Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion

Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion William J. Rogers, M.D. Alfred W. Stanley, Jr., M.D. John B. Breinig, M.D. John W. Prather, M.D. Huey G. McDaniel, M.D. Roger E. Moraski, M.D. John A. Mantle, M.D. Richard 0. Russell, Jr., M.D. Charles E. Rackley, M.D. Birmingham, Ala.

Solutions of glucose-insulin-potassium (GIK) have for many years been advocated as a potential metabolic support for ischemic, "jeopardized" myocardium in the early hours following an acute myocardial infarction. 1-3 The efficacy of these solutions and the possible mechanisms of action have, however, remained controversial2 -9 Reported studies have differed in patient selection, in route of GIK administration, in concentration of various components administered, and in rationale for the use of the GIK solution. One potential benefit of GIK in the early postinfarct period might be the suppression of plasma free fatty acids (FFA), 1~ known to be present in higher than usual concentrations during this periodlO, 13-~7 and reported to enhance ventricular irritability,~O, ls-~o to increase myocardial oxygen consumption, ~1-9~ and to depress myocardial mechanical performance. 23-~5 From the Division of Cardiology, Department of Medicine, University of Alabama Medical Center, University Station, and the Veterans Administration Hospital, Birmingham, Ala. This research was supported in part by the Myocardial Infarction Research Unit Program, Contract Number HL 43-67-1441, the Cardiovascular Research and Training Center, Program Project Grant Number HL 11,310 (Division of Heart and Vascular Diseases, National Heart and Lung Institute), NIH Grant Number T01LM00154, and the Clinical Research Unit Grant Number MO-RR00032-13 (General Clinical Research Centers Program, Division of Research Resources), National Institutes of Health. Received for publication July 22, 1975. Reprint requests: William J. Rogers, M.D., Division of Cardiology, Department of Medicine, University of Alabama Medical Center, Birmingham, Ala. 35294.

October, 1976, Vol. 92, No. 4, pp. 441-454

This report describes the development of a technique for GIK administration in a pilot group of 70 patients with unequivocal acute myocardial infarction (AMI). The objective of GIK administration was to suppress plasma FFA below the established myocardial FFA uptake threshold ~6 and to simultaneously increase the availability of carbohydrate as a myocardial substrate. The outcome of this initial cohort of 70 GIK-treated patients will be compared with t h a t of a group of 64 patients managed in the same coronary-care unit during the year prior to commencement of the GIK infusions. Patient population Clinical assessment. All patients included in this study were admitted with suspicion of acute myocardial infarction to the Myocardial Infarction Research Unit (MIRU) of the University of Alabama Medical Center. Patients in both the control and GIK-treated groups were evaluated and managed by at least one of the two senior authors (R. O. R., C. E. R.). Each patient had unequivocal evidence of acute myocardial infarction, defined as typical history together with (1) electrocardiographic (ECG) evidence of transmural infarction (evolutionary ST-T changes with Q-wave development) as well as elevated serum glutamic oxalacetic transaminase (SGOT) (normal, 0 to 40 I.U. per liter), or (2) ECG evidence of subendocardial injury (ST-T changes only) with marked elevation of SGOT (150 I.U.

American Heart Journal

441

Rogers et al.

Table

I.

Table

C o m p a r i s o n of p a t i e n t g r o u p s

Parameter No. of patients Sex

I

GIK

Control

70 59M, l l F

64 47M, 17F

Age: Mean* Range (yr.) History of angina History of prior infarct Time lapse from onset of pain to commencement of study (hr.) range Admission systolic BP S:~gallop on admission Cardiogenic shock on admission

53• 1 24-78 45 (71%) 23 {33%}

61 + 1 36-83 34 (53%) 18 (28%)

7.8 + 0.4 3-15 127 _+ 4 33 (47%)

7.4 _+ 1.0 1-25 130 + 4 26 (41%)

11 (16%)

10 {16%)

24 (34%) 24 (34%)

31 (48%) 22 {31%)

Radiological evidence of: Abnormal heart size Abnormal lung fields

ECG showing: Infarct location: Anterior Inferior Undetermined Infarct extent: Subendocardial Transmural

38 (54%~ 32 (46%) 0

27 (42%) 33 (52%) 4 (6~)

4 (6%) 66 194%)

4 (6%) 60 194%)

2.2 -~ 0.1 14.5 _-- 0.7 6.6 _~ 0.4

2.1 z 0.1 14.0 _~ 0.7 6.8 z 0.3

Prognostic indices (means): Killip score Peel score Norris score

= p < 0.001 ~GIK vs. controb. No other parameters differed significantly between patient groups. Continuous parameters are reported as mean ~ S.E.M.

per l i t e r or g r e a t e r ) a n d t y p i c a l t i m e - w i s e e v o l u t i o n of t h e a l t e r e d e n z y m e . T h e c o n t r o l p a t i e n t s were a r e t r o s p e c t i v e l y a n a l y z e d g r o u p of 64 c o n s e c u t i v e p a t i e n t s s a t i s f y ing t h e a b o v e c r i t e r i a a n d a d m i t t e d t o t h e M I R U d u r i n g t h e c a l e n d a r y e a r p r i o r to t h e o n s e t of t h e G I K s t u d y . T h e G I K - t r e a t e d p a t i e n t s were a p r o s p e c t i v e l y a n a l y z e d , n o n c o n s e c u t i v e series of 70 p a t i e n t s , a d m i t t e d to t h e M I R U f r o m N o v e m ber, 1972, t h r o u g h D e c e m b e r , 1974, w h o r e c e i v e d a G I K i n f u s i o n b e g i n n i n g w i t h i n 15 h o u r s ( m e a n , 7.8 _ 0.4 h o u r s ) of t h e o n s e t of t h e i r c h e s t p a i n (or i n i t i a l s y m p t o m of m y o c a r d i a l i n f a r c t i o n ) . C o m p a r i s o n of t h e t w o p a t i e n t g r o u p s is pres e n t e d i n T a b l e I. T h e G I K g r o u p h a d a m e a n age of 53 + 1 y e a r s c o m p a r e d t o 61 _ 1 y e a r s for t h e c o n t r o l g r o u p (p < 0.001), o t h e r w i s e t h e t w o groups had r e m a r k a b l y similar clinical characteristics. T i m e of o n s e t of c h e s t p a i n w a s n o t u n i f o r m l y well d o c u m e n t e d in t h e c o n t r o l g r o u p ;

442

II. S u m m a r y of c l i n i c a l p a r a m e t e r s c l u d e d i n p r o g n o s t i c indices*

arome er

I

Age

in-

I orr,s'" 0

X

X

0 0 0 0 0

X X X X X

X X 0 0 0

0 X X X X 0

X 0 X X X X

0 X 0 0 0 0

0 0 0

0 X X

X X 0

0 X

0 0

X X

History of.. Myocardial infarction Angina Dyspnea on exertion Hypertension Other cardiovascular disease

Physical examination: Heart rate Systolic blood pressure Shock $3 gallop R$1es Dyspnea, edema, orthopnea, hepatomegaly

Laboratory data: ECG Infarct location Infarct extent Dysrhythmia Chest x-ray: Heart size Lung fields

*Abbreviations: X = parameter included in prognostic index; 0 = parameter not includedin prognosticindex.More detaileddescriptions of the relativeweightingsof the variousparametersare describedin the originalreports by KillipJ~Peel,28and Norris2~and their associates.

however, i n t h e 47 c o n t r o l p a t i e n t s w i t h d o c u m e n t a t i o n , the m e a n interval from pain onset to a d m i s s i o n to t h e M I R U w a s n o t s i g n i f i c a n t l y different f r o m t h e i n t e r v a l f r o m first p a i n to c o m m e n c e m e n t of G I K i n f u s i o n i n t h e G I K group. T h e G I K r e c i p i e n t s i n c l u d e d 16 p a t i e n t s w i t h h i s t o r y of glucose i n t o l e r a n c e ; of these, t h r e e were i n s u l i n d e p e n d e n t , f o u r were d e p e n d e n t o n oral h y p o g l y c e m i c a g e n t s , a n d t h e r e m a i n d e r were r e c e i v i n g n o h y p o g l y c e m i c t h e r a p y o n admission. Assessment by prognostic indices. I n o r d e r to assess t h e r e l a t i v e " s e v e r i t y " o f e a c h p a t i e n t ' s i n f a r c t i o n a n d his prognosis, d a t a o b t a i n e d f r o m each p a t i e n t ' s a d m i s s i o n c l i n i c a l e v a l u a t i o n were scored a c c o r d i n g to t h e p r o g n o s t i c i n d i c e s of K i l l i p a n d K i m b a l l , 27 Peel a n d associates, 28 a n d N o r r i s a n d associates. 29 A c o m p a r i s o n of t h e clinical p a r a m e t e r s scored b y t h e s e i n d i c e s is p r e s e n t e d i n T a b l e II. T h e m e a n p r o g n o s t i c scores c a l c u l a t e d i n d e p e n d e n t l y b y t h e Killip, Peel, a n d N o r r i s m e t h o d s were r e m a r k a b l y s i m i l a r b e t w e e n t h e G I K a n d c o n t r o l g r o u p ( T a b l e I), c o n f i r m i n g

Octobel, 1976, Vol: 92, No. 4

G I K and A M I survival

TO

2000

GIK

INFUSION

1500 bJ

(D E3

n=55 p
u

~[

I000

I'-I--

LIJ 500

PRE-GIK

DURING

P O S T - GIK

GIK

Fig. 1. During GIK infusion,the mean plasma FFA fell from pre-GIK level of 944 • 57 to 289 _+ 16t~Eqper liter (p < 0.0005).During the 24 hours followingdiscontinuation of GIK, FFA were observedto rebound to a mean level of 420 -- 39 t~Eqper liter (p < .005). that the two patient populations were evenly matched for the subsequent mortality analysis. Method GIK-treated patient group. Following informed consent, and as soon as possible after admission to the MIRU, patients underwent right heart catheterization via an antecubital cutdown with insertion of a triple-lumen Swan-Ganz thermodilution catheter into the pulmonary artery, Baseline measurements of vital signs, pulmonary artery pressure, plasma FFA, glucose, blood urea nitrogen (BUN), creatinine, electrolytes, osmolarity, and SGOT were obtained. T h r o u g h the right atrial port of the Swan-Ganz catheter the patient was given a bolus o f 20 ml. of D50W and 5 U. of regular insulin followed immediately by an infusion containing 300 Gm. of glucose, 50 U. of regular insulin, and 80 mEq. of KC1 per liter of H~O, delivered at a constant infusion rate of 0.5 to 2.0 ml. per kilogram per hour (mean, 1.26 _ 0.04 ml. per kilogram per hour). T o maintain patency of the Swan-Ganz catheter; a solution containing 5,000 U. of heparin per liter of 0.5N saline was infused continuously at 10 c.c. per hour into the pulmonary artery port; 10 c.c. aliquots of this solution were flushed vigorously into the right

American Heart Journal

atrial and pulmonary artery ports of the catheter at hourly intervals. Baseline measurements were repeated at 4 to 6 hour intervals during the 48 hour G I K infusion in all patients and for 48 hours following GIK discontinuation in 21 patients. All patients had continuous rhyt hm monitoring, and arrhythmias received routine pharmacological therapy. 3~ Patients were kept at bed rest in the supine position and were allowed only clear liquids as oral intake during the 48 hour G IK infusion. Control patient group. Patients were managed in conventional fashion as previously described by Dowling and associates. 3~ Invasive hemodynamic monitoring was employed in 19/64 (30 per cent) of the total control patient group, including 10/19 (53 per cent) of the control patient nonsurvivors. Assay methods. Glucose, BUN, creatinine, electrolytes, and SGOT were determined by standard automated techniques on Technicon Model 1260 and Model AAII autoAnalyzers. Serum osmolarity was determined by the freezing point depression method on an automatic osmometer (Osmette A, Precision Systems, Inc.). Free fatty acids were analyzed by the m et hod of Duncombe. 31

443

Rogers

etal.

FFA

I00

:-2-1.2.2.:.2-i'i'1"i 75

-

li!!!!!ili',i',',',]

uER/L

2.2.2.2.2.1.1"i.i.i.2 2.1-2-2-2.1.2"1"1"1"i 1221112:1112212211111 121112122122222111111 2.1,12-i.1.1"2-2.1,1 2.2.2.2.2.2.2"1"2.1

if)

I'Z LLI

F-

1-2.1.1.2.1.1.2-2.1.2 1.1.1.2.1.1.1"1"1"1"i

50-

a.

< 550 ~Eq/L

.i.ii.i.2.?iiii

u. o

25

-

0 N-

II

32

8

< 1.0

1.0-- 1.5

>/I.5

RATE

(ml/kg/hr)

GIK

INFUSION

Fig. 2. Effect of GIK infusion rate on FFA. GIK in the previously described concentration reduced mean plasma FFA to subthreshold levels ( ~ 350 t~Eqper liter) most consistently when infused at rates of 1.5 ml. per kilogram per hour or greater. The only patient not suppressed to subthreshold levels with this dosage was receiving heparin in therapeutic doses. Data analysis. T h e hospital m o r t a l i t y rates of the G I K and control groups were c o m p u t e d and further analyzed by the subgroupings of Killip, Peel, and Norris to ascertain which clinical t y p e of infarction might be most benefited by G I K infusion. Statistical analysis. D a t a are r e p o r t e d as means _+ S.E.M. S t u d e n t ' s t test was used to assess differences between means of i n d e p e n d e n t observations; the chi-square test was used to assess differences between proportions. Results Optimal GIK infusion rate. Fig. I illustrates the dramatic FFA fall during G I K infusion. F F A fell in every patient having elevated levels before G I K infusion was initiated. M e a n p r e t r e a t m e n t FFA was 944 _ 57 tLEq per liter and average F F A during G I K t r e a t m e n t was 289 _ 16 ttEq per liter (p < 0.0005) (normal FFA levels are r e p o r t e d as 521 __ 128 (S.D.) tLEq per liter18). Also shown in Fig. 1 is the FFA " r e b o u n d " n o t e d during the 24 hours following discontinuation of G I K infusion. FFA levels during G I K infusion correlated in a general fashion with G I K infusion r a t e (r = 0.56, p < 0.0001, n = 51). Fig. 2 graphically d e m o n strates t h a t the plasma FFA was most consistently reduced to subthreshold levels ( < 350 t~Eq per liter 26) when the G I K infusion rate was --> 1.5 ml.

444

per kilogram per hour. Indeed only one of the patients infused at t h a t rate had a m e a n F F A during the infusion of higher t h a n 304 ~Eq per liter and t h a t patient, following a p u l m o n a r y embolus, was receiving t h e r a p e u t i c doses of heparin, an agent known to elevate FFA levels via activation of lipoprotein lipase2 2-34 Since Fig. 1 d e m o n s t r a t e d significant F F A r e d u c t i o n in every patient in w h o m FFA was initially elevated, all patients have been included in the subsequent m o r t a l i t y analysis regardless of G I K flow rate since it is evident t h a t the goal of FFA reduction was uniformly achieved, albeit n o t to subthreshold levels in every case. Predicted vs. observed mortality rates. T a b l e III presents the distribution of the G I K and control patients according to the prognostic index subgroupings of Killip, Peel, and Norris, respectively. Also included for comparison are t h e m o r t a l i t y data of Killip, Peel, and Norris. Distribution of patients into subgroups was similar among GIK, controls, and the Killip and Norris classifications (p > 0.10). In the Peel analysis, patients were subdivided similarly between G I K and controls; however, b o t h G I K and controls had a smaller proportion of p a t i e n t s in the first Peel subgrouping (uncomplicated infarcts) compared to Peel's p a t i e n t population. In the control population, the expected mortality rate, derived from the original m o r t a l i t y d a t a

October, 1976, Vol. 92, No. 4

G I K a n d A M I survival

Table III. Distribution of patients into prognostic index subgroups GIK group Deaths

Killip Subgroup Nol

No.

Obs.

A. Killip index: 1 2 3 4

19 32 7 12

0 3 1 7

70

11w

Totals

Mort. rate (%)

No.

Obs.

1.1 5.4 2.7 9.7

0 9 14 58

16 33 5 10

2 7 2 8

1.0 5.6 1.9 8.1

12 21 40 80

18.9

16

64

1982

16.6

30

I Exp.

Deaths

GIK group Peel Subgroup No.

Killip 27

Control group

Deaths

[ Exp.

Mort. rate (%)

Deaths, obs.

Mort. rate (%)

81 96 26 47

5 16 10 38

6 17 38 81

250

69

28

No.

Control group Mort. rate (%)

Deaths No.

Obs.

Peel'~8 Mort. rate (%)

No.

Deaths, obs.

Mort. rate (%)

(score)

No.

Obs.

B. Peel index: 1 (0-8) 2 (9-12) 3 (13-16) 4 (_>17)

8 22 16 24

0 0 1 10

0.2 2.8 3.8 15.3

0 0 6 42

12 12 22 18

0 2 5 12

0.3 1.5 5.2 11.5

0 17 23 67

203 176 139 110

5 22 33 70

2 12 24 64

Totals

70

llt

22.1

16

64

1982

18.5

30

628

130

21

I Exp.

Control group

GIK group Norris Subgroup No. (score)

Deaths No.

Obs.

I Exp.

Deaths

Mort. rate (%)

No.

Obs.

I

C. Norris Index: 1 ( < 4) 16 2 (4-5) 20 3 (6-7) 13 4 (8-9) 10 5 {10-11) 6 6 (>_ 12) 5 Totals

70

[ Exp.

Norris 2, Mort. rate

I Exp.

~)

No.

Deaths, obs.

Mort. rate (%)

0 0 1 3 4 3

0.5 1.6 2.9 4.0 3.9 3.9

0 0 8 30 67 60

6 25 16 10 3 4

0 6 4 4 1 4

0.2 2.0 3.5 4.0 2.0 3.1

0 24 25 40 33 100

132 200 159 128 66 72

5 16 35 51 43 56

2 8 22 40 65 78

11"

16.8

16

64

1982

14.8

30

757

205

28

Abbreviations: Obs. = observed number of patient deaths. Exp. = expected number of patient deaths computed as the product of number and per cent of deaths from Killip, Peel, or Norris. tP < 0.005 (obs. vs. exp. number of patient deaths). w < : 0.03 (obs. vs. exp. number of patient deaths). *p < 0.10 (obs. vs. exp. number of patient deaths). Not significant (p > 0.10) (obs. vs. exp. number of patient deaths). of Killip, Peel, and Norris, respectively, was not significantly different from the observed mortalit y r a t e (p > 0.10). H o w e v e r , the observed m o r t a l i t y r a t e i n t h e G I K - t r e a t e d g r o u p w a s 42 p e r c e n t (p < 0.03), 50 p e r c e n t (p < 0.005), a n d 35 p e r c e n t (p < 0.10) less t h a n p r e d i c t e d b y t h e Killip, Peel, and Norris indices, respectively (chisquare one-sided test). Mortality rates in the individual Killip, Peel, a n d N o r r i s s u b g r o u p s a r e s h o w n g r a p h i c a l l y in

American Heart Journal

Figs. 3, 4, a n d 5. T h e f i g u r e s s h o w t h a t t h e m o s t striking mortality reduction occurred with GIK treatment of the least complicated patients ( K i l l i p g r o u p s I a n d I I ; P e e l s c o r e 1 t o 16; N o r r i s s c o r e 1 t o 7). T h e o v e r - a l l m o r t a l i t y r a t e o f t h e c o n t r o l g r o u p w a s 29.7 p e r c e n t ( 1 9 / 6 4 ) a n d t h a t o f t h e G I K g r o u p 15.7 p e r c e n t ( 1 1 / 7 0 ) , t h e l a t t e r representing a statistically significant mortality r e d u c t i o n in t h e G I K r e c i p i e n t s (p < 0.05).

Clinical and pathological characteristics of

445

Rogers

et al.

I00

[]=GIK

75

n-70

[]

= CONTROL

9

= KILLIP

n =64

n = 250

~ 5o

19

N=

16

82

32

33

95

7

5

25

12

I0

48

KILLIP

CLASS

I

2

3

4

Fig. 3. Mortality rate vs. Killip class. The GIK recipients had a reduced mortality rate in each of the 4 Killip

classes compared to controls and to Killip's original series.27 Class 1 = no congestive failure; Class 2 = mild congestive failure ($3 gallop, basilar rales); Class 3 = pulmonary edema; Class 4 = cardiogenic shock.

I00

75 >I-

[]

= GIK

[]

= coNTRoL

n = 70

9

= PEEL

n = 64 67%

n = 628

--I

o 2E

2517%

0

10% 1 0 %

N=

PEEL I

SCORE

e

J2

i--8

2%

zz

z03 '

iz

,Ts

1"~9-12.--'~

,s

z2

,z9

~'15--16"--~

z4

'

,s

~,0

>~17

I

Fig. 4. Mortality rate vs. Peel score. The GIK recipients had a reduced mortality rate in each of the 4 Peel subgroups compared to controls and to Peel's original series.~8 The magnitude of the Peel score is directly proportional to Peel's estimate of the severity of the infarction based on admission clinical evaluation.

nonsurvivors. T a b l e IV describes t h e clinical p r e s e n t a t i o n , p r o g n o s t i c scores, a n d c o r o n a r y a n a t o m y of t h e n o n s u r v i v o r s i n t h e G I K a n d c o n t r o l groups. T h e m e a n ages of t h e G I K a n d c o n t r o l g r o u p n o n s u r v i v o r s were s i m i l a r . M e a n p r o g n o s t i c i n d e x scores of G I K n o n s u r v i v o r s were u n i f o r m l y h i g h e r t h a n t h o s e of t h e c o n t r o l g r o u p

446

n o n s u r v i v o r s , b u t t h e s e d i f f e r e n c e s were s t a t i s t i cally s i g n i f i c a n t o n l y i n t h e N o r r i s score (p = 0.056). Postmortem and/or angiographic documentat i o n of c o r o n a r y a r t e r y a n a t o m y was a v a i l a b l e i n n i n e of t h e 11 G I K n o n s u r v i v o r s a n d i n 15 o f t h e 19 c o n t r o l g r o u p n o n s u r v i v o r s . As s h o w n i n T a b l e

October, !976, Vol. 92, No. 4

GIK and A M I survival

IO0

MORTALITY

D=GIK

75

vs

NORRIS

SCORE

n=70

[]

= CONTROL n=64

9

= NORRIS n=757

67%

{~

65%

>I-. ._1 I,--

0

50 i:i ill

25%

24%

25

'!:ii!

iiii

5% 0 N=

{6

6

153

20

25

200

13

{6

160

IO

I0

{28

3

66

5

4

70

NORRIS SCORE

I I-'-4-5----{ ~ - 6 - 7 - - " ~ { ~ 8 - - 9 - - - { F - - , o - , f --~ t ~ ~,2 ~ 1 {9 <4 Fig. 5. Mortality rate vs. Norris score. The GIK recipients had a reduced mortality rate in each of the 6 Norris subgroups compared to Norris' original series~'~ and in five of the six subgroups compared to controls. The magnitude of the Norris score is directlyproportional to Norris' estimate of the severity of the infarctionbased on admission clinical evaluation.

IV and Fig. 6, the G I K nonsurvivors had severe diffuse (two- and three-vessel) coronary artery disease. Interestingly, one of the G I K recipients was found at autopsy to have a congenitally absent left coronary artery with "malnourished left ventricular myocardium," partially supplied by branches from the right coronary ar tery system, all of which were diseased (three-vessel disease equivalent). None of the GIK nonsurvivors was found to have uncomplicated "singlevessel disease." Coronary artery pathology in the control group nonsurvivors, on the other hand, was more evenly distributed among one-, two-, and 3-vessel stenoses (Fig. 6). Of the GIK recipients, one patient (No. 8) died of ruptured left ventricular free wall during his second day of GI K infusion. Another patient (No. 11) experienced rupture of the interventricular septum, rapid hemodynamic decompensation, and death 4 days following discontinuation of her 48 hour course of GIK. Patient No. 1 died following emesis and massive aspiration of gastric contents. Patient No. 6 had anoxic encephalopathy, flail chest, acute renal failure, hyperkalemia,

American Heart Journal

and died in cardiogenic shock 12 hours following GIK discontinuation. Of the control patients, there were three deaths secondary to ruptured left ventricle (patients Nos. 2, 3, and 16). Mortality rate related to history of prior myocardial infarction. Fig. 7 shows t h a t there was

a reduction of the mortality rate in G I K - t r e a t e d patients regardless of whether the patients had experienced a prior myocardial infarction. However, the reduction in mortality rate was most striking in patients not having had a prior myocardial infarction (fourfold reduction, p < 0.05). Complications. General. Complications of the G I K infusion

were infrequent and chiefly included hyperglycemia and hyperkalemia. Initial attempts at infusion of the GIK solution via the pulmonary artery port of the Swan-Ganz catheter resulted in a pneumonitis-like radiographic pattern. 3~ This pattern cleared upon discontinuance of GIK; subsequent patients infused via the right atrial port of the Swan-Ganz catheter did not experience this complication. Phlebitis at the infusion

447

R o g e r s et al.

Table IV. P r o g n o s t i c i n d e x s c o r e s a n d e x t e n t o f c o r o n a r y a r t e r y d i s e a s e i n n o n s u r v i v o r s Prognostic index scores Pt. No.

Age

Sex

MI site

Peel

Norris

Hours lived

2 4 4 4 4 2 3 4 4 4 2

20 27 23 22 27 21 16 18 18 26 17

9.42 12.84 10.52 9.75 13.56 6.70 11.56 11.66 10.48 12.81 8.54

52 2 2 24 60 60 96 24 34 434 144

3.4 0.3

21 1

10.7 0.6

85 37

1 1 2 2 2 2 2 2 2 3 3 4 4 4 4 4 4 4 4

11 13 14 15 14 10 21 18 17 17 14 18 26 26 27 22 22 22 27

5.42 4.70 5.86 5.92 5.48 7.76 6.32 9.26 9.25 10.00 8.62 5.14 6.96 8.06 10.25 15.86 12.14 13.91 12.03

4 29 106 6 68 19 53 5 26 280 46 73 23 262 6 2 219 12 44

2.8 0.3

19 1

8.6 0.7

68 21

NS

0.056

i

Killip

I

Hem. mon. ~;

Number of coronary arteries with > 50% stenosis

+ + + + + + + + + + +

2 3 3 3 U 2 3 3 U 3 3

0 0 0 0 0 + 0 0 + + 0 + + + + 0 + + +

U 2 2 1 3 3 3 U U 3 2 2 3 3 3 1 2 2 U

I

GIK group (n = 11): 1 58 2 63 3 69 4 57 5 52 6 61 7 58 8 58 9 72 10 59 11 64 Mean + S.E.M.

P

I A A A A I A A I A A

61 2

Control group (n = 19): 1 58 2 67 3 58 4 75 5 79 6 57 7 76 8 80 9 53 10 65 11 69 12 36 13 59 14 72 15 58 16 81 17 67 18 83 19 60 Mean + S.E.M.

M M M M F M M M F M F

M M M F F M M M F F M F M M F F F M M

I I A A I A A I A I A I U U A I A I A

66 3 NS$

NS

NS

*A = anterior; I = inferior; U = u n d e t e r m i n e d . "~Hem. m o n . = i n v a s i v e h e m o d y n a m i c m o n i t o r i n g performed; + = yes; O = n o . SNS = n o t significant (p > 0.10).

site, r e p o r t e d

b y o t h e r s 3-5 a s a c o m p l i c a t i o n

of

Marked

hyperglycemia

intravenous GIK infusion, was not observed in our series, presumably because the GIK was

were diabetic.

delivered directly into the right atrium.

insulin dependent,

Hyperglycemia.

Peak

glucose

during

GIK

i n f u s i o n a v e r a g e d 286 _+ 17 m g . p e r 100 m l . i n t h e 70 p a t i e n t s . S u p p l e m e n t a l

subcutaneous

or intra-

( g l u c o s e > 350 m g .

In

two

of these

serum

e x c e e d i n g 650 m g . p e r

patients,

both

glucose rose to levels

100 m l . d e s p i t e

supple-

mental insulin, requiring the GIK infusion to be terminated prematurely.

Asymptomatic

venous regular insulin was required for manage-

ically inapparent hypoglycemia

m e n t o f h y p e r g l y c e m i a i n 10 o f t h e 16 d i a b e t i c a n d i n n i n e o f t h e 54 n o n d i a b e t i c G I K r e c i p i e n t s .

GIK infusion.

448

per

100 m l . ) w a s n o t e d i n 13 p a t i e n t s , e i g h t o f w h o m

one patient

and clin-

was discovered in

( g l u c o s e 45 m g . p e r 100 m l . ) d u r i n g

October, 1976, Vol. 92, No. 4

GIK and A M I survival

//

100

I00 UNKNOWN

75

I-Z CD r

75 3 VESSEL

II .J f~

o z

GIK

n=70

= CONTROL *

5(:

f:L

[]=

n= 6 4

= p<.05

50

2 VESSEL

25

24%

25 -

VESSEL GIK (n = 11)

CONTROL (n = 19)

Fig. 6. Extent of coronary artery disease in nonsurvivors.

Data from coronary angiography or from postmortem studies showed that the GIK nonsurvivors had a greater preponderance of severe, diffuse {two- and three-vessel) coronary artery disease, compared to controls. Osmolarity. S e r u m osmolarity was m e a s u r e d during G I K infusion in 62 of the 70 G I K recipients and averaged 284 _ 2 mOsm. per liter (normal range, 280 to 305 mOsm. per liter). In only two patients was the serum osmolarity pathologically elevated (315 and 354 mOsm. per l i t e r - t h e s e were the two insulin-dependent diabetic patients previously m e n t i o n e d whose G I K infusion was t e r m i n a t e d p r e m a t u r e l y due to marked hyperglycemia. In 58 per cent (36/62) of the patients the serum osmolarity was n o r m a l and in 39 per cent (29/62) it was mildly depressed (267-279 mOsm per liter). Hyperkalemia. H y p e r k a l e m i a was the m o s t frequent and most p o t e n t i a l l y life-threatening complication encountered. P e a k serum potassium during G I K infusion averaged 5.1 • 0.1 m E q . per liter; however, serum potassium levels of > 6.0 mEq. per liter during G I K infusion were observed in seven of the 70 patients, all of w h o m h a d either altered renal function or diabetes, or both. In 21 patients in w h o m the serum potassium was monitored serially for 48 h o u r s after G I K infusion, potassium levels of 6.0 m E q . per liter or greater were detected in 38 per cent (8/21), all b u t one of whom had altered renal f u n c t i o n or diabetes. Mean serum potassium after infusion (5.8 • 0.2 mEq. per liter) was significantly greater (p < 0.0005) t h a n m e a n serum potassium during G I K infusion (4.5 • 0.1 m E q . per liter).

American Heart Journal

n =

4.7

NO PRIOR

46 M I

25

18

PRIOR

MI

Fig. 7. Mortality rate and prior myocardial infarction. Although the over-all mortality rate was reduced with GIK infusion, patients with no prior history of myocardial infarction had the most striking reduction in mortality rate.

Severe hyperkalemia was m a n a g e d by administration of sodium polystyrene sulfonate (Kayexalate) and by reducing the KC1 c o n t e n t of the G I K infusate. In general the h y p e r k a l e m i a was clinically well tolerated, w i t h o u t E C G evidence of QRS widening, h e a r t block, or o t h e r toxic manifestations. However, one G I K recipient ( p a t i e n t No. 6, Table IV) died in cardiogenic shock while hyperkalemic (K § 7.0 mEq. per liter) 12 h o u r s following discontinuation of his 48 h o u r course of GIK. Prior to G I K infusion this p a t i e n t h a d sustained cardiac arrest at home, prolonged cerebral anoxia, and flail chest following cardiopulm o n a r y resuscitation by paramedical personnel. During his entire hospital course, he was comatose, respirator-dependent, and m a r k e d l y oliguric. W h e t h e r hyperkalemia c o n t r i b u t e d to his death is uncertain, particularly since his E C G terminally showed no hyperkalemic manifestations. Pulmonary venous hypertension. Pathological elevation of the p u l m o n a r y a r t e r y end-diastolic pressure ( P A E D P ) , used as a n estimate of left ventricular filling pressure, ~6 was n o t generally a problem during G I K infusion. In only one p a t i e n t was G I K discontinued p r e m a t u r e l y because of elevated P A E D P (28 mm. Hg). In this p a t i e n t the

449

Rogers et al.

T a b l e V. C o m p a r i s o n o f r e p o r t e d c l i n i c a l a n d l a b o r a t o r y t r i a l s w i t h i n t r a v e n o u s G I K i n f u s i o n

Study

Sodi-Pallares et al.-', 1963 Mittra ~, 1965:~ Pentecost et al?, 1968 Fletcher et al.;, 1968 Medical Research Council'~, 1968:~ Maroko et a12~, 1972

No. pts. (GIK/ total)

Elapsed time since infarct (hours)

25/50

Maximum concentration ~

M a x i m u m infusion rate Max.

Glu gm.%

Ins U./L.

mEq./L.

10

20

40

6.3

1.2

2.5

K §

Glu Gm./hr.

Ins U./hr.

K~ Hours vol./hr. Rem E q J h r , infused (ml.) sultt

72-168

60

+

85/170 100/200

Mean 22 hr. 90% _<__24 hr.

10 10

20 30

40 30

8.3 6.3

1.7 1.9

3.3 1.9

336 48

83 63

+ 0

16/80 410/840

86% ~ 24 hr.

10 10

40 20

80 30

4.2 6.3

1.7 1.2

3.3 1.9

72 336

42 63

0 0

l& hr.

50

102

210

22.5

4.6

9.5

24

45

+

Pacing study Pacing study Mean 8 hr.

50 20 30

60 40 50

200 80 80

75.0 48.0 31.5

9.0 9.6 5.2

30.0 19.2 8.4

1 3/4 48

150 240 105

0 + +

14/37 (dogs) Lesch et al.:% 1974 8/18 Parker et al. :~, 1974 11/11 Present study, 1976w 70/134

*Glu = glucose, Ins = insulin, K + = potassium. t+ = beneficialeffect of GIK shown in study, 0 = no beneficialeffect shown. $Study in which GIK was preferentially administered orally (with subcutaneous insulin) to most patients, rather than intravenously. w from present study calculated for 70 kilogram subject at infusion rate of 1.5 ml. per kilogram per hour. GIK infusion was restarted 8 hours later, f o l l o w i n g diuresis, a n d c o n t i n u e d u n i n t e r r u p t e d for a n o t h e r 48 h o u r s . I n g e n e r a l , t h e P A E D P w a s f o u n d t o fall s l i g h t l y d u r i n g t h e 48 h o u r c o u r s e o f G I K infusion, a s h a s o f t e n b e e n o b s e r v e d in patients with acute myocardial infarction who a r e h e m o d y n a m i c a l l y m o n i t o r e d . 3~

Discussion Historical perspective. Numerous investigators h a v e e v a l u a t e d t h e effects o f i n t r a v e n o u s g l u c o s e i n s u l i n - p o t a s s i u m i n f u s i o n as a t r e a t m e n t for ischemic heart disease since the concept was i n t r o d u c e d b y S o d i - P a l l a r e s a n d a s s o c i a t e s . ',~ The design and results of several selected studies a r e p r e s e n t e d in T a b l e V. I t is c l e a r l y e v i d e n t t h a t t h e s e r e p o r t e d s t u d i e s d i f f e r e d w i d e l y in t h e c o n c e n t r a t i o n s of t h e glucose, i n s u l i n , a n d p o t a s s i u m i n f u s e d a n d in t h e v o l u m e a n d d u r a t i o n o f t h e infusion. F e w s t u d i e s l i m i t e d t h e i r p o p u l a t i o n t o p a t i e n t s w i t h i n f a r c t s < 15 h o u r s in age. T w o o f t h e l a r g e s t s t u d i e s :~, 6 a d m i n i s t e r e d G I K p r e f e r e n t i a l l y as a n o r a l r e g i m e n o f g l u c o s e a n d p o t a s sium along with subcutaneous insulin, rather than using the intravenous route. Several of the more recent clinical and laboratory studies, i n c l u d i n g t h e p r e s e n t one, h a v e u t i l i z e d m u c h higher infusion rates of glucose, insulin, and potassium than originally advocated by SodiPallares.

450

Theoretical benefits of G I K infusion. A l t h o u g h initially proposed by Sodi-Pallares and assoc i a t e s 1, 2 a s a " p o l a r i z i n g s o l u t i o n " t o p r e v e n t arrhythmias and further ischemic damage by r e p l e t i o n o f i n t r a c e l l u l a r p o t a s s i u m in i s c h e m i c cells, G I K m a y e x e r t i t s m a x i m a l b e n e f i c i a l effects v i a o t h e r r o u t e s . S u c h p o t e n t i a l b e n e f i t s o f GIK infusion might include the stabilization of c e l l u l a r m e m b r a n e p o t e n t i a l , 4~ t h e e n h a n c e m e n t of g l y c o l y t i c e n e r g y p r o d u c t i o n , 9 a n d the enhancement of contractility by a hyperosmol a r i t y effect. 41 H o w e v e r , i t is p o s s i b l e t h a t t h e g r e a t e s t b e n e f i t o f G I K lies in i t s a b i l i t y t o s u p p r e s s free f a t t y acids. Myocardial substrate interactions. U n d e r a e r obic c o n d i t i o n s , t h e p r e d o m i n a n t m y o c a r d i a l e n e r g y s u b s t r a t e in t h e f a s t i n g s t a t e is l i p i d (FFA).42, 43 F F A a r e e x t r a c t e d in d i r e c t p r o p o r t i o n to t h e i r a r t e r i a l c o n c e n t r a t i o n 4~'4~ a n d a r e n o t e x t r a c t e d w h e n a r t e r i a l F F A f a l l s b e l o w 350 # E q p e r liter, t h e a r t e r i a l " t h r e s h o l d " for F F A . 26 F F A m e t a b o l i s m , f u r t h e r m o r e , h a s a n i n h i b i t o r y effect on g l y c o l y s i s 47, ~s a n d , c o n v e r s e l y , c a r b o h y d r a t e intake suppresses myocardial FFA metabolism.43, 47, 49 In the setting of myocardial ischemia, drastic alterations in cardiac metabolism may occur. Serum FFA levels are markedly elevated) ~ 13-,7 probably secondary to release of norepinephrine and reduction of serum insulin levels2s, 17, 50

October, 1976, Vol. 92, No. 4

G I K and A M I survival

Although an excellent metabolic substrate under aerobic conditions, FFA may not be the optimum substrate for the ischemic myocardium along the periphery of the central core of irreversibly infarcted tissue. Unlike glucose, FFA cannot be metabolized anaerobically; furthermore, the aerobic metabolism of FFA requires slightly more oxygen per unit of energy yield t h a n does glucose21, 52 FFA have been shown experimentally to increase myocardial oxygen consumption, 2.... to reduce myocardial mechanical performance in the setting of hypoxia, 23-25 and to be arrhythmogenic,10, 18-20although this latter point is in dispute. '~3-56Glucose, on the other hand, does readily undergo anaerobic metabolism (glycolysis). It has been estimated t h a t glycolysis might be able to transiently support ischemic tissue on the periphery of an infarct, 57 especially if t h a t tissue has reduced contractility. Glucose-insulin infusions will not only stimulate myocardial carbohydrate metabolism 43 but will also reduce the availability of FFA, the latter via stimulation of FFA esterification and via inhibition of lipolysis.58-6~ Thus, by increasing both aerobic and anaerobic glucose metabolism and by decreasing FFA availability, GIK solutions could theoretically reduce myocardial oxygen demands ~1 and perhaps improve myocardial viability37 and performance. 62 Rationale for current GIK regimen. On the hypothesis that GIK might reduce infarct size and mortality rate through suppression of FFA, we sought a regimen which would suppress FFA in patients with acute myocardial infarction to 9 subthreshold levels ( < 350 t~Eq per liter). Studies performed in our laboratory on fasting, pain-free patients with stable coronary artery disease have recently demonstrated t h a t arterial-coronary sinus differences of FFA were zero when GIK (300 Gm. of glucose, 50 U. of regular insulin, and 80 mEq. of KC1 per liter of H~O) was infused at rates of _> 1.5 ml. per kilogram per hour23 In our initial studies with GIK infusion in patients with acute myocardial infarction, quantities o f GIK less than 1.5 ml. per kilogram per hour were not found to produce consistent reduction of FFA, especially during episodes of chest pain, when FFA would often rise abruptly. Increasing the infusion rate to 1.5 ml. per kilogram per hour suppressed FFA to subthreshold levels in both the presence and the absence of pain. 12 Fig. 1 shows that, in the present study, FFA

American Heart Journal

were dramatically reduced in every patient in whom FFA were initially elevated. In most cases, FFA were reduced to subthreshold levels. The importance of the infusion rate is shown in Fig. 2. The optimal infusion rate for consistent FFA suppression would appear again to be >_ 1.5 ml. per kilogram per h o u r - t h i s amounts to an hourly dosage of 31.5 Gm. of glucose, 5.2 U. of insulin, and 8.4 mEq. of KC1 in a 70 kilogram subject. These dosages are approximately 4 to 5 times the quantities originally administered by earlier investigators2-6 (Table V). Mortality data. Comparison of the mortality rates of the GIK-treated patients and controls shows a reduction in the over-all hospital mortality rate in the treated group of 47 per cent (p < 0.05). When the severity of infarction in each patient was assessed by the prognostic indices of Killip, Peel, and Norris, respectively, it was discovered that the mortality rate of the controls was not significantly different from t h a t predicted by the prognostic indices. The mortality rate of the GIK recipients was, however, significantly reduced by 42, 50, and 35 per cent in the Killip, Peel, and Norris predictions, respectively. It should be acknowledged t h a t the GIK recipients were not a consecutive series, and furthermore that the mean age of the G I K group was significantly less than that of the control group; otherwise the two patient populations were remarkably well matched by clinical criteria. The nonconsecutive state of the GIK group was, in general, chiefly dictated by technical and logistical problems, i.e,, the inability to hemodynamically monitor simultaneously multiple patients, and in no way represented an a t t e m p t to restrict GIK administration to uncomplicated infarcts. Indeed, the great similarity between the magnitude of the mean prognostic scores of the GIK and control populations, calculated independently by the methods of Killip, Peel, and Norris, further testifies to the similarity of the GIK and control groups. Study of the GIK patient deaths (Table IV, Fig. 6) reveals t h a t there were no deaths in patients having single-vessel coronary artery disease, few deaths in those with two-vessel disease, and also few deaths in patients having no history of prior myocardial infarction. These facts would support the thesis that, if G I K is to provide metabolic support, it must do so via perfusion of

451

Rogers et al.

ischemic tissue. Perfusion would be most difficult, if not impossible, in patients with severe two- and three-vessel coronary artery disease; this group would also likely include most patients with history of prior myocardial infarction. On the other hand, patients with single-vessel disease would receive maximal benefit through perfusion of ischemic areas via the uninvolved vessels and collateral channels. Complications of GIK administration. Despite the encouraging mortality statistics presented above, the GIK infusion was not without complications, especially in patients with altered renal function or diabetes. Although the major complications, hyperglycemia and hyperkalemia, were easily managed in most patients, one hyperkalemic, oliguric patient died in cardiogenic shock several hours following discontinuation of his course of GIK. Hyperkalemia in this patient could not be definitely incriminated as the cause of death, however, since no ECG evidence of potassium toxicity was evident. Two insulindependent diabetic patients had marked hyperglycemia and hyperosmolarity during GIK infusion, not responsive to supplemental insulin, necessitating premature termination of their GIK infusion. Guidelines for GIK administration. Because of these observed complications, we currently feel that GIK administration, though potentially of great benefit in the early postinfarct period, is still in the investigative stage, awaiting further controlled clinical trials and not yet ready for utilization by the community hospital. Our data would suggest t h a t an infusion of 1.5 ml. per kilogram per hour of the previously defined GIK solution would appear optimum to suppress FFA to subthreshold levels. Patients receiving GIK should be serially monitored with serum glucose, electrolytes, and PAEDP or pulmonary capillary wedge pressure. Serum potassium should be monitored for 24 to 48 hours following GIK discontinuation, since this is the period of maximum serum potassium levels. Hyperkalemia should be treated by reduction of potassium in the infusate as proposed by Sodi-Pallares and associates 64and, if necessary, by administration of sodium polystyrene sulfonate (Kayexalate). Hyperglycemia should be managed with supplemental insulin.' In conclusion, this study demonstrates t h a t patients with acute myocardial infarction can be

452

routinely instrumented and begun on a metabolic support regimen within 15 hours (mean, 8 _ 3 hours) of onset of chest pain. The data suggest that metabolic intervention with glucose-insulinpotassium in dosage sufficient to reduce free f a t t y acid levels to subthreshold may favorably influence the hospital mortality rate of acute myocardial infarction. Patients most likely to benefit from the GIK infusion would seem to be those without history of prior infarction and with relatively uncomplicated clinical presentation. The GIK infusion is not without complications, and meticulous attention to serum glucose and potassium is necessary during and immediately following discontinuance of GIK, especially in patients with diabetes or altered renal function. Additional controlled clinical studies would seem indicated to further investigate the efficacy of metabolic support of acute myocardial infarction with GIK, and to further elucidate its mechanism of action and its effects on myocardial electrical stability and mechanical performance. Summary

Free fatty acids (FFA), the predominant myocardial energy substrate, are present in increased quantities immediately following acute myocardial infarction (AMI) and may cause deleterious alterations in cardiac rhythm, oxygen consumption, and mechanical performance. In an attempt to suppress FFA and simultaneously increase the availability of carbohydrate as a myocardial substrate, 70 patients with unequivocal AMI were administered a right atrial infusion of glucose-insulin-potassium (GIK) (300 Gm. of glucose, 50 U. of regular insulin, and 80 mEq. of KC1 per liter of H20) at a constant rate of 0.5 to 2.0 ml. per kilogram per hour for 48 hours. A dramatic fall in FFA (944 _+ 57 to 289 _ 16 ttEq per liter, p < 0.0005) occurred during GIK infusion, and FFA rebounded to 420 _+ 39 ~Eq per liter (p < 0.005) when GIK was discontinued. The hospital mortality rate in the 70 GIK recipients was compared to t h a t of 64 untreated patients (controls) from the same coronary-care unit during the previous year. GIK and control groups had similar severity of infarction as assessed by prognostic scales of Killip, Peel, and Norris, respectively. The hospital mortality rate was reduced in the GIK recipients compared to the control group {11/70 vs. 19/64, p < 0.05). In patients without history of prior myocardial

October, 1976, Vol. 92, No. 4

GIK and A M I survival

infarction, the mortality rate was reduced fourf o l d i n G I K r e c i p i e n t s c o m p a r e d t o c o n t r o l s (6 vs. 24 p e r c e n t , p < 0.05). C o m p l i c a t i o n s o f G I K infusion were infrequent and included chiefly hyperglycemia and hyperkalemia, both of which dictated meticulous monitoring of serum chemistries. The data suggest that suppression of plasma FFA with GIK infusion may be associated with a significant reduction in the hospital mortality rate of acute myocardial infarction. The authors gratefully acknowledge the statistical analysis by Mr. John Burdeshaw, the secretarial assistance of Mrs. Betty D. Smith and Mrs. Katherine T. Young, and the helpful suggestions of Drs. Robert A. Kriesberg and Lloyd L. Hefner during the course of this investigation.

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American Heart Journal

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October, 1976, Vol. 92, No. 4