Title Changes of Kallikrein-Kinin System in Acute Phase ofHemorrhagic and Septic Shock

Author(s)MIYAMOTO, MASAAKI; SUDO, TAKAAKI;KAWAMURA, MASAO; ISHIYAMA, KENJI; KUYAMA,TAKESHI; KAKUTANI, TOMIO

Citation 日本外科宝函 (1989), 58(6): 475-484

Issue Date 1989-11-01

URL http://hdl.handle.net/2433/203912

Right

Type Departmental Bulletin Paper

Textversion publisher

Kyoto University

CORE Metadata, citation and similar papers at core.ac.uk

Provided by Kyoto University Research Information Repository

Arch Jpn Chir 58(6), 475～484, Nov., 1989

原著

Changes of the Kallikrein-Kinin System in Acute

Phase of Hemon・hagicand Septic Shock

MASAAKI MIYAMOTO, TAKAAKI Suno, MASAo KAWAMCRA‘KENJI ISHIYAMA, TAKESHI KuvAMA and TOMIO KAKUTANI"'

Second Department of 吋urgery,Kinki University School of Medicine (Director: Prof. TAKESHI KUYAMA)

ホDepartmentof Surgery, Y aenosato Hospital Received for Publication, Aug. 11, 1989.

Introduction

Various protease inhibitors with anti-shock effects are used for treating various shock states.

We evaluated the dynamics of the Kallikrein-kinin system, which is important as a site of action

for these drugs as well as a factor associated with the formation of the shock cycle、andclosely

associated coagulation・fibrinolysis and complement systems (Fig. 1) in the acute stage of shock.

Subjects and Methods

The subjects consisted of 17 patients with hemorrhagic shock and 5 with septic shock (mean

age, 43 years) who were treated at 2nd Department of Surgery, Kinki University School of

:VIedicine and at Critical and Emergency Center, Osaka Prefectural Hospital during the 2 years

and 6 months between January, 1985 and June, 1987 (Table 1). Hemorrhagic shock was defined

as bleeding with a blood pressure of 90 torr or less, and sepsis as arterial blood positive for bacilli

with organ failure. Shock was considered to have developed when blood pressure fell to 90 torr

or less. Shock improved in 12 of the 22 patients (55°句）、 and16 of the 22 patients (73%) died.

Improvement of shock was defined as continuance of a systolic blood pressure of 100 torr or more

for 6 hours within 48 hours of its onset.

The parameters measured were prekallikrein and high molecular weight kininogen (H:¥IW-

Kg), which are representative factors in the kallikrein kinin system, AT-III, pla,,rninogen (PLg),

and α2-macroglobulin （α2-'.¥IG) in the coagulation・fibrinolysi討 system,C3 in the complement

system, and lactic acid as a parameter of peripheral circulation. Blood was collected 0, 12, 24,

48, 72, and 96 hours after the development of shock, immediately centrifuged using a refrigerated

Key words: Kallikrein-kinin system, Coagulation・凸brinolysissys tern、H"morrhagicshock，山下ticshock, Prekal-likrein, High molecular weight kininogen.

索引用語：カリクレイン・キニン系，凝固・線溶系，出血性ショック．敗血症性ショック，プレカリクレイン，高分子キニノーゲン．

Present address: 2nd Department of日urgery,Kinki Universityぬhoolof ¥ledicine, 377 2，りhno-Higashi,Osakasayama-City, Osaka 589, Japan.

476 日外宝第58巻第6号（平成元年11月）

沼

トーnc。llagen

¥II a一一一一一一一

CI ump of f ibron

｜印刷｜ムllikre1

｜…叶」一 Pia

〕 p，。ducts。ff lb円円

n

oaEEEトl

，

n

LR

u

，

Au

a

ι 町

Kintnase I

Kin inase II= Angiotens1n I

converting enzyme Inactive products

Activation of Ph。spholipase A 2

仁二コ： measured fact肘Prostaglandins

Fig. 1. Correlation between Kallikrein-Kinin system and other systems, matters

centrifuge, and the plasma was stored at -20。C. Prekallikrein and HMW-Kg were measured

by the SDA method, AT-III, PLg, and α2-MG by the chromogenic synthetic substrate method,

C3 by the TIA method, and lactic acid by the enz戸naticmethod using lactate oxidase.

01234 11111

Table 1. Subjects (22 patients)

Age Sex Disease lmprovem開 t Outcome of shock

67 Male traumatic aortic rupture ＋ Death

43 Male hemopneumothorax. pelvic fracture ＋ Survival

43 Male small intestine rupture, intraabdominal Death hemorrhage

19 Male traumatic liver rupture ＋ Death

46 Male br90hial artery injury ＋ Survival

54 Male crushe<I thigh, pelvic fracture ＋ Deat狗

11 Male I iver and spleen rupture Death

72 Male depressed skull fracture Death

19 Male superior sagittal sinus fracture Death

49 Male brachiocephal ic trunk injury ＋ Death

49 Male a凶 ominal stab injury 寸ー Survival

18 Male facial and femoral bone fracture ＋ Survival

44 Male crushed thigh, pelvic fracture Death

54 Male super’or mesenteric artery and vein Death

＇＂』ur1es35 Female cervical duct injury ＋ Survival

18 M副e S<島clavianartery laceration ＋ Survlv副

49 Male superior mes開 tericartery m』ury ＋ Death

47 Male suture insufficiency Death (after operation for esoph司 eal cancer)

54 Male large intestinal cancer rupture Death

68 Male mesenterlc thrombosis Death

39 Female acute he作10「rhagicpancreatitls ＋ Death

39 Female suture insufficimcy Death (after叩 eration for pancreatic cancer〕

1 -17 : patients with 憎 morrh司 ic抽出k18 -22 patients with septic山田k

Patient

9

0

1

2

．，内，‘内4

内，‘

THE KALLIKREIN-KININ SYSTE'.¥1 IN HEY!ORRHAGIC AND SEPTIC SHOCK 477

｛も｝

100

80

40

lO

'" 100

80目

Prekal I ikrein

。l2 L.; 48

40 ~可＼ ¥ ¥ ‘＼

0 ll " "

IN=ll 1

日て72 Hhrs

l 、＝•，

72 96nrs

1. Patients with hemorrhagic shock

(<)

150

100

HMW-Kininogen

。←J。12 2..: " 72

。12 " " 72

Fig. 2.

Results

¥ 1 色nrs

h咽......9"'"" 。f hen田＂ hagic

shock

N=6,

Unu•咽...回 g•ouP

of hen崎＂＂司自 C

s，官提出助N=6,

~： L肺er 11m•t

of 向。F何回I

The 17 patients with hemorrhagic shock were divided into a group in whom shock improved

(improved group) and a group in whom shock did not improve (unimproved group). The time

courses of prekallikrein and ff'.¥IW Kg values in the two groups are shown in Fig. 2.

Prekallikrein and H:'II¥¥--Kg were already decreased at the initial consultation. showing acti¥・atir,n

of the kallikrein-kinin system at the verァearlystage of shock. The代 parametersreぐonredin

the improved group but not in the unimproved group. In the improved group. H:'II＼＼二Kg

recovered already after about 24 hours. while the recovery of prekallikrein wa' delayed. In the

Unllilproved group, prekallikrein transiently increased after 12-24 hours and tended to dり位、e

thereafter; the importance of these changes remains ob吋＿urt_

Ao, shown in Fig. 3, both AT-III and C3 were d引.－rea•、td at the initial consultation. They

tended to increase in the improved groupbut deer位、tin the unimproved group.

PLg wa' also decreased at the initial consultation and tend吋 toinげ同党 mthe improved

group. In the unimproved groupヲ ittended to be consumed.、h0－.口n写furtheractivation of the

fibrinolysis system.α2-¥IG was nearlv in the normal rangt in both zr山？＇ but tended to be

478 日外宝第58巻 第6号（平成元年11月）

Antithrombin III

｛もj

100

60

40

20

s

r

h

6

9

2

7

8

4

4

2

2

l

o

｛も｝100

60

40

20

0 12 24 49 72 96色

n<S

c。mplement3

100

80

40

20

0 12 24 48 72 96 hrs

｛も｝120

100

80

40

20

s

r

h

6

9

2

7

8

4

4

2

2

1

0

Fig. 3.

Improved oro帽

。f hem。rrh司出

sh。ck(N＝刊）

Unimpr師国 gr。upof hem。rrh司 ic

sh血 k

(N=6J

~ ・ Lower limit

。f normal

r副 ge

increased in the unimproved group (Fig. 4).

These results suggest rapid activation of the kallikrein-kinin, coagulation・fibrinolysis, and

complement systems following the development of hemorrhagic shock. There were apparent

differences in the reactions of these systems between the improved and unimproved groups.

Lactic acid markedly increased at the early stage, demonstrating peripheral circulatory

failure. It decreased with time in the improved group (Fig. 5).

2. Patients with septic shock

All the 5 patients with septic shock died. Shock improved only in 1 patient, in whom, the

parameters in each system tended to recover. However, in the other 4 patients in whom shock

did not improve, values of these parameter were already abnormal at the initial consultation and

did not improve with time (Figs. 6 and 7).

3. A patient with typical hemorrhagic shock who improved

Fig. 8 shows the recovery process of the parameters in the 3 systems in a 46-year-old male

with simple typical hemorrhagic shock. He developed severe hemorrhagic shock due to rupture

of the brachial artery resulting from stab injury to the brachium. Following cardiopulmonary

resuscitation (CPR) and surgery and transfusion of 26 units of blood, the condition dramatically

THE KALLIKREIN-KININ SYSTE:¥1 IN HEMORRHAGIC AND SEPTIC SHOCK 479

Plasm in笥狩n α2-Macr句 loblm

BO (my/di I

400

t川JOO

60 lOO

Imo＇。vedg，。咽。f hem。＂＂＂＂＇ c.... c.

'N= 11,

40 200

ミ~20 100

s

r

hn

6

9

2

7 a

a

－

－

2

2

1

0

0 12 24 48 72 96

"" ｛も｝

100

80 (mq/dll

400

)00

Unin'・F。ved9＇。up

。f herno"h司自C

・-・ (N=6)

20

200

市側司R

s

r

h

6

9

2

7

8

4

4

2

2

i

o

s

z

h

6

9

2

7

8

4

a

・2

2

l

o

~ No'm副

＇＂＂・e

Fig. 4.

improved.

In this patient, as suggested above in the patient who imJ?roved, despite continuously

decreased prekallikrein, HMW-Kg recovered after about 24 hours, and AT-III and C3 also

improved. These findings suggest the importance of inhibitors at the stage of HMW-Kg

activation by kallikrein rather than prekallikrein depletion in resuscitating patients from shock.

Discussion

Shock induces, unless its cause is removed, and appropriate treatment is done, destruction

of kinetic equilibrium in each biologic system, resulting in an irreversible state of disseminated

intravascular coagulation (DIC) with a very poor prognosis for Jife3>. Therefore, for treating

shock it is necessary to evaluate changes in parameters in the kallikrein-kinin, coagulation-

fibrinolysis, and complement systems. Recently the importance of chemical mediators has been

recognized, and especially, hydrolases that escape from lysosomes, which are minute granules in

the cell, have attracted attention. These proteases are considered to cause extensive cell injuries

in vital organs, aggravating shocks>. In this study, the dynamics of the 3 systems was evaluated

from the ultra-acute stage.

480 日外宝第58巻第6号（平成元年11月）

(rng/dl) 300

200

100

。

20

10

0 t:・2・：守・．．日士・・．－．

Lactic acid

0 12 24 48 72 96

Fig. 5.

hrs

Improved group of hemorrhagic shock

(N=11)

Unimproved group of hemor，・hagicshock

CN=6)

塁率： Normal range

Prekallikrein, HMW-Kg, AT-III‘PLg, and C3 were already decreased in the patients with

hemorrhagic or septic shock at the development of shock, suggesting activation of the 3 systems

from the ultra-acute stage. In the patients with hemorrhagic shock, these parameters improved

as the shock state improved司 showinga correlation with clinical condition. Retrospective

comparison of the mean volume of blood trans fusion showed no statistical difference between the

improved group (41 units) and the unimproved group (53 units). This finding excludes the

possibility of the contribution of blood transfusion to the difference between the improved and

unimproved groups.

THE KALLIKREIN-KININ SYSTEM IN" HEMORRHAGIC AND討EPTICSHOCK 481

Septic shock

（も）

100 r Prekallikrein (N=5)

（も）

100

ー』0

5

50

＼ツ H剛ー…gen （同

'-. I 、＼

、ケベV ←ー fmprov回

0 12 24 48 72 hrs

＋一一 Unimproved

group

. 72.

nrs

（‘J 100

(mg/dl) 100

C3 (N=5) AT-m (N=5)

50

人 ------1ι ？ヴシ」

,f

4

2

2

1

0

0

48 72 hrs すl2 • 24 ' 48

』

72 hrs

Fig. 6.

Of the patients with septic shock, only 1 showed improvements in shock, demonstrating the

seriousness of this pathologic condition. Attention should be also paid to the underling diseases

that induced sepsis. Septic shock in these patients was the terminal condition of highly lethal

diseases such as esophageal cancer, suture insufficiency after radical operation for pancreatic

cancer, rupture of large intestinal cancer, and acute thrombosis of the superior mesenteric artery.

The underlying disease was not successfully treated, and there is high possibility that shock was

already irreversible when its diagnosis was made. This may be a cause of the no improvement.

In the 1 patient who improved, intensive treatment was initiated at a relatively early stage under

a diagnosis of acute hemorrhagic pancreatitis, and weaning from a respirator and discontinuation

of hypertensors were successful. However, she died of necrosis of the entire stomach of unknown

cause的・ In acute pancreatitis, UEHARA 7J reported decreased plasma prekallikrein, a negative

correlation between kallikrein-like activity and prekallikrein activitv町 anddecreased high mo-

lecular and low molecular kininogen. In our study, the patient with acute pancreatitis also

showed decreases in plasma prekallikrein and HMW Kg at the early stage but their increases as

shock improved.

As dynamics of the kinin system in septic shock司 WERLEet al Bl. showed in patients or animals

in septic shock, a correlation between decreases in blood pressure during shock and decreases in

blood kininogen associated with release of kinin. KADOKURA2> produced strangulation ileus

in the upper small intestine in dogs and observed that blood plasma kinin gradually increased as

482 日外宝第58巻 第6号（平成元年11月）

Septic shock

lrng/dl) 300 - -0

( ~）

100 γーα2-Macrogloblin (N=5) Plasrninogen (N=SJ

100

・～～－－－－－

Oトえ二。・－－ Improved

group

200

・－ Unimproved

group

d

4自--------r2hrs 0 12 24 48

s

r

h

、，ι7

0 12 24

(mg/dl J

400 r

300ト 1

" I 、－、、h

200 I園、、．

Lactic acid ＇~＇＝ 5)

100

． 0 12 24 48 72.

nrs

Fig. 7.

the ileus progressed, reaching markedly high values at the time of death. In association with

these observations, SHIBA5l and HENMr1l reported that blood kininogen tended to decrease while

kallikrein and plasmin activity increased with the progression of ileus. 0’DONNELL et al. 4>

measured kinin and prekallikrein in 21 patients with sepsis and observed a decrease in blood

prekallikrein in all patients and an especially marked decrease in those with hypotension. The

decreases in these parameters seem to be consumption associated with enhanced activity of the

kinin system, and inhibition of kinin activity may be important for resuscitation from the shock

cycle. Our findings may provide rationale for the effectiveness of aprotinin, which inhibits the

kinin system at the stage of the action of kallikrein on HMW-Kg, and urinastatin with mul-

tivalent effects.

Conclusion

We serially measured representative parameters in the 1) Kallikrein-kinin system, 2) co-

agulation・fibrinolysis system, and 3) complement system in 17 patients with hemorrhagic shock

and 5 patients with septic shock from the acute stage of shock and obtained the following results.

1. In the patients with hemorrhagic shock, these 3 systems were simultaneously activated from

the very early stage of shock but tended to improve as shock improved.

2. In the patients with septic shock, the 3 systems were di伍cultto improve.

THE KALLIKREIN-KININ SYSTE:¥l IN HE¥WRRHAGIC A:-¥D SEPTIC SHOCK

(%) (mg/dl) 150

100

50

。0 12 24 48 72

C3

HMW-K1n1nogen

AT-m

Prekallikrein

Lactic acid

96ι nrs

Fi邑.8. A improved case of hemorrhagic shock 46 years old, male, brachia!

artery injury, dead on arrival (DOA), base excess (B.E.）ー12.

483

3. The decreases in prekallikrein and HM＼.＼にKgseem to be consumption associated with

enhanced activity of the kallikrein-kinin system, suggesting the involvement of a certain

factor that inhibits activation of HMW-Kg by kallikrein in improvement of shock.

Acknowledgments

We would like to express deep thanks to KIKUSHI KATSURADA, Director of Emergency Department, Osaka

Prefectural Hospital for use of precious cases of hemorrhagic shock.

The abstract of this report was presented at the 36th congress of the Japan society of anesthesiology on April 13,

1989 (Yamaguchi city).

References

1) Henmi H: Analysis on the protective effect of anti-kinin and antトkininformingenzymes to experimental

shock. J Jpn Surg Soc 73: 808-820, 1972 (in Japanese).

2l Kadokura ~： Studies on plasma-Kinin in intestinal obstruction with special references to the relationship

between kinin and endotoxemia. J Nippon Med Sch 52: 63 72, 1985 (in Japanese).

3l Kugimiya H: A pathophysiological and biochemical study on the experimental traumatic shock in rats-

~ relationship between coagulation／品rinoliticsystem and DIC-Jpn J Anesthesial 31: 75 84, 1982 (in

Japanese).

484 日外宝第58巻 第6号（平成元年11月）

4) 0’Donnell TF, Clowes GH, Blackburn GL, et al: Proteolysis associated with a de五citof peripheral energy

fuel substrates in septic man. Surgery 80: 192 195, 1976.

5) Shiba T: Changes of plasmin activity in acute intestinal obstruction, various kinds of shock and surgical

operative invasion. J Jpn Surg Soc 69: 608 630, 1968 (in Japanese).

6) Tamakuma, S Hase K, Yokoyama S, et al: Anti shock effects of protease inhibitor. Jpn J Acute Med 10:

805-811, 1986 (in Japanese)

7) Uehara S: Studies on KallikreirトKininsystems in pancreatitis. Biliary Tract and Pancreas 4: 679-686,

1983 (in Japanese).

8) Werle E: Plasmakinine. Dtsch Med Wochenschr 92: 1573-1580, 1967 (in Japanese).

9) Yamamoto M‘Miyamoto M, Tsujimoto M, et al: Total gastric necrosis associated with sepsis, report of

a case. Stomach and Intestine 23: 311 316, 1986 (in Japanese).

和文抄録

出血性・敗血症性ショックにおける急性期

カリクレイン・キニン系動態について

近畿大学医学部第2外科学教室（主任．久山健教授）

東大阪市八戸の里病院外科（角谷冨男院長）

宮本正章，須藤峻章，河村正生，石山堅司

久山 健，角谷冨男

現在，各種シ司ツクiζ対しその抗シ司ツク作用に着 1. 出血性ショック症例においては，シ司ツク発生と

目されて様々な proteaseinhibitorが用いられている 共に極めて早期よりとれら 3系は一斉に活性化が

が，とれら薬物の作用点として，また，ショックサイ 始まり，ショックの改善に伴い，とれら因子の明

クJレを形成する一因として重要な位置を占めるカリク らかな改善傾向が認められた．

レイン・キニン系，及びとれと密接に関連する凝固・ 2. 敗血症性シ司ツク症例においては，上記3系とも

線溶系，補体系のショック超急性期よりの動態につい 改善しにくい傾向がみられた．

ての知見は意外と少ない 本研究は，出血性シ司ツク 3. プレカリクレイン， HMW-Kgの減少は，カ

症例17例，敗血症性ショック症例 5例について， l〕 リクレイン・キニン系の活性冗進に伴う消費と考

カリクレイン・キニン系， 2）凝固・線溶系， 3）補 えられ，カリクレインによる HMW-Kgの活

体系の各代表的因子をショック趨急性期より経時的に 性化を抑制する何らかの因子がショックの改善IC

測定し，以下の結果を得た． 寄与する可能性が示唆された．