제 34, 36장 고혈압 설현주

서론 출혈, 감염, 고혈압은 모성사망 및 이환의 3대 질환 전자간증(preeclampsia) – 임신 중기 이후 발병하는 고혈압 질환으로 유일하게 임신에 의하여 발병하고 임신의 종결과 함께 치유되는 내과적 합병증 병태생리 및 치료법은 완전히 밝혀지지 않음.

서론 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 전자간증-자간증(Preeclampsia and eclampsia syndrome) 가중합병전자간증(Preeclampsia syndrome superimposed on chronic hypertension) 만성고혈압(Chronic hypertension)

Chronic hypertension 임신 전 진단되었거나 임신 20주 전에 진단되는 고혈압 가임기 여성의 고혈압 유병률 30대 3.4%, 40대 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 preeclampsia도 발생 가능 (superimposed preeclampsia)

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 Cr >2 mg/dL

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 velocimetry를 예측에 사용하기도 함. Low dose aspirin, 예방 목적으로 투여 태아상태평가 태아성상제한의 발병 여부를 주기적으로 확인함. NST, BPP 등을 태아안녕을 평가함.

만성고혈압 임신부의 산전관리 혈압조절 SBP>150~160 mmHg, DBP≥100 mmHg 표적장기 손상이 있으면 경증의 고혈압에서도 치료가 권고됨. adrenergic blocking agent (ex, methyldopa, β-blocker, αβ-blocker), CCB ACE inhibitor, ARB는 임신 중 사용 금기임. 분만관련 처치 태아성장제한이나 전자간증과 같은 합병증이 발생한 경우 임상적 판단에 의해 분만 시기를 결정함. 분만방법 역시 산과적 요인에 따라 결정하게 됨.

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 Headache Absent Present Visual disturbances Upper abdominal pain Oliguria Convulsion (eclampsia) Serum creatinine Normal Elevated Thrombocytopenia Serum transaminase elevation Minimal Marked Fetal-growth restriction Obvious Pulmonary edema 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.

전자간증의 빈도 및 위험인자 Nulliparous population, 3-10% Young, nulliparous women Obesity, multifetal gestation, >35years old women hyperhomocysteinemia, metabolic syndrome, African-American ethnicity ※Reduced risk; Smoking, placenta previa 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.

자간전증의 병인 및 기전 Two-stage model

전자간증의 요인 및 기전 Placental implantation with abnormal trophoblastic invasion of uterine vessels Immunological maladaptive tolerance between maternal, paternal (placental), and fetal tissue 산모와 태아간의 동종이식거부반응 과장된 선천면역반응 Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy (prostacyclin-thromboxane의 불균형, 산화스트레스, 혈관생성인자_sFlt-1, PlGF, sEng의 불균형) Genetic factors including inherited predisposing genes as well as epigenetic influences.

태반측요인 (abnormal trophoblastic invasion) Incomplete trophoblastic invasion

태반측요인 (abnormal trophoblastic invasion) diminished perfusion, hypoxic enviroment는 placental debris 혹은 microparticles을 방출하여 systemic inflammatory response를 유발 defective placentation은 gestational hypertension, preeclampsia syndrome, preterm delivery, growth-restricted fetus, placental abruption을 유발

면역학적 요인 (immunologic factors) Maternal immune tolerance에 의해 정상 임신 유지 Tolerance dysregulation에 의해 preeclampsia발생 가능 First pregnancy Increased paternal antigenic load (ex, molar pregnancy) Trisomy 13 (elevated anti-angiogenic factor, sFLT-1) Immune maladaptation (reduced HLA-G…) increased Th1 action, Th1/Th2 ratio changes.

유전적 인자 (genetic factors)

병태생리 Vasospasm Endothelial cell activation - increased pressor responses Endothelin증가 Angiogenic imbalance antiangiogenic proteins인 sFlt-1, sEng의 증가 angiogenic protein인 PlGF감소

병태생리 1. Cardiovascular system – hyperdynamic 혈압상승, 혈관수축과 비정상 혈관 반응성(angiotensin II에 대한 과도한 반응성) 심박출량이 보통이거나 약간 감소 (혈압에 의한 afterload 증가와 preload의 감소) 2. Blood volume -Severe hemoconcentration 분만 후 갑작스럽게 hematocrit이 감소하는 것은 산후출혈의 지표일 수 있으므로 주의관찰이 필요함.

혈액 및 응고인자 변화 Thrombocytopenia Hemolysis HELLP syndrome (hemolysis, low platelet, elevated liver enzyme) Coagulation – subtle changes like intravascular coagulation DIC Endocrine changes: renin, angiotensin II, angiotensin 1-7, aldosterone의 감소 (정상임신에서는 증가) Deoxycorticosterone 증가 Vasopressin, atrial natriuretic peptide는 비슷함. Fluid and electrolyte changes: Extracellular fluid의 증가에 의한 edema (endothelial injury에 의해 발생)

Kidney Anatomical changes-glomerular endotheliosis 사구체여과율과 신장혈류량의 감소 Proteinuria (>300mg/24h), 단백뇨량으로 질병의 중증도를 평가하지 않음. Prerenal oliguria가 나타남 Cr이 1 mg/mL이상 상승하나 분만 후 10일 내에 정상화됨. Oliguria는 수액정주가 치료법은 아님. Acute renal failure는 드물게 발생하며 대부분 출혈에 의함

Liver 전자간증에 동반된 간 손상은 혈중 간효소수치의 증가가 동반된 경도의 간세포괴사부터 피막하혈종 혹은 간파열까지도 발생할 수 있음. 간효소수치의 증가 (elevated AST and ALT) HELLP syndrome – hemolysis, elevated liver enzyme, low platelet 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

Brain 임상증상 Headache and scotomata blurred vision, diplopia Convulsion – eclampsia magnesium sulfate투여 Blindness, 대부분 resolution되며 무증상의 serous retinal detachment는 흔한 편임. Generalized cerebral edema – mental change, 갑작스런 혈압 상승에 민감하여 edema가 더욱 악화될 수 있음.

병태생리 Brain (headache) cerebral hemorrhage seizure

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/miscellaneous Antithrombin-III(AT-3), atrial natriuretic peptide (ANP), β2-microglobulin, haptoglobulin, transferrin, ferritin, 25-hydroxyvitamin D, genetic markers, cell-free fetal DNA, serum and urine proteonomics and metabolomic markers, hepatic aminotransferases

예방 (some methods to prevent preeclampsia that have been evaluated in randomized trials) 위의 어느 것도 예방효과가 확립된 것은 없음. Preeclampsia발생 고위험에서 low dose aspirin은 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, aspirin + heparin, aspirin + ketanserin

치료 Preeclampsia발생이 의심되면 자주 산전진찰을 받도록 하여야 함. 조기 진단이 태아와 산모의 예후를 향상시킬 수 있음. Termination of pregnancy with the least possible trauma to mother and fetus Birth of an infant who subsequently thrives Complete restoration of health to the mother One of the most important clinical questions for successful management is precise knowledge of fetal age.

평가 (Early diagnosis of preeclampsia) - hospitalization Detailed examination followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain Weight determined daily Analysis for proteinuria on admittance and at least every 2 days thereafter 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 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. Evaluation of fetal size and well-being and amnionic fluid volume, with either physical examination or sonography.

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. 이른 임신 주수로 임신을 유지하고자 할 때 fetal well-being test (NST or BPP)를 반드시 평가하여야 함. 유도분만이 가능하지만 성공적인 유도분만을 방해하는 소견이 있거나 응급상황이 예견되는 경우 C/S을 하기도 함.

치료 1. Mild or moderate preeclampsia 1) hospitalization vs outpatient management 2) antihypertensive therapy 3) 37주 이후 면 분만을 고려하나 38주 이전에 신생아 이환율이 증가한다는 보고가 있음. 2. Severe preeclampsia - eclampsia에 준해서 치료 1) 항경련제 2) 항고혈압제 3) 분만: 34주 이후 중증의 고혈압이 발생하거나 34주 전이라도 산모나 태아에게 위험한 상황이라면 분만 3. Eclampsia

치료 Early-onset severe preeclampsia (24~34주 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

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

eclampsia의 치료 Control of convulsions using loading dose of magnesium sulfate. Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high Avoidance of diuretics unless there is obvious pulmonary edema, limitation of intravenous fluid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents Delivery of the fetus to achieve a remission of preeclampsia

Magnesium sulfate to control convulsions 자간증, 중증 전자간증 경증의 전자간증 임신부에게 황산마그네슘의 예방적 치료에 대해서는 논란이 있음. 진통 동안과 분만 후 24시간 동안 사용 is not given to treat hypertension for eclampsia, continued for 24 hours after the onset of convulsion

마그네슘황산염의 약리학, 독물학 therapeutic range, 4.8~8.4 mg/dL, 4~7 meq/L GFR을 확인하기 위해 혈중 크레아티닌 수치를 확인 GFR이 감소되어 Cr>1.0이면 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. Prompt tracheal intubation and mechanical ventilation

마그네슘황산염 투약시 확인사항 the patellar reflex is present Respirations are not depressed Urine output the previous 4hrs exceeded 100mL 자궁에 대한 효과 초기 부하량을 정주하는 동안 일시적인 자궁수축의 감소가 있지만 지속적인 영향을 미치지는 않음. 옥시토신 자극, 분만까지의 시간, 분만방법에 차이가 없음. 태아에 대한 영향 일시적으로 태아심박동의 변이가 감소될 수 있으나 이로 인해 나쁜 결과가 초래되지는 않음. neuroprotection for VLBW

Who should be given magnesium sulfate? Severe preeclampsia & eclampsia should be given magnesium sulfate prophylaxis.

항고혈압 약제 치료 Management of severe hypertension SBP ≥ 160mmHg or DBP ≥110mmHg Hydralazine 5mg (IV) q 15-20min Labetolol 10~20mg (IV) q 10min Nifedipine 10mg (PO) q 30min Diuretics-not used to lower blood pressure to treatment of pulmonary edema ※ fluid therapy – Lactated Ringer’s solution 60-125mL/h

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 higher risk for hypertension in the second pregnancy

Long-term sequences Cardiovascular and neurovascular morbidity hypertension ischemic heart disease stroke Renal sequelae chronic renal disease Neurological sequelae