경희대학교 의과대학·의학전문대학원

전체 글

(1)

34, 36 장

고혈압

(2)

서론

① 출혈 , 감염 , 고혈압은 모성사망 및 이환의 3 대 질환

② 전자간증 (preeclampsia) – 임신 중기 이후 발병하는 고

혈압 질환으로 유일하게 임신에 의하여 발병하고 임신의

종결과 함께 치유되는 내과적 합병증

③ 병태생리 및 치료법은 완전히 밝혀지지 않음 .

(3)

서론

① 임신성고혈압 (Gestational hypertension)

formerly termed pregnancy-induced

hypertension. If preeclampsia syndrome does not

develop and hypertension resolves by 12 weeks

postpartum, it is redesignated as transient

hypertension

② 전자간증 - 자간증 (Preeclampsia

and

eclampsia

syndrome)

③ 가중합병전자간증 (Preeclampsia syndrome

superimposed on chronic hypertension)

④ 만성고혈압 (Chronic hypertension)

(4)

Chronic hypertension 임신 전 진단되었거나 임신 20 주 전에 진단되는 고혈압 가임기 여성의 고혈압 유병률 30 대 3.4%, 40 대 10.8%(‘11) 백의고혈압 (white-coat hypertension) 고려 임신 중 혈압이 조절되는 경우가 있으며 임신경과에서 비교적 예후가 좋은 편이나 반면 , 고혈압이 악화되고 단백뇨 , 증상 및 경련이 동반되는 경우 preeclampsia 도 발생 가능 (superimposed preeclampsia)

(5)
(6)

Chronic hypertension

BP>135/85 mmHg 임신의 금기증

cerebrovascular thrombosis or hemorrhage myocardial infarction

cardiac failure

임신의 상대적 금기증

persistent diastolic pressure ≥110 mmHg multiple antihypertensives

(7)

만성고혈압 임신부의 산전관리

임신 전 또는 임신 초기에 이차성 고혈압을 감별하고 표적장기 손상

유무를 확인하기 위한 충분한 평가가 이루어져야 함 .

4-40%, superimposed preeclampsia

Uterine artery Doppler velocimetry 를 예측에 사용하기도 함 . Low dose aspirin, 예방 목적으로 투여

태아상태평가

(8)

만성고혈압 임신부의 산전관리

혈압조절

BP control, SBP>150~160 mmHg, DBP≥100 mmHg

표적장기 손상이 있으며 경증의 고혈압에서도 치료가 권고됨 .

adrenergic blocking agent (ex, methyldopa, β-blocker, αβ-blocker), CCB

ACE inhibitor, ARB 는 임신 중 사용 금기임 . 분만관련 처치

태아성장제한이나 전자간증과 같은 합병증이 발생한 경우 임상적 판

단에 의해 분만 시기를 결정함 . 분만방법 역시 산과적 요인에

(9)
(10)
(11)

Indicators of Severity of Gestational

Hypertensive Disorders

Abnormality Nonsevere Severe

Diastolic blood pressure <110 mm Hg  ≥110 mm Hg Systolic blood pressure <160 mm Hg  ≥160 mm Hg Proteinuria  None to positive  None to positive

Headache Absent Present

Visual disturbances Absent Present Upper abdominal pain Absent Present

Oliguria Absent Present

Convulsion (eclampsia) Absent Present

Serum creatinine Normal Elevated

Thrombocytopenia Absent Present

Serum transaminase elevation Minimal Marked

Fetal-growth restriction Absent Obvious

Pulmonary edema Absent Present

• The differentiation between nonsevere and severe gestational

hypertension or preeclampsia can be misleading because what might be apparently mild disease may progress rapidly to severe disease.

(12)

전자간증의 빈도 및 위험인자

Nulliparous population, 3-10%

위험인자

① Young, nulliparous women

② Obesity, multifetal gestation, >35years old women hyperhomocysteinemia, metabolic syndrome,

African-American ethnicity ※Reduced risk

(13)

원인

① Placental implantation with abnormal trophoblastic invasion of uterine vessels

② Immunological maladaptive tolerance between maternal, paternal (placental), and fetal tissues ③ Maternal maladaptation to cardiovascular or

inflammatory changes of normal pregnancy

(prostacyclin-thromboxane 의 불균형 , 산화스트레스 , 혈 관생성인자 _sFlt-1, PlGF, sEng 의 불균형 )

④ Genetic factors including inherited predisposing genes as well as epigenetic influences.

(14)

자간전증의 병인 및 기전

(15)

자간전증의 병인 및 기전

다음의 여성에서 잘 발생

->vascular endothelial damage, subsequent vasospasm, transudation of plasma, thromobotic sequelae

• Are exposed to chorionic villi for the first time

• Are exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole

• Have preexisting renal or cardiovascular disease

• Are genetically predisposed to hypertension developing during pregnancy.

(16)

태반측요인

(abnormal trophoblastic

invasion)

(17)

태반측요인 (abnormal trophoblastic invasion)

• diminished perfusion, hypoxic enviroment 는 placental debris 혹은 microparticles 을 방출하여 systemic inflammatory

response 를 유발

• defective placentation 은 gestational hypertension,

preeclampsia syndrome, preterm delivery, growth-restricted fetus, placental abruption 을 유발

(18)

면역학적 요인 (immunologic factors)

Maternal immune tolerance 에 의해 정상 임신 유지

Tolerance dysregulation 에 의해 preeclampsia 발생 가능 First pregnancy

Increased paternal antigenic load (ex, molar pregnancy) Trisomy 13 (elevated antiangiogenic factor, sFLT-1)

Immune maladaptation (reduced HLA-G…)

(19)
(20)

Pathogenesis

① Vasospasm

② Endothelial cell activation

- increased pressor responses

③ Endothelin 증가

④ Angiogenic imbalance

antiangiogenic proteins 인 sFlt-1, sEng 의 증가

angiogenic protein 인 PlGF 감소

(21)

병태생리

Cardiovascular system – hyperdynamic

① 혈압상승 , 혈관수축과 비정상 혈관 반응성 (angiotensin II 에 대한

과도한 반응성 )

② 심박출량이 보통이거나 약간 감소

(22)

병태생리

Blood volume-Severe hemoconcentration

It is important to recognize that a substantive cause of this fall in hematocrit is usually the consequence of blood loss at delivery.

(23)

병태생리

혈액 및 응고인자 변화

• Thrombocytopenia

• Hemolysis

• HELLP syndrome (hemolysis, low platelet, elevated liver enzyme)

• Coagulation – subtle changes like intravascular coagulation

(24)

병태생리

Volume homeostasis Endocrine changes:

• renin, angiotensin II, angiotensin 1-7, aldosterone 의

감소 ( 정상임신에서는 증가 )

• Deoxycorticosterone 증가

• Vasopressin, atrial natriuretic peptide 는 비슷함 . Fluid and electrolyte changes:

• Extracellular fluid 의 증가에 의한 edema (endothelial injury 에 의해 발생 )

(25)

병태생리

Kidney

Anatomical changes-glomerular endotheliosis 사구체여과율과 신장혈류량의 감소 Proteinuria (>300mg/24h), 단백뇨량으로 질병의 중증도를 평 가하지 않음 . Prerenal oliguria 가 나타남 Cr 이 1 mg/mL 이상 상승하나 분만 후 10 일내에 정상화됨 . Oliguria 는 수액정주가 치료법은 아님 .

(26)

병태생리

Liver

HELLP syndrome – hemolysis, hepatocellular necrosis, thrombocytopenia

간효소수치의 현저한 증가 (elevated AST and ALT)

피막혈종 혹은 간파열이 발생할 수 있음 (Hepatic hemorrhage, subcapsular hematoma, rupture)

임상증상 - 우상복부통증 (epigastric pain)

※ Acute fatty liver of pregnancy is sometimes confused with preeclampsia

(27)
(28)

병태생리

Brain 임상증상

① Headache and scotomata blurred vision, diplopia

② Convulsion – eclampsia magnesium sulfate 투여

③ Blindness, 대부분 resolution 되며 무증상의 serous retinal detachment 는 흔한 편임 .

④ Generalized cerebral edema – mental change, 갑작스

(29)

병태생리

Brain (headache)

cerebral hemorrhage

seizure

(30)

예측

(predictive tests for development of the

preeclampsia)

Testing Related To: Examples Placental perfusion/vascular resistance

Roll-over test, isometric handgrip or cold pressor test,

angiotensin-II infusion, midtrimester mean arterial pressure, platelet angiotensin-II binding, renin, 24-hour ambulatory

blood pressure monitoring, uterine artery or fetal transcranial Doppler velocimetry

Fetal-placental unit endocrine

dysfunction

Human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), estriol, pregnancy-associated protein A (PAPP A), inhibin A, activin A, placental protein 13, corticotropin-releasing

hormone, A disintegrin, ADAM-12, kisseptin

Renal dysfunction Serum uric acid, microalbuminuria, urinary calcium or kallikrein, microtransferrinuria, N-acetyl-β-glucosaminidase, cystatin C, podocyturia

Endothelial

dysfunction/oxidant stress

Platelet count and activation, fibronectin, endothelial adhesion molecules, prostaglandin, thromboxane, C-reactive protein, cytokines, endothelin, neurokinin B, homocysteine, lipids, antiphospholipid antibodies, plasminogen activator-inhibitor (PAI), leptin, p-selectin, angiogenic factors to include placental growth factor (PlGF), vascular endothelial growth factor

(VEGF), fms-like tyrosine kinase receptor-1 (sFlt-1), endoglin Others/miscellaneo

us Antithrombin-III(AT-3), atrial natriuretic peptide (ANP), βmicroglobulin, haptoglobulin, transferrin, ferritin, 25- 2

-hydroxyvitamin D, genetic markers, cell-free fetal DNA, serum and urine proteonomics and metabolomic markers, hepatic aminotransferases

(31)

예방 (some methods to prevent preeclampsia that have been evaluated in randomized trials)

위의 어느 것도 예방효과가 확립된 것은 없음 .

Preeclampsia 발생 고위험에서 low dose aspirin 은 예방 목적으로 권장 .

Dietary manipulation—low-salt diet, calcium supplementation,

fish oil supplementation

Exercise – physical activity, stretching

Cardiovascular drugs—diuretics, antihypertensive drugs

Antioxidants—ascorbic acid (vitamin C), α-tocopherol (vitamin

E), vitamin D

Antithrombotic drugs—low-dose aspirin, aspirin/dipyridamole,

(32)

치료

Preeclampsia 발생이 의심되면 (suspected) 자주 산전진찰을 받도 록 하여야 함 .

조기 발견

① Termination of pregnancy with the least possible trauma to mother and fetus

② Birth of an infant who subsequently thrives ③ Complete restoration of health to the mother

One of the most important clinical questions for

successful management is precise knowledge of fetal

age.

(33)

평가 (Early diagnosis of preeclampsia) - hospitalization

① Detailed examination followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain

② Weight determined daily

③ Analysis for proteinuria on admittance and at least every 2 days thereafter

④ Blood pressure readings in the sitting position with an

appropriate-size cuff every 4 hours, except between 2400 and 0600 unless previous readings had become elevated ⑤ Measurements of plasma or serum creatinine and liver

transaminase levels, and hemogram to include platelet

quantification. The frequency of testing is determined by the severity of hypertension. Some recommend measurement of serum uric acid and LDH levels and coagulation studies. However, the value of these tests has been called into

question.

⑥ Evaluation of fetal size and well-being and amnionic fluid volume, with either physical examination or sonography.

(34)

치료 , Consideration for delivery

Termination of pregnancy is the only cure for preeclampsia. • severity of preeclampsia

• gestational age

• condition of the cervix

Severe preeclampsia demands anticonvulsant and usually antihypertensive therapy followed by delivery.

Preterm 으로 임신을 유지하고자 할 때 fetal well-being test (NST or BPP) 를 반드시 평가하여야 함 .

Labor induction or cesarean delivery

질식분만을 위한 유도분만 가능하나 성공적인 유도분만을 방해하는 소

(35)

치료

Mild and moderate hypertension

1) hospitalization vs outpatient management 2) antihypertensive therapy

3) 37 주 이후 면 분만을 고려하나 38 주 이전에 신생아 이환율이 증

(36)

치료

중증 전자간증 - 자간증에 준해서 치료 ( 항경련제 , 항고혈압제 + 분만 )

34 주 이후 중증의 고혈압이 발생하거나 34 주 전이라도 산모나 태아에게 위

험한 상황이라면 분만

Early-onset severe preeclampsia (24~34 주 전의 전자간증 ) 1) delayed delivery, to improve neonatal outcome

; controversies

; few beneficial effect

; serious maternal complication (placental abruption,

pulmonary edema, eclampsia, cerebrovascular hemorrhage, maternal death)

2) Glucocorticoids for lung maturation

3) Corticosteroids to ameliorate HELLP syndrome ; no advantages

(37)
(38)
(39)

자간증 (Eclampsia) – generalized tonic-clonic convulsion 대부분의 경련은 분만 중 혹은 분만 후에 발생

placental abruption, neurological deficits, cerebral hemorrhage, aspiration pneumonia, pulmonary edema, HELLP syndrome, cardiopulmonary arrest, acute renal failure, death

(40)
(41)

자간증의 치료

① Control of convulsions using loading dose of

magnesium sulfate.

② Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high

③ Avoidance of diuretics unless there is obvious

pulmonary edema, limitation of intravenous fluid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents

④ Delivery of the fetus to achieve a remission of preeclampsia

(42)

Magnesium sulfate to control convulsions 자간증 , 중증 전자간증

경증의 전자간증 임신부에게 황산마그네슘의 예방적 치료에 대해서는 논란이 있음 .

진통 동안과 분만 후 24 시간 동안 사용 is not given to treat hypertension

for eclampsia, continued for 24 hours after the onset of convulsion

(43)

마그네슘황산염의 약리학 , 독물학

therapeutic range, 4.8~8.4 mg/dL, 4~7 meq/L GFR 을 확인하기 위해 혈중 크레아티닌 수치를 확인

GFR 이 감소되어 Cr>1.0 이면 유지 용량을 줄이는 것이 권장 . 독성 ; ~ 10meq/L (12 mg/dL), patellar reflex disappear > 12meq/L, respiratory paralysis and arrest

• calcium gluconate or calcium chloride, 1 g intravenously, along with withholding further

magnesium sulfate, usually reverses mild to moderate respiratory depression.

(44)

마그네슘황산염 투약시 확인사항

• the patellar reflex is present • Respirations are not depressed

• Urine output the previous 4 hrs exceeded 100mL 자궁에 대한 효과 초기 부하량을 정주하는 동안 일시적인 자궁수축의 감소가 있지만 지속적인 영향을 미치지는 않음 . 옥시토신 자극 , 분만까지의 시 간 , 분만방법에 차이가 없음 . 태아에 대한 영향 일시적으로 태아심박동의 변이가 감소될 수 있으나 이로 인해 나쁜 결과가 초래되지는 않음 . neuroprotection for VLBW

(45)

Who should be given magnesium sulfate?

Severe preeclampsia & eclampsia should be given magnesium sulfate prophylaxis.

(46)

항고혈압 약제 치료

Management of severe hypertension

SBP ≥ 160mmHg or DBP ≥110mmHg ① Hydralazine 5mg (IV) q 15-20min ② Labetolol 10~20mg (IV) q 10min ③ Nifedipine 10mg (PO) q 30min

Diuretics-not used to lower blood pressure to treatment of pulmonary edema

(47)

자간증의 분만

Cesarean delivery

Vaginal delivery, labor induction, often labor spontaneously These women, who consequently lack normal pregnancy

hypervolemia, are much less tolerant of even normal blood loss than are normotensive pregnant women.

Counseling for future pregnancies

(48)

Long-term sequences

Cardiovascular and neurovascular morbidity hypertension

ischemic heart disease stroke

Renal sequelae

chronic renal disease Neurological sequelae

(49)

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