerebral cortical perfusion was measured by the krypton clearance technique and pial artery diameter by the image-splitting method.
Cerebral cortical blood flow did not alter with P aC02 changes during trimetaphan hypotension, but some responsiveness to CO2 persisted during nitroprusside hypotension, though at less than half control levels. No changes in pial artery diameter were seen with CO2 during hypotension under either technique. It is postulated that CO2 responsiveness persisted with nitroprus side because cerebral blood flow (CBF) values were higher when hypotension was produced with this drug, as compared with trimetaphan. It would appear that hypocapnia does not further reduce CBF during trimetaphan hypotension but does do so with nitroprusside. However, the combination of hypocapnia and nitroprusside hypotension did not in any instance lower CBF below the
values found during trimetaphan hypotension. Key Words: Cerebral blood flow-Induced hypotension-Cerebrovascular responses to CO2-Pial artery
diameters-Trimetaphan-Sodium nitroprusside.
might increase the hazard of cerebral ischaemia. However, Okuda and colleagues (1976) found no change in regional cortical blood flow (rCBF) when Paco2 was reduced during hypotension with halothane in the baboon. The present study was de signed to determine the influences of Paco2 altera tion during hypotension induced by trimetaphan or nitroprusside.
There is continuing debate about the use of spontaneous or controlled ventilation during in duced hypotension under general anaesthesia. Hypocapnia is the usual result of controlled venti lation as clinically employed, and the combination of low PaC02 with reduced blood pressure (BP) Dr. Gregory's present address is Physiology Department, The Rowett Research Institute, Bucksburn, Aberdeen AB2 9SB, Scotland. Dr. Ishikawa's present address is Department of Anesthesiol ogy, Yamaguchi University Hospital, 1144 Ube-shi, Yamaguchi ken, Japan 755. Address correspondence and reprint requests to Prof. McDowall at Department of Anaesthesia, 24 Hyde Terrace. Leeds LS2 9LN, England.
METHODS The study was performed in 10 cats of either sex and mean weight of 2.4 kg (range, 1.8-3.1 kg). No premedication was given, and anaesthesia was in1 95
P. GREGOR Y ET
196
duced rapidly with nitrous oxide/oxygen (2: 1) and more than 5% halothane in a specially designed cage. When consciousness had been lost, 75 mg suxamethonium was administered intramuscularly and a cuffed endotracheal tube inserted. The animals were ventilated to normocapnia throughout the surgical preparation with a Starling ventilator, using an anaesthetic gas mixture of nitrous oxide/ oxygen and halothane. End-tidal Pco2 was continu ously displayed by a mass spectrometer (Medi shield). Paralysis was maintained with intramuscular pancuronium, 0.05 mg/kg, every 30 min, and intra venous replacement fluids were administered con tinuously (compound sodium lactate injection B.P. Hartmann's solution at a rate of 5 mllkg/h). Rectal temperature was maintained at 38°C with a heating blanket. A catheter was passed through one femoral artery into the abdominal aorta for the measurement of BP (Statham transducer; Devices amplifier and re corder). A second catheter was passed through the other femoral artery for sampling of arterial blood and for the removal of blood where necessary to achieve hypotension. A catheter in one femoral vein was for the administration of replacement fluids, and one in the other vein was for the administration of hypotensive drugs. A catheter was inserted in the right lingual artery and advanced so that its tip lay at the junction with the common carotid. Krypton-85 dissolved in saline was injected through this cathe ter for the measurement of rCBF. A burr hole of 1.5 cm diameter was made over the parietal cortex with its centre on a line drawn between the external au ditory meatuses and 1.5 cm lateral to the midline and the dura was opened. The exposed brain was covered with a thin plastic sheet (Melinex). A Geiger-Muller tube was placed over the ex posed cortex and shielded from the surrounding tis sues with lead sheet. Krypton-85 dissolved in saline was injected over a 2 min period into the carotid artery, and rCBF was determined from the clear ance curve according to the equation F
0.693 x =
T1/2
A
x 60 x lOO mlllOO g/min,
where A is the brain:blood partition coefficient of krypton corrected for the existing haematocrit (Glass and Harper, 1962) and T 1/ 2 the time in seconds to half-clearance of the radioactivity. Measurements of the diameter of pial arteries and arterioles on the cortical surface were made using
J Cereb Blood Flow Metabol, Vol. I, No. 2, 1981
AL.
the image-splitting technique (Baez, 1966). Some 5-7 vessels of diameter less than 200 JLm were selected for each experiment, illuminated with a cold light source (Schott), and measured directly through the image-splitting eyepiece (Vickers). At each flow determination, measurements were made of arterial pH, P02 and Pco2 (Radiometer); arterial halothane concentration (gas chromato graph); and arterial haematocrit and haemoglobin. Due to equipment failure, blood halothane values were not obtained in one trimetaphan and two ni troprusside experiments. Arterial P02 was main tained close to 150 mm Hg by adjusting the inspired oxygen percentage. The respiratory rate and tidal volume were set to maintain a minimum Paco2 (18-22 mm Hg), and these were kept constant throughout the experiment. Various levels of Paco2 were obtained by changing the concentration of in spired CO2, adjustments being made by reference to the end-tidal CO2 display. At the end of surgery the inspired halothane concentration was reduced to 0.5-0.7% and held at this level for the remainder of the experiment. No measurements were made for a period of at least I h after opening the dura. There after, measurements of rCBF and pial artery diam eter were made during normotension at hypocapnia, normocapnia, and hypercapnia, the order of Paco2 being determined randomly. Mean BP was then re duced to 35 mm Hg, again at random Paco2, and the measurements repeated. In 5 cats BP was reduced by practolol and trimetaphan and in 5 by practolol and nitroprusside, the order of the experiments being random. Prac tolol was administered intravenously in an initial dose of 0.2 mg/kg and thereafter in bolus doses of 0.1 mg/kg at 30 min intervals. Trimetaphan and ni troprusside were given by continuous infusion with a pump; the maximum rate of trimetaphan infusion was limited to 10 mg/kg/h, and the maximum total dose of nitroprusside was 1 mg/kg given diluted to approximately 20 ml in 5% dextrose. The duration of hypotension was limited to 90 min. If the required BP was not achieved by drug administration, blood was removed. The mean value (±SD) of maximum blood removal in the trimetaphan group was 6.6 ± 5.1 mllkg and in the nitroprusside group 7.6 ± 6.5 mllkg. All blood pressures were measured with ref erence to the level of the exposed area of cerebral cortex. To calculate CO2 responsiveness during the con trol phase, rCBF measurements were plotted against Paco2 in each experiment and the line of best
197
CBF RESPONSES TO CO2 DURING HYPOTENSION
fit applied by least-squares analysis. The intercept of this line with the y axis at a Paco2 of 30 mm Hg was noted and is subsequently referred to as rCBF 30. This value was taken as 100%, and all flows measured at other values at PaC02 were calculated as percentages of rCBF 30. Finally, the results of %rCBF 30 from all experiments were plotted against PaC02 and the slope of best fit defined by least-squares analysis. This gave CO2 responsive ness during normotension, and the same calcula tions were performed on CBF values obtained dur ing hypotension. The vascular diameter measurements were di vided into two groups; those obtained from vessels less than 100 p,m during normotension and those from vessels 100- 200 p,m. The diameter of each vessel in the control stage of normocapnia was termed 100%, and all diameters measured sub sequently were calculated as percentages of this value, both at different Paco2 and during hypoten sion. The vascular diameter measurements were grouped into values obtained at hypocapnia, nor mocapnia, and hypercapnia for each of the nor motensive and hypotensive stages. Values quoted are means together with their standard errors. Differences between mean values were tested by unpaired or paired t-test, as required by the specific circumstances, and p < 0.05 was considered to be significant.
RESULTS The results of measurements of blood Po2 , haemoglobin, halothane, and rectal temperature are
given in Table 1, from which it will be seen that the only significant difference between the subgroups was a fall in haemoglobin from 1l.9 to 9.0 gllOO ml during nitroprusside and a slightly higher rectal temperature in this group, as compared with trimetaphan during normotension (38.0 ± 0.2 vs. 38.6 ± O. I °C). During normotension the mean value for rCBF 30 in the trimetaphan group was 85.0 ± 1l.0 mU I 00 glmin compared with the 93.9 ± 14.1 in the nitroprusside group (Table 2). The slope of the CO2 response lines during normotension were +3.02/mm Hg Paco2 (r = 0.91) and +2.87 (r = 0.78) in the two groups, respectively. Since CO2 respon siveness during normotension in the two groups was the same, all values have been plotted together in Fig. I , which shows a responsiveness of +2.94/mm Hg (r = 0.83). When hypotension to 36 mm Hg was produced by practoloUtrimetaphan, rCBF 30 fell to 53% of con trol (Table 2), whilst at a BP of 37 mm Hg with practoloUnitroprusside, reduction was to 62% of control; the higher rCBF 30 with the latter drug was not significantly different statistically from the value during trimetaphan. There was no response of rCBF to alterations in Paco2 at mean BP 36 mm Hg in the trimetaphan group (Fig. 2); in contrast, during nitroprusside hypotension, CO2 responsiveness persisted (Fig. 3), though at less than half the value seen in the normotensive stage (Table 2). Vascular diameter showed the expected changes when Paco2 was altered during normotension (Table 3). Vessels with resting diameters of less than 100 p,m showed a significantly different reactivity of +1.52 ± 0.17% per mm Hg in the trimetaphan group
TABLE 1. Mean I'(llues (±SD) (�f the initial experimentall'ariahles
Group Trimetaphan (5) Control Hypotension
Nitroprusside (5) Control Hypotension
BP (mm Hg)
Pao2 mmHg
(g1100 ml)
Blood halothane (mgllOO mil
Rectal temp. eC)
Hb
125.9 ±3. 8 (n = 26) 35. 9±0. 2 (n = 18)
173 ± 3. 8 (n = 16) 160±4. 5 (n = 16)
11. 9±0. 4 (n = 12) 9. 9±1. 1 (n = 15)
9.6±0. 7 (n = 6) 10. 2±1. 0 (n = 6)
38. 0 ± 0. 2 (n = 26) 37. 9±0. 3 (n = 17)
120.0 ±3. 6 (n = 35) 36. 5±0. 3 (/I = 19)
169±3. 8 (n = 19) 159±4. 5 (n = 16)
11.9±1. 1 (n = 18) 9. 0±0. 3" (n = 15)
11. 6±0. 9 (n = 9) 10. 0±0. 4 (n = 3)
38. 6 ± 0. 1" (/I = 30) 38. 6 ± 0. 3 (n = 12)
" Significant difference VS. normotension. Significant difference between groups. Number of experiments given in parentheses in left column; n, number of measurements. Ahhreviations: BP, blood pressure; Hb, haemoglobin content. II
J Cereh Blood FloII' Metabol. Vol. 1, No. 2. 1981
P. GREGORY ET AL.
198
TABLE 2. Cerebral blood floII' (CBF) during normotension and hypotension normalized to P"C02 of JO mm HI', and percentaRe changes in CBF with variations of P"C02 Hypotension
Control
125.9 ±3.8 (n = 26)
Blood pressure (mm Hg) rCBF 30 (mIIIOO g/min) CO, sensitivity (% CBF/mm Hg)
TMP
NTP
35.9 ±0.2 (n = 18)
36.5±0.3 (n = 19)
44.8±9.9
58.5±5.8 (n = 5)
NTP
TMP
Variable
120.0±3.6 (n = 35)
85.0±11.0 (n = 5)
93.9 ±14.1 (1/ = 5)
+3.02
(1/ = 35,
(n = 5)
+2.87
(n = 26. r = 0.91)
+ 1.25
�0.13
(1/ = 19,
(11 = 18, I'
1' = 0.78)
= 0.01)
1' = 0.79)
Abbreviations: TMP, trimetaphan; NTP, nitroprusside.
rhagic hypotension to 30- 40 mm Hg. At a higher mean BP, i.e., 60 mm Hg, Haggendal and Johansson (1965) observed some residual responsiveness to CO2 during haemorrhage in the dog. It seems clear from these findings that haemorrhagic hypotension abolishes CO2 responsiveness at a mean BP of 50 mm Hg and below. The case is less certain during drug-induced hypotension. On the one hand, Hamer and as sociates (1973) reported that 5% CO2 increased CBF in dogs during trimetaphan-induced hypotension at a mean cerebral perfusion pressure of 40 mm Hg, while Okuda and colleagues (1976), working in this laboratory, found no CBF response to Pco2 change during halothane-induced hypotension to a mean BP of 45 mm Hg in the baboon. In the study of Okuda et al., high levels of halothane might have blocked CO2 responses of the cerebral vessels, but in the present study, conducted during trimetaphan
and +2.11 ± 0.24% per mm Hg in the nitroprusside group. The values for vessels in the range 100- 200 /Lm were +1.00 ± 0.17% per mm Hg Paco2 and +1.24 ± 0.15%, respectively. All vessels dilated with the induction of hypotension; vessels less than 100 /Lm did so more than those of 100- 200 /Lm di ameter but to the same extent with either drug. Al teration of Paco2 caused no further change in vas cular diameter during hypotension with either drug (Table 3).
DISCUSSION Harper and Glass (1965) demonstrated that CO2 responsiveness of the cerebral circulation was ab sent during haemorrhagic hypotension to a mean BP of 50 mm Hg in the dog. In agreement with this, Russell (1971) found in the rabbit that pial arteries did not dilate with hypercapnia during haemor200 180 160 CBF
./'
140 120
/'
100
/'''\:'
80
y r
60 15 I
' 20
= =
11.6 0.83 ,
PaC0
2
mm
H 9
45
+
2.94x
50 ,
' 55
FIG. 1. Percentage responsiveness of cerebral cortical blood flow (% CBF) to alteration of arterial Peo2 in 10 cats under light anaesthesia.
J Cereb Blood Flow Metabol, Vol. 1, No. 2, 1981
CBF RESPONSES TO CO2 DURING HYPOTENSION
199
140 130
%
rC BF
120
x
110 100
-
90
x
x
X
lr x
x
x x
x
-
x
- "*-x- - x - �-
y = 102.4 - 0.14x r = .01
80
x
70
x
15 I
' 20
25 I
30 I
35 ,
PaC02
I
40
mmHg
I
45
50 ,
55 ,
FIG. 2. Percentage responsiveness of cerebral cortical blood flow (% rCBF) to alteration of arterial Peo2 in 5 cats during trimetaphan-induced hypotension.
hypotension, no CO2 responsiveness was found. The differences between the results of Hamer and co-workers (1973) and those presented here could be due to the lower mean BP used in the present study (mean pressure of 36 mm Hg vs. 40 mm Hg), to species difference, or to differences in the methods used to measure CBF. Krypton clearance from an area of parietal cerebral cortex was mea sured in the present experiments, while Hamer and colleagues used the Kety-Schmidt technique. The validity of this latter method in the dog is open to question, due to contamination of sagittal sinus
blood samples with blood from extracerebral tis sues. In the present study some response to Paco2 was observed during nitroprusside hypotension, though this was at only half the level seen during normoten sion. This difference from the trimetaphan results may have been due to the higher values for rCBF 30 during nitroprusside, even though these did not reach statistical significance. It has been assumed that the absence of response to hypercapnia during hypotension is due to maximum dilatation of the vessels in response to the
FIG. 3. Percentage responsiveness of cerebral cortical blood flow (% rCBF) to alteration of arterial Peo2 in 5 cats during nitroprusside-induced hypotension.
J Cereb Blood Flow Metabal. Vol. 1. No. 2. 1981
P. GREGORY ET AL.
200
TABLE 3. Percelltage ill diameter ofpia/ {[rteries II'ith hypotellsioll alld with I'ariatioll of P" CO2 (me{[IIS ± SEM) Hypotension
Control Vessel diameter
NTP
TMP
TMP
NTP
Less than 100 !Lm
Change (%) in diameter with BP reduction Change (%) in
diameter/mmHg
change in Paco2
+32,) ± 5.3" (/1 = 16) + 1.52 ± 0,17" (11 = 26)
+ 2,11 ± 0.24".11 (II = 42)
Greater than 100 !Lm Change (%) in diameter with BP reduction Change (%) in diameter/mm Hg change in P"co2
+1.00 ± 0.17" (II = 26)
+1.24 ± 0.15" (II = 31)
+0.03 (II
± =
+14.6 (II
±
+0.04
:±.
(n
=
=
+32.4 ± 3.3" (n = 21)
0.15 30)
-0.02 ± 0.13 (n = 35)
5.4" 13)
+13,5 (II
0.08 28)
+0.09 ± 0,04 (II = 27)
± =
2.0" 18)
" Significant increase in diameter. /1 Significant difference between groups,
low BP. However, cerebrovascular resistance, which is an index of vascular dilatation, was lower during nitroprusside than trimetaphan hypotension and fell yet further with hypercapnia. An alternative explanation would be that during trimetaphan hypotension a metabolic acidosis existed in the ex tracellular fluid of the cortex that abolished any re sponse to either hypo- or hypercapnia, the pH being below the range of vascular responsiveness. In the case of nitroprusside, the metabolic acidosis may have been less severe due to better-maintained ce rebral perfusion ( Stoyka and Schutz, 1975; Michenfelder and Theye, 1977; Maekawa et aI., 1979), so that alterations in PaCOZ could still pro duce changes in the pH of the extracellular fluid that were within the responsive range. A study is cur rently in progress in this laboratory to test this hy pothesis by direct measurement of cortical ex tracellular fluid pH during drug-induced hypoten sIOn. Although a difference in flow response to Pacoz was observed between nitroprusside and trimeta phan hypotension, there were no changes in measured vascular diameter produced by COz dur ing either technique of hypotension. Since the ves sels studied were 40- 200 /Lm in diameter, it is likely that the differences in flow response observed were the result of changes in vessels, either smaller or larger than this. However, direct comparison of changes in the vascular diameter produced by PaCOz between trimetaphan and nitroprusside for vessels
J Cereb Blood Flow Metabol, Vol. I, No. 2, 1981
less than 100 /Lm cannot be made, since a statistical difference was present in the control phase. The reason for this difference is not known, since the vessels were selected at random and the experi ments were performed in random order. It should be emphasized that the direct flow measurements yielded identical flow responses to COz change in the two groups during the control phase. The observed relationship between increases in arterial diameter with BP reduction and initial ves sel diameter is in agreement with the results of Mac Kenzie and colleagues (1979), who were studying haemorrhagic hypotension. The clinical objective of this work was to add evidence to the debate on the advisability, during general anaesthesia, of combining hypocapnia with induced hypotension through the use of controlled hyperventilation or, alternatively, of allowing spontaneous ventilation with the resultant mild hypercapnia. In so far as animal experimental work can be translated to clinical practice, the present results taken in conjunction with the previous study of Okuda et aI. (1976) would indicate that when hypotension to low BP is achieved with halothane or trimetaphan, the level of Pacoz makes no differ ence to regional cerebral perfusion. During nitro prusside hypotension, some responsiveness persists, but the lowest CBP values produced by combining hypocapnia with nitroprusside hypotension were no lower than those produced by trimetaphan hypo tension at all PaC02 levels.
201
CBF RESPONSES TO CO2 DURING HYPOTENSION
It might be suggested that the present results can not be applied clinically because hypotension was induced at normocapnia prior to CO2 manipulation. In clinical practice, of course, hypocapnia is com monly induced prior to hypotension. This objection is not valid, however, since the sequence of Pcoz manipulation was randomized. so that in some ex periments hypotension was induced during hypo capnia. The results did not differ with the sequence of CO2 alteration. It should be stressed that in both the present and previous studies, all measurements have been made in animals with normal cerebral circulation. The situation in areas of damaged or diseased brain is unknown.
ACKNOWLEDGMENT This study was supported by the Medical Re search Council, London. The authors wish to thank Mr. David Myers for skilled technical assistance and Mrs. M. Albers for expert secretarial help.
REFERENCES Baez S (1966) Recording of microvascular dimensions with an image-splitter television microscope. ] Appl Ph y siol 21:299- 301
Glass HI, Harper AM (1962) The measurement of the partition coefficient of krypton between brain cortex and blood by a double isotope method. Phys Med Bioi 7:335-339 Haggendal E, Johansson B (1965) Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta Physiol Scand Suppl 258:27-53 Hamer J, Hoyer S, Stoeckel H, Alberti E, Packschies P (1973) The effects of hypercarbia on cerebral blood flow and car bohydrate metabolism in deep normovolaemic arterial hypotension. In: Adl'{/Ilces ill Neurosurgery Vol. I (Schiir mann K. Brock M, Reulen HJ, Voth 0, eds) , Berlin, Springer- Verlag, pp. 167-175 Harper AM, Glass HI (1965) Effects of alterations in the arterial CO2 tension on the blood flow through the cerebral cortex at normal and low arterial blood pressure.] Neurol Neurosurg Psychiatry 28:449-452 MacKenzie ET, Farrar JK, Fitch W, Graham DI, Gregory PC. Harper AM (1979) Effects of hemorrhagic hypotension on the cerebral circulation. l. Cerebral blood flow and pial ar teriolar caliber. Stroke 10:711-718 Maekawa T, McDowall DG, Okuda Y (1979) Brain-surface oxy gen tension and cerebral cortical blood flow during hemor rhagic and drug-induced hypotension in the cat. Anesthesiology 51:29-36 Michenfelder JD, Theye RA (1977) Canine systemic and cerebral effects of hypotension induced by hemorrhage, trimetaphan. halothane or nitroprusside. An esthesiology 46:188-195 Okuda y, McDowall DG, Ali MM, Lane JR (1976) Changes in CO, responsiveness and in autoregulation of the cerebral circulation during and after halothane-induced hypotension. ] Neuml Neurosurg Psychiatry 39:221-230 Russell RWR (1971) The reactivity of the pial circulation of the rabbit to hypercapnia and the effect of vascular occlusion Brain 94:623-634 Stoyka WW, Schutz H (1975) The cerebral response to sodium nitroprusside and trimetaphan controlled hypotension. Call An aesth Soc] 22:275-283
J Cereh Blood
FIOlI'
Metahol. Vol. I, No. 2. 1981