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Continuous regional blood flow determinations with radioactive krypton85
Continuous Determinations RICllARI) J. SANDERS, M.D., AND ROBERT C. SULLIVAN, M.D., University o[ Colorado School of Medicine
A simple and practical method for the continuous measurement of regional blood flow is by indicator dilution. If a known concentration of an indicator is continuously injected into a v e s s e l at a constant rate, the concentration of the indicator distally is inversely proportional to the flow rate (Fig. 1). In calculating the flow it is e s s e n t i a l to know the indicator concentration proximal to the site of injection and to subtract this value from the distal c o n c e n t r a t i o n . Unfortunately, when the commonly used indicators are infused continuously, recirculation raises the proximal concentration so high that measurements distal to the infusion become ~ncreasingly i n a c c u r a t e .
Indicator introduced a! steady rate
Conc. proximal to injection
For this reason, t h e s e indicators can be used for o n l y a few determinations, and are impractical for continuous measurements over I ong periods. Krypton 8s is the beta emitting isotope of a noble gas, whose physical properties make it an ideal indicator for blood flow determinations. The gas can be d i s s o l v e d in saline and injected into any v e s s e l . B e c a u s e it is poorly soluble in liquid (partition coefficient is 20:1 for air: liquid), 4 the radioactive gas r a p i d t y c r o s s e s the alveolar membrane as it reaches the pulmonary capillaries. Ninty-five per cent of the gas is exhaled on its first circulation through the lungs (Figs. 2 and 5). It is this property of minima} reclrculation which s e t s Kr as apart from other indi cators.
Conc. distal to injection
Flow is inversely proportional to the concentroUon of indicolor dis¢ol to inje cHon Fig. I. Principle of blood flow measurement. As an indicator is introduced, its concentration distally is inversely proportional to the flow rate. Wl~en repeated or continuous injections are used, the proximal concentration must be subtracted from the distal coneentrat ion. From the University of Colorado School of Medicine a n d the Veterans Administration tlospita|, Denver, Colorado. This work was aided, in part, by U.S.P.H.S. Grant ~tl-6436. Submitted for publication June 20, 1962. JSR -
VoL II!, No, 4 - June, 1963
Fig. 2. Fate of intra-arlerialKraS. After i'ntraarterial injection, Kr8s is absorbed by the tissues, delaying its appearance in venous blood. As the tis, sues become saturated, Kr8s enters the venous circulation, but over 95 per cent is exhaled on its firsl circuit through the lungs so very little KraSrecireu lares. (See Figure 5.)
185
186
SANDERS and SULLIVAN
JSR
MATERIAL AND METilODS
Table
Seven mongrel dogs were a n e s t h e t i z e d with intravenous Nembutal. The a b d o m e n was opened and the aorta mobilized below the renal arteries. The animals were heparinized, the aorta divided, and each end cannulated. Blood from the proximal aorta w a s directed into a reservoir and pumped back into the distal aorta at a c o n s t a n t rate by means of an o c c l u s i v e pump. Inflow to the r e s e r v o i r w a s controlled with a s c r e w clamp. The output of the pump w a s frequently c h e c k e d by o c c l u d i n g the distal half of the reservoir and timing the outflow of 100 or 200 cc. of blood with a stop watch. P o l y e t h y l e n e c a t h e t e r s (PE-90) were p l a c e d in the thoracic aorta and sacral artery for sampling proximal and distal to the Kr s5 infusion (Fig. 3). A solution of Kr 8s d i s s o l v e d in s a l i n e (about 0 . 3 5 # c . / c c . ) was continuously infused through a p o l y e t h y l e n e c a t h e t e r into the distal aorta for 30 to 90 minutes with a constant s p e e d infusion pump (Harvard Instrument Co., Model No. 600-900). F i v e cubic centimeter blood samp l e s were drawn from the proximal and distal c a t h e t e r s into oiled, heparinized syringes at regular time intervals throughout the infusion.
I.
-
Vol. lit, No. 4 -
Kr 8s Determination
June,
o/Blood
1963 Flow
Mean Mean Mean Kr as Flow (Range) Pump KrSS Mean Pump Flow Dog Flow Flow No. (cc./min,) (ee./min.) Per cent 10t 102 I03 104 105 106 107
430 428 345 400 600 425 475 515 475 510 375 510
Range 345~00 Mean Std. Deviation
450 428 358 436 594 442 517 556 513 551 379 515
109 99 104 109 108 108 108 101 101
358-594
99-109
105% 100 104
(95-120%) (97-107) (95-124) (104-116) (94-109) (94-t 19) (98-119) (96-122) (95-128) (103-116) (88-108) (96-105)
(88-128) 105%
7.6%
The s y r i n g e s were s e a l e d , and later their radioa c t i v i t y determined by injecting them into an airtight chamber fitted over the end window of a Geiger-Mfiller tube (Amprex, Model 200 CB). A standard s c a l e r w a s used for counting ( B e r k e l e y , Model 2000). Calculation of the blood flow was a s follows: Blood flow =
cts. injected per minute
co.
cts. per cc. in d i s t a l sample
rain.
R£NAb ART.
RESULTS
PUMP
RESERVOIR TO MEASURE-""> PUMP FLOW
OUTFLOW
~ss
1
Fig. 3. Method for continuous blood flow determination in the dog. The abdominal aorta is freed and cannulated. Aortic blood flow is'maintained a t a fixed rate by t h e pump. Flow from the animal to the pump is adjusted by a screw clamp to maintain the reservoir at a constant level and keep pump inflow and outflow equal. The double reservoir permits frequent pump calibrations by clamping the connecting tubing, without al~ering the hemodynamics of the circuit. KrSS 'reclrculation is measured by Sampling proximal to the infusion from the thoracic aorta.
We obtained 122 blood flow determinations during 12 s e p a r a t e runs in s e v e n dogs ( T a b l e 1). The measured pump flows ranged from 3 ~ to 5 9 4 c c . / m i n . The flows measured by the Kr s s method w e r e 88 to 128 per cent of the a c t u a l pump flows, a v e r a g i n g 105 per cent, with a standard deviation of 7.6 per cent. The amount of r e c i r c u l a t i o n during 90 minutes of continuous Kr s s infusion w a s measured in the thoracic aorta proximal to the infusion s i t e (Fig. 3). The r a d i o a c t i v i t y in thoracic aortic blood never e x c e e d e d 5 per cent Of the a c t i v i t y distal to the infusion. Furthermore, the d i s t a l arterial concentration maintained a constant l e v e l during the entire 90 minutes, showing no e v i d e n c e of gradual i n c r e a s e , a s would be e x p e c t e d if recirculation w a s s i g n i f i c a n t (Fig. 5).
BLOOD FLOW DE*~FERMINATION WlTI] Kr ss
J S R -- Vol. lit, No. 4 -- June, 1963 PUMP
006 #/ 400
-
~
~
T a b l e 2. L o s s o / K r S S Tbrougb P o l y e t h y l e n e Tubing
FLOW ~
Pump Speed cc./min,
i
300 ~ FLOW
----'-..---~ ~ . " i **
*,m=.
iN
=
!
~
129 % -III %
* ® ~'i
-
co/rot n
RANGE OF PUMP FLOW ~00
.
O .
.
.
.
.
~0
.
.
.
.
(205-
230 co/rain )
$0
DISCUSSION Preliminary experiments with continuous Kr as infusion were performed with a p l a s t i c bag as the Kr sS source. It was soon d i s c o v e r e d that KrSSdiffused through p l a s t i c , so the p l a s t i c bag was replaced by a large g l a s s syringe. It was a l s o found that p l a s t i c tubing permitted Kr sS l o s s through its w a l l s (Table 2). To determine the e x t e n t o f this, a syringe filled with Kr as solution and connected to 36 i n c h e s of polye t h y l e n e tubing was c o n t i n u o u s l y emptied by a
iBo, AoarA ~t~srA~ r p d ~ t u s R ~ t . .
l
I000'
-°i i
THO~A¢~C AORTA ( P |S
30
%of Counts 18 Inches from Syringe
%of Counts 36 Inches from Syringe
5,24
I00
98
94
2.74 1.62 0.96
IO0
96 94 87
92 90 79
I00 100
40
Fig. 4. Blood flow determinations in Dog ~l. Fourteen blood determinations were done in 30 minutes and all are in a range greater than the pump flow. This illustrates a consistent source of error with a relatively steady flow.
0
%of Counts in Syringe
.
~0 MINUTES
I100
187
*IS
~. . . . . . . 60
7S
tO
~0.~
~0
time In MI~#I@#
Fig. 5. Distal aorta, thoracic aorta and femoral vein Kras blood levels during 90 minutes of continuous intra-arterial infusion. The rise in venous concentration lags b e h i n d the arterial concentration becausd of tissue absorption. As the tissues become saturated and the venous level rises, the Kr8s is exhaled by the lungs; thus, very little KrBs recirculates and thoracic aortic concentration remains low.
c o n s t a n t infusion pump* s e t at various s p e e d s . Samples were o b t a i n e d at the s y r i n g e , 18 i n c h e s , and 36 i n c h e s from it, and their Kr s s concentration determined. The Kr s s concentration* is e x p r e s s e d a s a per cent of the syringe concentr~-t~on ( T a b l e 2). Diffusion of Kr as through the tubing appears to be d i r e c t l y r e l a t e d to the length of Lime the s o l u t i o n is in contact with its w a l l s . To mininaize errors from this source, calibration of the stock Kr s s s o l u t i o n was performed by c o l l e c t i n g a small sample after it had p a s s e d through a similar length of tubing, and at the s a m e s p e e d as was used in the experiment. Even with t h e s e p r e c a u t i o n s , most of the earlier experiments demonstrated a c o n s i s t e n t t e n d e n c y to o v e r e s t i m a t e the flow. A typical example of t h i s is s e e n in Figure 4. In s e e k i n g the source of this error, it was noted that when the same technique w a s used to measure venous blood flow, the error disappeared. ~° It then became apparent that the high arterial pressure was in some way affecting the infusion rate. Indeed, it was found that when the infusion s y r i n g e was run at slow s p e e d s a g a i n s t p r e s s u r e s of 100 to 200 ram. Hg, the volume collected from the infusion s y r i n g e was l e s s than the volume c o l l e c t e d at the same s e t t i n g under no pressure. The main reason for this was that small amounts of the i n f u s a t e has been l e a k i n g out the back end of the syringe. When this fluid was c o l l e c t e d and its volume s u b t r a c t e d from the i n f u s a t e , most of the errors d i s a p p e a r e d . The s t u d i e s p r e s e n t e d in Table 1 r e f l e c t this improvement in a c c u r a c y . N e v e r t h e l e s s , the Kr as flows still averaged 5 p e r cent more than the pump flows. T h i s small error might be due to the p l a s t i c tubing losing more Kr 8s through its walls in a high p r e s s u r e s y s t e m than a low p r e s s u r e s y s t e m .
*Harvard Instrument Co., Model 600-900.
188
JSR
SANDERSand SULLIVAN
This technique a n s w e r s the need for a simple method of c o n t i n u o u s l y monitoring blood flow. It is applicable to experimental work, to extracorporeat circulation m e a s u r e m e n t s and to clinical work, such as cardiac output determinations s, to It requires a minimal amount of equipment and trained p e r s o n n e l . Although s u b j e c t to some error, the a c c u r a c y of the method is about the s a m e a s with other dye t e c h n i q u e s and F i c k cardiac output m e a s u r e m e n t s . The main s o u r c e of error a p p e a r s to be l e a k a g e of Kr ss from the syringe and tubing s y s t e m s . When this h a s occurred, however, the d i s c r e p a n c y has been a constant one, so that relative blood flow c h a n g e s have still been a c c u r a t e l y recorded. Kr as has s e v e r a l other clinical u s e s , including the measurement of cerebral blood flowS; the detection of left-t0-right 9 and rightto-left shunts6; the d e t e r m i n a t i o n of p a t e n c y of portacaval shuntsT; the evaluation of pulmonary diffusion, 3 puhnonary A-V f i s t u l a s z and porta-pulmonary a n a s t o m o s e s ~ ; and the measurement of cardiac o u t p u t S , ~o KrSS is a convenient g a s with which to work. Its physical half-life of 10 },ears permits it to be stored for long periods of time. Its b i o l o g i c a l half-life of a few minutes, plus the fact that 99.5 per cent of i t s e m i s s i o n s are beta rays', makes it relat i v e l y s a f e for p a t i e n t s and p e r s o n n e l . Its chief virtue as an indicator l i e s in its poor s o l u b i l i t y in fluid, so t h a t it is c o n t i n u o u s l y e x c r e t e d from the body as it t r a v e r s e s the lungs. Thus, reeirculation is kept at a minimum over long periods of time, and proximal s a m p l e s are unn e c e s s a r y to e s t a b l i s h a new background for each determination.
SUMMARY 1. Krypton as d i s s o l v e d in s a l i n e was continuously infused for 30 to 90 minutes into the distal a o r t a s of s e v e n dogs, w h o s e aortic blood flows were maintained at a c o n s t a n t measured level by m e a n s of a reservoir and pump. 2. From determinations of the Kr s s concentration of blood s a m p l e s drawn distal to the infusion, the blood flow could be c a l c u l a t e d by the s i m p l e dilution principle. 3. The 122 Kr as blood flow determinations a v e r a g e d 105 per cent e 7.6 per c e n t of the measured pump flows. 4. Blood s a m p l e s , proximal to the infusion, demonstrated that recirculation of the Kr as did not e x c e e d 5 per cent after 90 minutes of infusion.
-
Vol. II1, No. 4 -- J u n e , 1965
5. The method is a simple and p r a c t i c a l one, a p p l i c a b l e to a variety of s i t u a t i o n s .
This project was performed with the technical assistance of Mrs. Pat Painter and Mr. Norman Whipple, to whom the authors are deeply indebted.
REFERENCES i. Albert, S. N., Albert, C. A., and Fazekas, J. F,: A rapid and simple method for measuring the. rate of cerebral blood flow in humans with krypton. J. Lab. & Clin. Med., 56:473-82, 1960. 2. Fritts, II. W., Jr., Ilardewig, A., Rochester, D. F., Durand, J., and Cournand, A.: Estimation of pulmonary arteriovenous shunt-flow using intravenous injections of T-1824 dye and Kras. J. Clin. Invest., 39:1841, I960. 3. Gurtncr, 11. P., Briseoe, W.A., and Cournand, A.: Studies of tile ventilation-perfusion relationships in the lungs of subjects with chronic pulmonary emphysema, following a single intravenous injection of radioactive krypton (KrSS). I. Presentation and validation of a theoretical model. J. Clin. Invest., 39:I080, 1960.
4. tlardewig, A., Rochester, [). F., a n d 13riscoe, W. A:: Measurement of solubility coefficients of krypton in water, plasma and human blood, using radioactive KraS. J. Appl. Physiol., 15:723-25, 1960. 5. Lassen, N.A., and Munck, O.: The cerebral blood flow in man determined by the use of radioactive krypton. Acta physiol, seandinav., 33:30, 1955. 6. Long, R. T. L., Waldhausen, J. A., Cornell, W.P., and Sanders, R. J.:.Detection of right-to-left circulator), shunts: A new method utilizing injections of Krvptona s. Proc. Soc. Exper. Biol. & Med., 102:456, 1959. 7. Long, R. T. L., Lombardo, C. R., and Braunwald, E.: Use of radioactive krypton and eardiogreen dilution curves in the detection of experimental portal-systemic vefious shunts. Ann. Surg., 151:146, 1960. 8. Rochester, D. F., Durand, J., Parker, J. O., Fritts, H. W., Jr., and f!arvey, R. M.: Estimation of right ventricular output in man using radioaCtive krypton as. 3. Clin. Invest., 40:643-8, 1961. 9. Sanders ~ R. J , , and Morrow, A. G.: The identification and quantification of left-to-rlght circulatory shunts: A new diagnostic method utilizlng the inhalation o f a'radioactive 'gas, Kr as. Am. J. Med., 26:508-I6, 1959. 10. Sanders, I/. J., and Sullivan, I/~: Cardiac output determination with radioactive krypton 8 5 In preparation. 11 ; Shaldon, S.; Caesar, J., Chiandussi, L., Williams, H.S., Sheville, E., and Sherlock, S.: The demonstration of ports-pulmonary anastomosis in portal cirrh0sis;with the use of radioactive krypton. New Engtand J. Med., 265:410-414, 1961.
A simple and practical method for the continuous measurement of regional blood flow is by indicator dilution. If a known concentration of an indicator is continuously injected into a v e s s e l at a constant rate, the concentration of the indicator distally is inversely proportional to the flow rate (Fig. 1). In calculating the flow it is e s s e n t i a l to know the indicator concentration proximal to the site of injection and to subtract this value from the distal c o n c e n t r a t i o n . Unfortunately, when the commonly used indicators are infused continuously, recirculation raises the proximal concentration so high that measurements distal to the infusion become ~ncreasingly i n a c c u r a t e .
Indicator introduced a! steady rate
Conc. proximal to injection
For this reason, t h e s e indicators can be used for o n l y a few determinations, and are impractical for continuous measurements over I ong periods. Krypton 8s is the beta emitting isotope of a noble gas, whose physical properties make it an ideal indicator for blood flow determinations. The gas can be d i s s o l v e d in saline and injected into any v e s s e l . B e c a u s e it is poorly soluble in liquid (partition coefficient is 20:1 for air: liquid), 4 the radioactive gas r a p i d t y c r o s s e s the alveolar membrane as it reaches the pulmonary capillaries. Ninty-five per cent of the gas is exhaled on its first circulation through the lungs (Figs. 2 and 5). It is this property of minima} reclrculation which s e t s Kr as apart from other indi cators.
Conc. distal to injection
Flow is inversely proportional to the concentroUon of indicolor dis¢ol to inje cHon Fig. I. Principle of blood flow measurement. As an indicator is introduced, its concentration distally is inversely proportional to the flow rate. Wl~en repeated or continuous injections are used, the proximal concentration must be subtracted from the distal coneentrat ion. From the University of Colorado School of Medicine a n d the Veterans Administration tlospita|, Denver, Colorado. This work was aided, in part, by U.S.P.H.S. Grant ~tl-6436. Submitted for publication June 20, 1962. JSR -
VoL II!, No, 4 - June, 1963
Fig. 2. Fate of intra-arlerialKraS. After i'ntraarterial injection, Kr8s is absorbed by the tissues, delaying its appearance in venous blood. As the tis, sues become saturated, Kr8s enters the venous circulation, but over 95 per cent is exhaled on its firsl circuit through the lungs so very little KraSrecireu lares. (See Figure 5.)
185
186
SANDERS and SULLIVAN
JSR
MATERIAL AND METilODS
Table
Seven mongrel dogs were a n e s t h e t i z e d with intravenous Nembutal. The a b d o m e n was opened and the aorta mobilized below the renal arteries. The animals were heparinized, the aorta divided, and each end cannulated. Blood from the proximal aorta w a s directed into a reservoir and pumped back into the distal aorta at a c o n s t a n t rate by means of an o c c l u s i v e pump. Inflow to the r e s e r v o i r w a s controlled with a s c r e w clamp. The output of the pump w a s frequently c h e c k e d by o c c l u d i n g the distal half of the reservoir and timing the outflow of 100 or 200 cc. of blood with a stop watch. P o l y e t h y l e n e c a t h e t e r s (PE-90) were p l a c e d in the thoracic aorta and sacral artery for sampling proximal and distal to the Kr s5 infusion (Fig. 3). A solution of Kr 8s d i s s o l v e d in s a l i n e (about 0 . 3 5 # c . / c c . ) was continuously infused through a p o l y e t h y l e n e c a t h e t e r into the distal aorta for 30 to 90 minutes with a constant s p e e d infusion pump (Harvard Instrument Co., Model No. 600-900). F i v e cubic centimeter blood samp l e s were drawn from the proximal and distal c a t h e t e r s into oiled, heparinized syringes at regular time intervals throughout the infusion.
I.
-
Vol. lit, No. 4 -
Kr 8s Determination
June,
o/Blood
1963 Flow
Mean Mean Mean Kr as Flow (Range) Pump KrSS Mean Pump Flow Dog Flow Flow No. (cc./min,) (ee./min.) Per cent 10t 102 I03 104 105 106 107
430 428 345 400 600 425 475 515 475 510 375 510
Range 345~00 Mean Std. Deviation
450 428 358 436 594 442 517 556 513 551 379 515
109 99 104 109 108 108 108 101 101
358-594
99-109
105% 100 104
(95-120%) (97-107) (95-124) (104-116) (94-109) (94-t 19) (98-119) (96-122) (95-128) (103-116) (88-108) (96-105)
(88-128) 105%
7.6%
The s y r i n g e s were s e a l e d , and later their radioa c t i v i t y determined by injecting them into an airtight chamber fitted over the end window of a Geiger-Mfiller tube (Amprex, Model 200 CB). A standard s c a l e r w a s used for counting ( B e r k e l e y , Model 2000). Calculation of the blood flow was a s follows: Blood flow =
cts. injected per minute
co.
cts. per cc. in d i s t a l sample
rain.
R£NAb ART.
RESULTS
PUMP
RESERVOIR TO MEASURE-""> PUMP FLOW
OUTFLOW
~ss
1
Fig. 3. Method for continuous blood flow determination in the dog. The abdominal aorta is freed and cannulated. Aortic blood flow is'maintained a t a fixed rate by t h e pump. Flow from the animal to the pump is adjusted by a screw clamp to maintain the reservoir at a constant level and keep pump inflow and outflow equal. The double reservoir permits frequent pump calibrations by clamping the connecting tubing, without al~ering the hemodynamics of the circuit. KrSS 'reclrculation is measured by Sampling proximal to the infusion from the thoracic aorta.
We obtained 122 blood flow determinations during 12 s e p a r a t e runs in s e v e n dogs ( T a b l e 1). The measured pump flows ranged from 3 ~ to 5 9 4 c c . / m i n . The flows measured by the Kr s s method w e r e 88 to 128 per cent of the a c t u a l pump flows, a v e r a g i n g 105 per cent, with a standard deviation of 7.6 per cent. The amount of r e c i r c u l a t i o n during 90 minutes of continuous Kr s s infusion w a s measured in the thoracic aorta proximal to the infusion s i t e (Fig. 3). The r a d i o a c t i v i t y in thoracic aortic blood never e x c e e d e d 5 per cent Of the a c t i v i t y distal to the infusion. Furthermore, the d i s t a l arterial concentration maintained a constant l e v e l during the entire 90 minutes, showing no e v i d e n c e of gradual i n c r e a s e , a s would be e x p e c t e d if recirculation w a s s i g n i f i c a n t (Fig. 5).
BLOOD FLOW DE*~FERMINATION WlTI] Kr ss
J S R -- Vol. lit, No. 4 -- June, 1963 PUMP
006 #/ 400
-
~
~
T a b l e 2. L o s s o / K r S S Tbrougb P o l y e t h y l e n e Tubing
FLOW ~
Pump Speed cc./min,
i
300 ~ FLOW
----'-..---~ ~ . " i **
*,m=.
iN
=
!
~
129 % -III %
* ® ~'i
-
co/rot n
RANGE OF PUMP FLOW ~00
.
O .
.
.
.
.
~0
.
.
.
.
(205-
230 co/rain )
$0
DISCUSSION Preliminary experiments with continuous Kr as infusion were performed with a p l a s t i c bag as the Kr sS source. It was soon d i s c o v e r e d that KrSSdiffused through p l a s t i c , so the p l a s t i c bag was replaced by a large g l a s s syringe. It was a l s o found that p l a s t i c tubing permitted Kr sS l o s s through its w a l l s (Table 2). To determine the e x t e n t o f this, a syringe filled with Kr as solution and connected to 36 i n c h e s of polye t h y l e n e tubing was c o n t i n u o u s l y emptied by a
iBo, AoarA ~t~srA~ r p d ~ t u s R ~ t . .
l
I000'
-°i i
THO~A¢~C AORTA ( P |S
30
%of Counts 18 Inches from Syringe
%of Counts 36 Inches from Syringe
5,24
I00
98
94
2.74 1.62 0.96
IO0
96 94 87
92 90 79
I00 100
40
Fig. 4. Blood flow determinations in Dog ~l. Fourteen blood determinations were done in 30 minutes and all are in a range greater than the pump flow. This illustrates a consistent source of error with a relatively steady flow.
0
%of Counts in Syringe
.
~0 MINUTES
I100
187
*IS
~. . . . . . . 60
7S
tO
~0.~
~0
time In MI~#I@#
Fig. 5. Distal aorta, thoracic aorta and femoral vein Kras blood levels during 90 minutes of continuous intra-arterial infusion. The rise in venous concentration lags b e h i n d the arterial concentration becausd of tissue absorption. As the tissues become saturated and the venous level rises, the Kr8s is exhaled by the lungs; thus, very little KrBs recirculates and thoracic aortic concentration remains low.
c o n s t a n t infusion pump* s e t at various s p e e d s . Samples were o b t a i n e d at the s y r i n g e , 18 i n c h e s , and 36 i n c h e s from it, and their Kr s s concentration determined. The Kr s s concentration* is e x p r e s s e d a s a per cent of the syringe concentr~-t~on ( T a b l e 2). Diffusion of Kr as through the tubing appears to be d i r e c t l y r e l a t e d to the length of Lime the s o l u t i o n is in contact with its w a l l s . To mininaize errors from this source, calibration of the stock Kr s s s o l u t i o n was performed by c o l l e c t i n g a small sample after it had p a s s e d through a similar length of tubing, and at the s a m e s p e e d as was used in the experiment. Even with t h e s e p r e c a u t i o n s , most of the earlier experiments demonstrated a c o n s i s t e n t t e n d e n c y to o v e r e s t i m a t e the flow. A typical example of t h i s is s e e n in Figure 4. In s e e k i n g the source of this error, it was noted that when the same technique w a s used to measure venous blood flow, the error disappeared. ~° It then became apparent that the high arterial pressure was in some way affecting the infusion rate. Indeed, it was found that when the infusion s y r i n g e was run at slow s p e e d s a g a i n s t p r e s s u r e s of 100 to 200 ram. Hg, the volume collected from the infusion s y r i n g e was l e s s than the volume c o l l e c t e d at the same s e t t i n g under no pressure. The main reason for this was that small amounts of the i n f u s a t e has been l e a k i n g out the back end of the syringe. When this fluid was c o l l e c t e d and its volume s u b t r a c t e d from the i n f u s a t e , most of the errors d i s a p p e a r e d . The s t u d i e s p r e s e n t e d in Table 1 r e f l e c t this improvement in a c c u r a c y . N e v e r t h e l e s s , the Kr as flows still averaged 5 p e r cent more than the pump flows. T h i s small error might be due to the p l a s t i c tubing losing more Kr 8s through its walls in a high p r e s s u r e s y s t e m than a low p r e s s u r e s y s t e m .
*Harvard Instrument Co., Model 600-900.
188
JSR
SANDERSand SULLIVAN
This technique a n s w e r s the need for a simple method of c o n t i n u o u s l y monitoring blood flow. It is applicable to experimental work, to extracorporeat circulation m e a s u r e m e n t s and to clinical work, such as cardiac output determinations s, to It requires a minimal amount of equipment and trained p e r s o n n e l . Although s u b j e c t to some error, the a c c u r a c y of the method is about the s a m e a s with other dye t e c h n i q u e s and F i c k cardiac output m e a s u r e m e n t s . The main s o u r c e of error a p p e a r s to be l e a k a g e of Kr ss from the syringe and tubing s y s t e m s . When this h a s occurred, however, the d i s c r e p a n c y has been a constant one, so that relative blood flow c h a n g e s have still been a c c u r a t e l y recorded. Kr as has s e v e r a l other clinical u s e s , including the measurement of cerebral blood flowS; the detection of left-t0-right 9 and rightto-left shunts6; the d e t e r m i n a t i o n of p a t e n c y of portacaval shuntsT; the evaluation of pulmonary diffusion, 3 puhnonary A-V f i s t u l a s z and porta-pulmonary a n a s t o m o s e s ~ ; and the measurement of cardiac o u t p u t S , ~o KrSS is a convenient g a s with which to work. Its physical half-life of 10 },ears permits it to be stored for long periods of time. Its b i o l o g i c a l half-life of a few minutes, plus the fact that 99.5 per cent of i t s e m i s s i o n s are beta rays', makes it relat i v e l y s a f e for p a t i e n t s and p e r s o n n e l . Its chief virtue as an indicator l i e s in its poor s o l u b i l i t y in fluid, so t h a t it is c o n t i n u o u s l y e x c r e t e d from the body as it t r a v e r s e s the lungs. Thus, reeirculation is kept at a minimum over long periods of time, and proximal s a m p l e s are unn e c e s s a r y to e s t a b l i s h a new background for each determination.
SUMMARY 1. Krypton as d i s s o l v e d in s a l i n e was continuously infused for 30 to 90 minutes into the distal a o r t a s of s e v e n dogs, w h o s e aortic blood flows were maintained at a c o n s t a n t measured level by m e a n s of a reservoir and pump. 2. From determinations of the Kr s s concentration of blood s a m p l e s drawn distal to the infusion, the blood flow could be c a l c u l a t e d by the s i m p l e dilution principle. 3. The 122 Kr as blood flow determinations a v e r a g e d 105 per cent e 7.6 per c e n t of the measured pump flows. 4. Blood s a m p l e s , proximal to the infusion, demonstrated that recirculation of the Kr as did not e x c e e d 5 per cent after 90 minutes of infusion.
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Vol. II1, No. 4 -- J u n e , 1965
5. The method is a simple and p r a c t i c a l one, a p p l i c a b l e to a variety of s i t u a t i o n s .
This project was performed with the technical assistance of Mrs. Pat Painter and Mr. Norman Whipple, to whom the authors are deeply indebted.
REFERENCES i. Albert, S. N., Albert, C. A., and Fazekas, J. F,: A rapid and simple method for measuring the. rate of cerebral blood flow in humans with krypton. J. Lab. & Clin. Med., 56:473-82, 1960. 2. Fritts, II. W., Jr., Ilardewig, A., Rochester, D. F., Durand, J., and Cournand, A.: Estimation of pulmonary arteriovenous shunt-flow using intravenous injections of T-1824 dye and Kras. J. Clin. Invest., 39:1841, I960. 3. Gurtncr, 11. P., Briseoe, W.A., and Cournand, A.: Studies of tile ventilation-perfusion relationships in the lungs of subjects with chronic pulmonary emphysema, following a single intravenous injection of radioactive krypton (KrSS). I. Presentation and validation of a theoretical model. J. Clin. Invest., 39:I080, 1960.
4. tlardewig, A., Rochester, [). F., a n d 13riscoe, W. A:: Measurement of solubility coefficients of krypton in water, plasma and human blood, using radioactive KraS. J. Appl. Physiol., 15:723-25, 1960. 5. Lassen, N.A., and Munck, O.: The cerebral blood flow in man determined by the use of radioactive krypton. Acta physiol, seandinav., 33:30, 1955. 6. Long, R. T. L., Waldhausen, J. A., Cornell, W.P., and Sanders, R. J.:.Detection of right-to-left circulator), shunts: A new method utilizing injections of Krvptona s. Proc. Soc. Exper. Biol. & Med., 102:456, 1959. 7. Long, R. T. L., Lombardo, C. R., and Braunwald, E.: Use of radioactive krypton and eardiogreen dilution curves in the detection of experimental portal-systemic vefious shunts. Ann. Surg., 151:146, 1960. 8. Rochester, D. F., Durand, J., Parker, J. O., Fritts, H. W., Jr., and f!arvey, R. M.: Estimation of right ventricular output in man using radioaCtive krypton as. 3. Clin. Invest., 40:643-8, 1961. 9. Sanders ~ R. J , , and Morrow, A. G.: The identification and quantification of left-to-rlght circulatory shunts: A new diagnostic method utilizlng the inhalation o f a'radioactive 'gas, Kr as. Am. J. Med., 26:508-I6, 1959. 10. Sanders, I/. J., and Sullivan, I/~: Cardiac output determination with radioactive krypton 8 5 In preparation. 11 ; Shaldon, S.; Caesar, J., Chiandussi, L., Williams, H.S., Sheville, E., and Sherlock, S.: The demonstration of ports-pulmonary anastomosis in portal cirrh0sis;with the use of radioactive krypton. New Engtand J. Med., 265:410-414, 1961.