Love’s Labour’s Lost CCM Inter-Hospital Grand Round 13 Nov 2012 SK Yung Chairman: Dr Osburga Chan Queen Elizabeth Hospital
Case 3 F/25, Indian Para 0, Gestation 31 weeks Good past health Attended AED 19/2/2011 for acute onset of headache and epigastric pain ~ 2 hours
Case 3 Tympanic temp 370 C BP/P 141/70, 71/min Developed generalized tonic convulsion ~ 1 min aborted by valium 5 mg IM in AED cubicle Post ictal drowsiness Transferred to the resuscitation room for further management
Case 3 BP/P 180/110, 76/min Urine multistix Alb 4+, RBC 3+ Hstix 4. 7 Mg. SO 4 4 g loading then 1 g/hour Obstetric and anesthetic colleagues informed 2 more short lasting seizures aborted by valium
Case 3 P/E Uterus size 32 weeks, cephalic above brim USG : Single fetus, Fetal heart rate ~ 160/min GCS E 3 V 3 M 5. Sa. O 2 by pulse oximetry not measured well as patient struggling Decided for intubation before transfer to operation theatre for emergency LSCS
Case 3 Intubated by RSI. Grade 1 larynx Post intubation BP/P 166/79, 115/min, Sa. O 2 100% Proceeded to emergency LSCS Female baby, Apgar score satisfactory Intraop blood loss 400 ml Post op not extubated and transferred to ICU
Case 3 On arrival to ICU BP high side 151/101, 90/min Sa. O 2 100% on Fi. O 2 0. 4 BP under control with labetalol infusion CT Brain (plain) No abnormalities detected
Case 3 AN in QEH since 13 weeks G 2 P 0 (history of surgical TOP in 2005) Husband : Indian Obesity BMI ~ 34. OGTT : no GDM Otherwise AN unremarkable Last seen 10 days before admission (31 weeks) BP 150/85, recheck 123/65 Urine x albumin -ve
Case 3 Hb cancelled a few times (haemolyzed), recheck = 12. 4 Plt 66, WCC 15. 6, Blood smear not available (Saturday) Clotting profile normal Na 136, K cancelled, Ur 5. 1, Cr 77 ABG p. H 7. 24, p. CO 2 4. 4, p. O 2 15, HCO 3 14, BE -12. 5 ALT 121, ALP 117, Bilirubin 4 Urate 0. 43
Case 3 CXR enlarged cardiac silhouette ? related to supine film, not congested, no consolidation ECHO showed good EF, no RWMA, no pericardial effusion Treated as eclampsia, suspected HELLP BP stabilized with oral methyldopa and nifedipine SR, weaned off labetalol infusion, seizure free Metabolic acidosis improved, fully conscious Extubated on the next day
Case 3 Hb 12. 4 (19/2) 9. 1 (20/2) 9. 9 (21/2) Plt 68 (19/2) 26 (20/2) 21 (21/2) Clotting profile normal Cr 77 (19/2) 183 (20/2) 280 (21/2) Remained oliguric despite cautious fluid challenge Urine x Haemoglobin 3+. CK mildly elevated ~ 300 LDH 2748 (19/2) 2507 (20/2) 1288 (21/2)
Case 3 ALT 121 (19/2) 370 (20/2) 240 (19/2) AST 517 (20/2) ALP 117 (19/2) 86 (20/2) 98 (21/2) GGT 16 (20/2) Bilirubin 4 (19/2) 37 (20/2) 25 (19/2) Direct bili 13, indirect bili 23 (20/2) Haptoglobin < 0. 08 Ammonia not elevated
Case 3 Blood smear 21/2/2011 A few schizocytes Impression ? HELLP ? TTP Plasmapheresis (replacement with cryo-reduced plasma) since 21/2/2011 Haemofiltration since 22/2/2011 for oliguric renal failure and pulmonary congestion
Case 3 Hbs. Ag –ve , HIV -ve USG abdomen 22/2/2011 Unremarkable except small right pleural effusion Autoimmune markers including ANA, Anti. ENA, ANCA, Anti-cardiolipin Ab all -ve
Case 3 Seen by Haematology colleagues: Lots of overlap between HELLP and TTP Checking ADAMTS-13 level after plasmapheresis renders the interpretation difficult ADAMTS-13 checked 25/2/2012 Level = low (245. 1, reference 253 - 2238) Antibody +ve Comment Borderline decrease of ADAMTS 13 NOT consistent with TTP The Antibody result probably spurious, may represent cross reaction
Case 3 Platelet improved to 120 & LDH 239 Plasmapheresis stepped down from daily to alternate day regime after 8 days Then stopped 4 days later when platelet count normalized (266) Dialysis independent 9 days since commencement Wean off antihypertensives RFT and Platelet count normalized on subsequent follow ups Patient defaulted after 2 OPD sessions
Pre-eclampsia and related complications
Definitions Eclampsia = to shine forth in Greek “Ek” = out “Lampein” = shine Pre-eclampsia = the state before eclampsia
Definitions New onset hypertension after 20 weeks of pregnancy with significant proteinuria (NICE guideline ‘Hypertension in pregnancy’ Aug 2010) Hypertension Mild 140/90 – 149/99 Moderate 150/100 – 159/109 Severe >= 160/110 Significant proteinuria Urinary protein: creatinine ratio > 30 mg/mmol OR A validated 24 hour urine collection > 300 mg protein (Concerning the reagent-strip testing, it is recommended to be read by an automated reading device and if result >= 1+, use a spot urinary protein: creatinine ratio or 24 hour urine collection to quantify proteinuria)
Definitions SEVERE pre-eclampsia = pre-eclampsia with severe hypertension and/or with symptoms, and/or biochemical and/or haematologic impairment
Definitions HELLP (Hemolysis, elevated liver enzymes, low platelets) Variable and inconsistent diagnostic criteria Definition by UKOSS (UK Obstetric surveillance system) in 2011 All pregnant women with new onset of Elevated liver enzymes (AST >= 70 U/L or GGT >= 70 U/L or ALT >= 70 U/L) AND Platelet count < 100 x 109/L AND Haemolysis defined by abnormal blood smear or serum LDH >= 600 U/L or total bilirubin >= 20. 5μmol/L) OR Hypertension (SBP >= 140 mm. Hg or DBP >= 90 mm. Hg) OR Proteinuria 1+ (0. 3 g/l) or more on dipstick testing, a protein: creatinine ratio of 30 mg/mmol or more on a random sample, or a urine protein excretion of 300 mg or more per 24 hours
Definitions Eclampsia = A convulsive state associated with preeclampsia
Risk factors High risk Previous history of preeclampsia Preexisting vascular disease e. g. hypertension Preexisting renal disease Type 1 / 2 DM Autoimmune disease e. g. SLE / APS Moderate risk Age >= 40 Nulliparity Pregnancy interval of more than 10 years Family history of preeclampsia BMI >= 30 kg/m 2 Multiple pregnancy (NICE guideline ‘Hypertension in pregnancy’ Aug 2010)
Epidemiology Exact incidence unknown In developed countries e. g. UK/US, quoted to be around 5% for overall incidence 0. 5% for severe disease 0. 05% for eclampsia HKCOG audit 2004 2. 5% for overall incidence of hypertensive disorder in pregnancy 0. 7% for severe disease 0. 035% for eclampsia
Pathophysiology Abnormal placentation Pre-eclampsia reported in pregnancy without uterus (abdominal pregnancy) and pregnancy without fetus (molar pregnancy) Characteristic pathology = shallow cytotrophoblast invasion and restricted endovascular remodeling ? Immunological/genetic factors contributing to the development of abnormal placenta ? ? Ischemic placenta liberates factors into maternal circulation leading to generalized endothelial dysfunction and exaggerated inflammatory response Elevated levels antiangiogenic molecules e. g. s. FLT-1 documented The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Pathophysiology Systemic endothelial dysfunction/ exaggerated inflammatory response with Capillary leakage and reduction of effective circulating volume Platelet activation, intravascular thrombosis and platelet consumption Vasoconstriction with enhanced response to vasoactive substances e. g. angiotensin II Patients with pre-existing vascular/ renal disease particularly prone to develop superimposed pre-eclampsia Multiple end organs can be involved to variable extents Severe damage can occur without significant hypertension The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Renal One of the most vulnerable organs in pre-eclampsia Characteristic lesion = ‘glomeular endotheliosis’ Endothelial cell swelling, obliteration of endothelial fenestrate, occlusion of capillary lumens Relative VEGF deficiency ? related to excessive s. Flt-1 with disruption of glomerular endothelium leading to proteinuria Oliguria and raised Ur/Cr related to renal vasoconstriction and reduced effective circulating volumes, correlates with severe disease Raised uric acid level ? due to increased reabsorption (with sodium retention) , also increased production from trophoblast The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Hepatic ? Hepatic sinusoids blocked by intravascular fibrin deposition with ischaemia Clinically manifesting as epigastric/ right upper quadrant pain, elevated transaminases / coagulopathy At extremes, can have subcapsular haematoma/ liver rupture The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Haematological Microvascular endothelial dysfunction Platelet activation and fibrin deposition leading to turbulent blood flow Red blood cells became fragmented when subjected to shear stress -> haemolytic anaemia Thrombocytopenia due to accelerated consumption The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Neurological 2 theories trying to explain cerebral abnormalities in preeclampsia/ eclampsia with endothelial dysfunction having a central role 1. Vasospasm (cerebral overregulation in response to raised CPP/ hypertension with ischaemia and cytotoxic edema) 2. Hyperperfusion with breakdown of blood brain barrier with leakage of plasma/RBC with vasogenic edema (autoregulatory capacity of cerebral circulation exceeded with regions of vasoconstriction and forced vasodilatation) The latter one is more favoured and known as PRES (Posterior Reversible Leucoencephalopathy Syndrome) Neurological complications of pre-eclampsia GG. Zeeman Seminars in perinatology 2009; 33: 166 -172
Neurological The posterior circulation is particularly vulnerable because of less sympathetic innervation and lower ability to respond to elevated blood pressure Maybe complicated with intracranial haemorrhages / cerebral infarction Most common clinical manifestations Headache Seizures Visual disturbance Altered mental state Neurological complications of pre-eclampsia GG. Zeeman Seminars in perinatology 2009; 33: 166 -172
Neurological Note: despite the name of posterior reversible leucoencephalopathy syndrome, the deficit is not necessarily reversible and residual lesions have been reported in follow up MRI up to 7 years post insult Neurological complications of pre-eclampsia GG. Zeeman Seminars in perinatology 2009; 33: 166 -172
Neurological imaging CT scan Localized hypodense lesions at gray white matter junction in parieto-occipital lobes. Less commonly in frontal, inferior temporal lobes, basal ganglia and thalamus Intracranial haemorrhages usually at the striatocapsular area, thalamus, cerebellum and brain stem Neurological complications of pre-eclampsia GG. Zeeman Seminars in perinatology 2009; 33: 166 -172
Neurological imaging MRI Much more effective than CT T 2 hyperintense signals at parieto-occipital and temporal lobes, occasional involvement of basal ganglia and/or brainstem ‘New’ MRI techniques for better characterization / differentiating from other causes E. g. diffusion weighted imaging and apparent diffusion coefficient mapping (ADC) Neurological complications of pre-eclampsia GG. Zeeman Seminars in perinatology 2009; 33: 166 -172
Cardiopulmonary Increase demand on cardiac function, increased capillary permeability and lowered oncotic pressure Prone for development of pulmonary edema especially if iatrogenically volume overloaded The origins and end-organ consequence of pre-eclampsia. G. Eastabrook et al. Best Practice & Research Clinical Obstetrics and Gynaecology 2011; 25: 435 -447
Complications Preeclampsia B Sibai et al. Lancet 2005; 365: 789 -99
Peripartum management Treatment of acute hypertension Prevention and control of eclampsia Fluid management In women with severe pre-eclampsia, limit maintenance fluid 80 ml/hour unless there are other ongoing fluid losses e. g. haemorrhage (NICE guideline ‘Hypertension in pregnancy’ Aug 2010) Thromboembolism prophylaxis Close monitoring of fetal condition before delivery
Treatment of acute hypertension Why is it important? How should the BP be measured? How should the BP be controlled?
Why is it important? One of the top ten recommendations in CEMACE 2003 -2005
Why is it important? ‘The single most serious failing in the clinical care provided for mothers with pre-eclampsia was the inadequate treatment of their systolic hypertension. In several cases this resulted in a fatal intracranial haemorrhage…. ’ 14 women died from preeclampsia related complications and 9 were intracranial haemorrhages
Why is it important? One of the top ten recommendations in CEMACE 2006 -2008
Why is it important? ‘It is disappointing that in this triennium, as flagged up in the last report, the single most serious failing in the clinical care provided for mothers with pre-eclampsia was the inadequate treatment of their systolic hypertension. In several women, this resulted in a fatal intracranial haemorrhage…’ 19 women died from preeclampsia related complications and 9 were intracranial haemorrhages History keeps repeating itself
Why emphasizing so much on treating systolic hypertension? Obstet Gynecol 2005; 105: 246– 54 Retrospective review of 28 women with severe pre-eclampsia and stroke (26 cases were haemorrhagic) 24 women treated immediately before their stroke, 23 had a SBP >= 160 mm. Hg, DBP more variable, only 3 >= 110 Conclusion : A paradigm shift is needed toward considering antihypertensive therapy for severely pre-eclamptic and eclamptic patients when SBP >= 155– 160 mm Hg
BP measurement Invasive BP monitoring is theoretically most accurate (with appropriate calibration and damping) and provide real time measurement If non invasive BP measurement Appropriate cuff size Brachial artery at the level of the heart Korotkoff 5 should be used for diastolic BP for sphygmomanometer measurement If an automated BP monitor is used, it should be a validated one for use in pregnancy and preferably in preeclampsia
Automated BP machine tend to underestimate systolic pressure in preeclampsia J villar et al. International journal of Gynaecology and Obstetrics 85 Supp 1 2004: S 28 -S 41
How should the blood pressure be controlled? NICE Guideline 2010
How should the blood pressure be controlled? ACOG committee opinion for emergent therapy for acute onset severe hypertension with pre-eclampsia or eclampsia 2011 The goal is not to normalize BP but to achieve a range of 140160/90 -100 1 st line therapy IV labetalol and hydralazine are both considered 1 st line medications Less information available for the use of calcium channel blockers Mg. SO 4 is NOT recommended as an antihypertensive
How should the blood pressure be controlled? ACOG committee opinion for emergent therapy for acute onset severe hypertension with preeclampsia or eclampsia 2011 E. g. Labetalol as first line 20 mg IV over 2 mins, repeat BP measurement in 10 minutes 40 mg IV over 2 mins if target not achieved, repeat BP measurement in 10 minutes 80 mg IV over 2 mins, if target not achieved, repeat BP measurement in 10 minutes Hydralazine 10 mg IV over 2 mins if target not achieved Note: Parental labetalol can cause neonatal bradycardia and should be avoided in women with asthma/ heart failure. Hydralazine may increase the risk of maternal hypotension (SBP < 90)
How should the blood pressure be controlled? ACOG committee opinion for emergent therapy for acute onset severe hypertension with preeclampsia or eclampsia 2011 2 nd line therapy Consider labetalol / nicardipine by infusion pumps Sodium nitroprusside should be reserved for extreme emergencies in view of concerns about cyanide and thiocyanate toxicity and increase for intracranial pressure
Additional considerations In case of severe hypertension, maternal stabilization should occur before delivery even in urgent circumstance Induction of general anaesthesia and intubation should never be undertaken without first steps to minimize the hypertensive response to intubation e. g. A short acting opiate bolus (e. g. alfentanil 10 -20 mcg/kg or remifentanil 1 mcg/kg) A bolus dose of labetalol 10 -20 mg i. v. Adjuvant measures e. g. adequate pain control should be provided for optimal BP control
Peripartum management Prevention and control of eclampsia Treatment of acute hypertension Fluid management In women with severe pre-eclampsia, limit maintenance fluid 80 ml/hour unless there are other ongoing fluid losses e. g. haemorrhage (NICE guideline ‘Hypertension in pregnancy’ Aug 2010) Thromboembolism prophylaxis Close monitoring of fetal condition before delivery
Prevention and control of eclampsia
Control of eclampsia Collaborative Eclampsia trial. Lancet 1995; 345: 1455 -63 Less recurrent seizures compared with diazepam and phenytoin Mg. SO 4 maintained for 24 hours after the last seizure Cochrane reviews in 2008 by Duley L et al comparing Mg. SO 4 vs. Diazepam Phenytoin Lytic cocktail (usually chlorpromazine, promethazine and pethidine) Mg. SO 4 more effective preventing recurrence of convulsions, maternal deaths, neonate being admitted to NICU
Prevention of eclampsia Magpie trial Lancet 2002; 359: 1877 -90 Mg. SO 4 better than no treatment/placebo in preventing eclampsia 4 g loading then 1 g/hour, to be given for 24 hours following delivery Cochrane review in 2008 by Duley L et al compared magnesium sulphate with placebo or no anticonvulsant: Statistically significant reduction for risk of eclampsia, RR 0. 41, 95% CI 0. 29 to 0. 58, NNT 100, 95% CI 50 to 100 Non statistically significant reduction for maternal mortality No clear difference in serious maternal morbidity / neonatal death An economic analysis found that Mg. SO 4 was cost effective. The cost effectiveness improved with severity of pre-eclampsia (Simon J, Gray A, Duley L et al. Cost-effectiveness of prophylactic magnesium sulphate for 9996 women with pre-eclampsia from 33 countries: economic evaluation of the Magpie Trial. BJOG 2006; 113: (2)144 -51.
Additional considerations for HELLP Differential diagnoses Treatment
DDx of HELLP Acute fatty liver of pregnancy TTP/HUS SLE, catastrophic antiphospholipid syndrome Viral hepatitis Severe sepsis
DDx of HELLP Imitators of severe pre-eclampsia. Baha M. Sibai. Seminars in perinatology 2009; 33: 166 -172
DDx of HELLP Imitators of severe pre-eclampsia. Baha M. Sibai. Seminars in perinatology 2009; 33: 166 -172
Treatment As for severe pre-eclampsia Use of corticosteroids are NOT recommended in HELLP (high-quality evidence that corticosteroids used in the management of HELLP syndrome do not improve any clinically important outcomes either antenatally or postnatally. NICE guideline 2010) Special attention to associated coagulopathies and hepatic complications e. g. subcapsular haematoma
Take home message Pre-eclampsia is a multisystem disorder related to abnormal placentation and endothelial dysfunction Early delivery and good support care most important in the management of severe pre-eclampsia Control of hypertension in particular systolic blood pressure In case of severe hypertension, maternal stabilization should occur before delivery even in urgent circumstance Mg. SO 4 is effective for the control and prevention of eclampsia
Thank you
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