Endocrine Emergencies in Obstetrics

Darren Farley, MDClinical Assistant Professor

Division of Maternal-Fetal MedicineDept. of Obstetrics and Gynecology

University of Kansas School of Medicine – Wichita

• No financial interests to disclose.

OUTLINE• Diabetic Ketoacidosis• Thyrotoxicosis & Thyroid Storm• Primary Hyperparathyroidism• Pheochromocytoma• Addisonian Crisis

• Misc - FFDNA

• Pregnancy changes• Diagnosis• Management

Diabetic Ketoacidosis

Case• 26 yo P2002, type 1 DM, with

nephropathy, LVH, and CHTN• What is best treatment during

pregnancy?• 1-Amlodipine• 2-Labetalol• 3- Lisinopril• 4- 1,2• 5-No treatment unless BP >180/110

Glucose physiology in pregnancy

• Glucose production increases with advancing gestational age

• Insulin resistance increases with advancing gestational age

• Insulin response to glucose tolerance test - increases with advancing gestational age

Incidence of DKA• Nonpregnant -

– 1-5 episodes per 100 patients / year– Mortality 5-10%

• Complicates 2-9% of diabetic pregnancies• A leading cause of fetal loss• Fetal mortality rate

– 1963 – 50-90% – Now – 10-20%

• Maternal mortality - now 1% (previously 15-50%)

Foley p 143

DKA—signs/symptoms

HyperventilationKetotic breathTachycardiaHypotensionDry MMDisorientationComa

PolyuriaPolydipsiaN/VAbdominal painWeaknessWeight loss

Factors precipitating DKA in pregnancy

• Emesis• Infection• Non-compliance• Insulin pump failure• ß-sympathomimetic drugs• Steroids• Poor management• PE

Diagnosis

• DKA -

• D –Diabetic - >180mg/dL• K –serum acetone, Ketones 1:2 or greater• A –Acidosis – arterial pH<7.3, HCO3-

<15, anion gap [Na – (Cl +HCO3)] >12

Management• Maternal Resuscitation

– IV fluids– Insulin– Search for underlying cause – infection,

noncompliance, etc – I/Os, monitoring glucose (q1-2hr), – ABG, pH, anion gap, electrolytes (q2-4hr)– Fetal monitoring*

• Withhold intervention toward delivery on behalf of the fetus until maternal metabolic disturbances are corrected

• Oxygen and correct maternal positioning while correcting disturbances

Management -• Fluid replacement

– Fluid deficit is 100cc/kg (7-10L for total deficit)• Accurate I/Os, BUN, Creatinine• Replace 75% of deficit in 1st 24 hrs, remainder over the

hospitalization– NS (use isotonic solution to prevent rapid decline in plasma

osmolarity and resultant cellular swelling and cerebral edema)

– 1L NS in first hour, 500 mL/hr hours 2 and 3 (NS 1st 3 hrs)– LR or ½ NS at 250cc/hr in initial 24 hr until 75% of volume

deficit is replaced• LR is used to avoid further acidosis (LR pH 6.5, vs 5.0 of NS)• Sodium load with NS – possible hypernatremia, switch to LR or ½

NS if Na >150meq/L

Insulin (0.1)• Insulin therapy (inhibits lipolysis and ketogenesis,

leads to suppression of hepatic glucose production)– Loading dose 0.1U/kg regular insulin

• 50 units / 500 mL NS (1cc = 0.1units, 10 cc = 1unit)– Infusion 0.1units/kg/hour– If plasma glucose does not decrease by 10% in first hour

or by 20% in second hour – repeat loading dose or double infusion rate

– When glucose ~250mg/dL or less, add D5 to the fluids and reduce the hourly rate by 1/2

– Continue infusion of insulin until serum bicarbonate and anion gap normalize

Insulin• Use regular insulin• Pump monitor infusion rate• Label insulin line with rate (units/volume)• IV insulin is compatble with IV magnesium and oxytocin• Mix and flush tubing and bag of insulin to prevent binding to plastic bag• Obtain blood samples from arm opposite the infusion• Glucose levels hourly during labor• Have amp of D50 at bedside for hypoglycemia• Use glucose-free solutions for boluses for hydration, anesthetics• Before discontinuation of IV insulin, give SQ dose to prevent rebound

hyperglycemia

• Insulin half lives – Regular IV – 5 min– Regular IM – 2hr– Regular SQ – 4hr

Insulin sensitivity factor – 1500 rule

• How much of a reduction in blood glucose should you expect for each 1.0 unit of insulin delivered to the patient

• 1500 rule– Insulin sensitvity factor = 1500/TDI– Ex – if TDI = 50units

• 1500/50 = 30mg/dL blood glucose drop per 1.0 unit of insulin

• To correct a patient’s blood glucose to 100mg/dL:• Patient’s blood glucose -100 / 30 = Supplemental units of

insulin

Example insulin sliding scale:• Blood glucose Insulin aspart (SQ units)• <70 Hypoglycemia protocol• 70-120 zero units• 121-150 1 unit• 151-200 2 units• 201-250 3 units• 251-300 4 units• 301-350 5 units• 351-400 6 units• >400 7 units, call MD

Switching to subcutaneous insulin and insulin pump

• Patient should be tolerating a full diet• Total daily dose needed after resolution of DKA• Classic split – NPH and regular

– AM 2/3 total daily dose (2/3 NPH, 1/3 regular)– PM 1/3 total daily dose (1/2 regular dinner, ½ NPH HS)

• NPH and humalog/novolog– NPH (60%), 2/3 AM, 1/3 HS– Novolog (40%), 1/3 with each meal

• Glargine/detimir & novolog/humalog• If switching to pump – reduce TDI by 25%

– 50% basal dose / 24hr to get hourly basal rate– 50% is bolus dose with meals (1/3 with each meal)

Insulin preparations & pharmacokineticsCreasy p977

Insulin Peak onset (h)

Duration (h)

Comments

Lispro (Humalog)

1 2 OOA 10 min; no need to delay meal intake

Aspart (Novolog)

1 2 OOA 10 min; no need to delay meal intake

Regular 2 4 Good coverage of individual meals if injected 20 min preprandial; postprandial hypoglycemia

NPH 4 8 Intermediate acting control, give upon wakening and at bedtime, risk of 3AM hypoglycemia

Glargine (Lantus)Detimir(Levimir)

5 24 Less peak, limited pregnancy experience, increased risk of nocturnal hypoglycemia or undertreatmentduring the day

Potassium administration• Anticipated potassium deficit in a pregnant patient with DKA is 5-10 meq/kg• Replacement usually delayed for the first 2-4hr of therapy, since K+ is usually

elevated until patient diureses has been established (at least 0.5cc/kg/h). • Once IV fluids and insulin therapy are started serum K+ may drop quickly as a

result of urinary loss and intracellular shift. When K+ is <5 and adequate diuresis has been established (0.5cc/kg/h) then K administration should begin

• 40-60meq KCl/liter of NS• If K+ is ≥4, give 10-20meq• If K+ is <4, give 30-40 meq• Replace K cautiously, watching UOP and serum K+ frequently, every 4hr• Replace entire K+ deficit (5-10meq/kg) over the span of the patient’s entire

hospitalization• Alternatively – with DKA induced maternal phosphate deficiency, K2PO4

(KPhos) may be given as K replacement instead of KCL

Bicarbonate therapy• Only if arterial pH <6.9-7.0 and HCO3 < 5meq/L• Rapid undiluted correction of metabolic acidosis with NaHCO3 is

unwarranted and may lead to severe hypokalemia, hypernatremia, impaired oxygen delivery, and a paradoxical fall in CSF pH

• One ampule (44meq NaHCO3) is diluted in 1000mL of ½NS• Total deficit of bicarbonate can be calculated (obtain the base

deficit on the ABG)• Bicarb (meq) regained to fully correct metabolic acidosis = Base

deficit (meq/L) x patient weight (kg) / 4• Since oxygen hemoglobin affinity is augmented in the presence of

an alkalotic shift of the oxygen-hemoglobin disassocation curve to the left, it is prudent not to fully correct the patient’s metabolic acidosis, ensuring better oxygen delivery to the fetus

Case• 26 yo P2002, type 1 DM, with

nephropathy, LVH, and CHTN• What is best treatment during

pregnancy?• **1-Amlodipine (possible renal

protection)• 2-Labetalol• 3- Lisinopril• *4- 1,2 (if a 2nd agent needed)• 5-No treatment unless BP >180/110

Thyroid

Case• 30 yo P1001 at 10 weeks with Grave’s

Disease• What is recommended regarding her

antithyroid medications?• 1 – No treatment • 2- PTU in 1st trimester, methimazole in

2nd/3rd

• 3 – PTU throughout pregnancy• 4 – Methimazole throughout pregnancy

Changes in Pregnancy - Thyroid gland enlarges; HCG effect ; Free T4 concentrations – unchanged (0.7-1.8ng/dL); Free T3 unchanged (2.3-4.2 pg/dL)

Thyroid storm

• Thyrotoxicosis – clinical and biochemical state resulting from over-production and exposure to thyroid hormone– Most common cause – Grave’s disease – T3 thyrotoxicosis – uncommon

• Thyroid storm – acute, severe exacerbation of hyperthyroidism

Thyroid storm - Diagnosis• Exacerbation of hyperthyroidism/thyrotoxicosis

– Common precipitants– Heart failure from excessive thyroxine is more common in

pregnant women• Diagnosis is clinical

– Hypermetabolism - Fever, perspiration, warm, flushed skin– Cardiovascular - Tachycardia, atrial fibrillation, CHF– CNS - Irritability, agitation, tremor, mental status change

(delirium, psychosis, coma)– GI - Nausea, vomiting, diarrhea, jaundice– Dehydration

• Supporting laboratory evidence– Leukocytosis, elevated LFTs, hypercalcemia, low TSH,

high free T4, and/or T3

Thyroid storm - Management

• Supportive measures while instituting medical management (block, inhibit, block, block)

• High M-F morbidity/mortality rate if treatment is delayed

• Workup for inciting causes, maternal echocardiography

Thyroid storm - Management• ICU, medical management, supportive care

– Block, Inhibit, Block, Block

• IV fluids, electrolytes• Cardiac monitoring• Cooling measures (blanket, sponge bath, acetaminophen)• Oxygen • No salicylates (increased T4)• NG tube if unable to swallow (may need for PTU)• Consideration of PA catheter for central hemodynamic

monitoring to guide β-blocker therapy during hyperdynamic cardiac failure

Thyroid storm

• BLOCK –– Propylthiouracil – 1 gram PO or crushed in

NG tube, then 200mg PO q 6 hrs– blocks synthesis of T3 by BLOCKING

conversion of T4 to T3• Inhibit• Block• Block

Thyroid storm• Block• INHIBIT – after 1 hour of initial PTU load (to

prevent inadvertent release of T4 as a result of this therapy) – iodide is given to INHIBIT release of T4 and T3 by the thyroid gland– Na iodide 500-1000 IV q 8hr– SSKI 5 drops PO q 8hr– Lugol’s solution 10 drops PO q 8hr– *Lithium carbonate 300mg q6hr (if history of iodine

induced anaphylaxis)• Block• Block

Thyroid storm• Block• Inhibit• BLOCK – Dexamethasone (or corticosteroid

equivalent) 2mg IV q6hr x 4 doses – this therapy BLOCKS further peripheral conversion of T4 to T3

• Block

Thyroid storm

• Block• Inhibit• Block• BLOCK – beta-BLOCKERS

(propranolol 20mg PO/IV q 8hr; labetalol 200 mg PO q 6hr) to treat tachycardia (rate control of <120 bpm)

Thyroid storm• Treatment• PTU – 1gm PO, then 200mg q6hr• Sodium iodide 500 mg or 10gtts of oral Lugol’s

solution q 8 hrs – start 1 hr after PTU load to inhibit thyroid release of T3 and T4– if iodine allergy, give lithium carbonate 300mg q6hr

• Dexamethasone 2mg IV q6hr x4 to block peripheral conversion of T4 to T3

• Labetalol 200mg po q8hr for HR >120• Phenobarbital 300mg IV q8hr prn agitation

Thyroid storm

• Compliance is key• Takes 4-6 weeks for TFTs to normalize• PTU – common cause of hepatitis

Case• 30 yo P1001 at 10 weeks with Grave’s

Disease• What is recommended regarding her

antithyroid medications?• 1 – No treatment • **2- PTU in 1st trimester, methimazole in

2nd/3rd trimesters• 3 – PTU throughout pregnancy (LFTs)• 4 – Methimazole throughout pregnancy

Parathyroid gland

Hyperparathyroidism• More common in women than men (3:1) ; Avg age - 55yo• 145 cases reported during pregnancy• Symptoms – weakness, fatigue, kidney stones, bone pain,

pancreatitis, mental disturbances; most found incidentally • Diagnosis – elevated levels of ionized calcium in the presence of

elevated PTH• Pregnancy changes –

– Majority of calcium is bound to albumin– Reduced serum albumin levels in pregnancy– Acquisition by the fetus of 25-30g of calcium– Increase in GFR and the expanded extracellular fluid volume

result in an overall decrease in total serum calcium levels by 0.5mg/dL

• Ionized calcium levels are not affected• PTH levels stay the same or slightly decrease• Primary hyperparathyroidism - ~90% due to parathyroid

adenoma (9% with parathyroid hyperplasia, 2% parathyroid cancer)

• 20% have nephrolithiasis

Hyperparathyroidism• Definitive treatment - surgical removal of the glands• 25% of asymptomatic patients have progressive disease (decrease of bone

mass)• Pregnancy – treat to reduce risk of neonatal tetany, miscarriage, stillbirth

seen with maternal hypercalcemia; fetal testing• Mithramycin and bisphosphonates contraindicated during pregnancy – C• Asymptomatic. mild hypercalcemia – monitoring, surgery after pregnancy• Symptomatic –

– If symptomatic and not a surgical candidate - Oral phosphate therapy1.5g/day TID; only if serum phosphate is <3mg/dL, phosphate administration should be adjusted to maintain serum phosphate <4mg/dL

– Furosemide – increases excretion of calcium in the urine, can be given orally to help decrease Ca2+

– Symptomatic patient, progressive, hypercalcemia (>12mg/dL) or if there is a deterioration of renal function – surgery by experienced parathyroid surgeon; do not defer because of the pregnancy if she is symptomatic and has hypercalcemia

• Hypercalcemia crisis – progressive hypercalcemia with hypovolemia, renal insufficiency, altered mentation, pancreatitis, seizures (can mimic eclampsia)

• Hydration with NS (2-3L over 3-6hr)• Correct electrolyte abnormalities• Furosemide (decreases distal tubular calcium reabsorption) 10-40mg IV

every 2-4 hrs to maintain UOP at 200mL• Calcium restriction• Persistent hypercalcemia –

– Calcitonin (100-400 units/day), effective, tachyphylaxis occurs in 4-6 days

– Glucocorticoids –• can decrease GI calcium absorption, • dexamethasone 2mg IV q6hr • hydrocortisone 100mg IV q8; • prednisone 1mg/kg

• Neonatal hypocalcemia – predictable, preventable• Transient neonatal tetany should not be associated with long-term

sequelae

Hyperparathyroidism

Adrenal

Pheochromocytoma• Rare tumor of catecholamine-secreting chromaffin cells (90% sporadic)• Maternal mortality – 2% (16% in 1980), • Fetal loss – 11% (26% in 1980), due to earlier diagnosis (83% diagnosed

antenatally now vs 52% in 1980) – Ahlawat 1999, Hermayer 1999, Almog 2000• Plasma metanephrines – best test – 99% sensitivity, 89% specificity• Clonidine suppression test – helps distinguish between elevated blood levels of

norepinephrine due to increased sympathetic nerve stimulation vs. due to pheochromocytoma– Clonidine inhibits neurally mediated catecholamine release– Clonidine given – then catecholamine levels are drawn; expect to see

decrease in norepinephrine levels;• If no decrease in NE levels (decrease by 50%, or minimal NE of

500pg/mL or less) then the catecholamines are coming from another source than neurally mediated (pheochromocytoma)

• MRI to localize the tumor – 90% of tumors arise in adrenal glands; after delivery – radioactive iodine-labeled metiodobenzylguanidine scintigraphy offers greater than 95% specificity in detection

Pheochromocytoma –Symptoms/signs

• Symptomatic hypertension - severe, fluctuating, paroxysmal– HA, perspiration, palpitations, tachycardia– Excessive truncal sweating

• Postural hypotension• Different from preeclampsia – no

proteinuria, hyperuricemia, edema

Pheochromocytoma• Management• Pharmacologic control of HTN and tachycardia• Alpha adrenergic receptor blockade • Phenoxybenzamine – 20mg BID and gradually increase (10mg qod) to max

dose (20-40mg bid/tid) • Phentolamine 5-10mg IV/IM, reserved for emergency or preoperative

situations• Prazosin – 1mg PO BID/TID, increase to max daily dose of 6-15mg divided in

BID/TID• Labetalol – 100mg BID, increase by 100mg BID every 2 weeks, max

2400mg/day; if discontinuing, taper dose over 1-2 weeks• IV boluses – 20mg IV over 2 minutes, increase by 20mg every 10min until

BP is controlled, max dose of 300mg IV acutely (within 6 hours)• infusion – 2mg/min until BP control, switch to oral dosing – 200-400mg

every 6-12 hours• Nitroprusside – 0.25micrograms/kg/min IV infusion to control BP; max

infusion rate is 10microgram/kg/min• Metyrosine may be used if HTN is still uncontrolled

Pheochromocytoma• Beta blockade – use if tachycardia or arrhythmia, predominately adrenaline

secreting tumors; selective/short acting agents preferred• *Use only after α-blockade has been started because unopposed α-adrenergic

activity may lead to vasoconstriction and a marked increase in BP• Metoprolol – 50-200mg BID PO• Atenolol – 50mg PO every day and increase after 10-14 days to a max of 100mg

every day• Propranolol – only use if adequate alpha blockade has been started; 40mg PO BID,

increase every 3-7 days to a max of 480mg daily, BID

• Fluid management

• Surgical management • Timing depends on medical control, tumor size, risk of malignancy, stage of

pregnancy (best in second trimester), laparoscopy vs laparotomy• Third trimester – C/S after confirmation of lung maturity with adrenalectomy OR

vaginal delivery and laparoscopic removal of the tumor postpartum• Magnesium sulfate has been used (4g bolus, 2g/hr) has been used in nonpregnant

patients for operative control during surgical removal of pheochromocytoma

Dildy p429

Addisonian Crisis

Addisonian Crisis• Incidence – rare during pregnancy• Diagnosis – ACTH stimulation test• Acute adreno-cortical insufficiency in pregnancy• Can occur in pregnancy when a patient with chronic adrenal insufficiency is

stressed or in one who is undiagnosed• May result from an OB complications that results in DIC, such as severe

preeclampsia or eclampsia, abruptio placenta, amniotic fluid embolus, postpartum hemorrhage

• Can occur and cause an emergency• Presents with n/v, abdominal pain, shock, frequently fatal (similar

presentation to acute pyelonphritis, gram negative bacillemia, fulminant meningococcal infection (Waterhouse-Friderichsen syndrome)

• Early recognition• Error by giving stress dose steroids

Normal Plasma Total and Free Cortisol, Urinary Free Cortisol and ACTH Levels in Normal Pregnancy

Nonpregnant Third trimesterTotal cortisol 0900 11.3 ± 3.5mg/mL

324 ± 100nmol/L36.0 ± 7mg/mL1029 ± 200nmol/L

Total cortisol 2400 3.6 ± 2.6 mg/mL103 ± 76nmol/L

23.5 ± 4.3 mg/mL470 ± 124nmol/L

Plasma free cortisol0900

0.6±0.3 mg/mL18 ± 9nmol/L

1.3 ± 0.4 mg/mL32 ± 12 nmol/L

Plasma free cortisol2400

0.2 ± 0.1mg/mL6 ± 4 nmol/L

0.6 ± 0.2mg/mL17 ± 5 nmol/L

Urinary free cortisol 4.7-9.5mg/day13-256nmol/day

82.4-244.8mg/day229-680nmol/day

Plasma ACTH 15-70pg/mL3.3-15.4pmol/L

20-120pg/mL4.4-26.4pmol/L

Foley p132

Addisonian Crisis• Treatment – IV bolus of hydrocortisone succinate 200mg

followed by 100mg hydrocortisone succinate in 1liter of NS over 30minutes; then put 100 mg of hydrocortisone succinate in each liter of NS that is infused until the patient is adequately hydrated; may take up to 5 liters

• Hypoglycemia may be prevented by instituting a 50-gm glucose infusion

• Since the patient will receive up to 600mg of hydrocortisone succinate with this protocol, no added mineralocorticoid is needed

Conclusions

• Maternal stabilization• DKA, if possibility – ABG, serum ketones

– If no urine ketones, no DKA• Thyroid storm – block, inhibit, block,

block• Fetal surveillance• Compliance prevents complications

Misc

FFDNA per ACMG - 2016

End

• ???

• References:• Foley MR, Strong TH, Garite TJ.

Obstetric Intensive Care Manual, 2nd Ed. • Creasy R, Resnik R. Maternal-Fetal

Medicine Principles and Practice. 5th Edition

• Uptodate.com online source.

Eclampsia prophylaxis/treatment

Extra endo emergencies not addressed Aug 2016 GR

Diabetes Insipidus

DI – Pregnancy Effect• 1 in 5000 deliveries• Caused by abnormality in vasopressin secretion, an abnormality of vasopressin action

or vasopressin degradation– Polydypsia, polyuria, dehydration, hypernatremia

• Central - caused by decreased production of vasopressin by the paraventricular nuclei of the hypothalamus– Pregnancy worsening of prior DI – *placenta vasopressinase (60% of DI worsens

during pregnancy)• Subclinical central DI may be unmasked for the first time during pregnancy,

because the need for vasopressin release, low serum osmolality and because of increased clearance of vasopressinase

– CNS tumor (e.g., prolactinoma), Granuloma (e.g., sarcoid), Histiocytosis X, Aneurysm, Lymphocytic hypophysitis

– Sheehan syndrome• Nephrogenic – X-linked abnormality of vasopressin V2 receptor• Transient vasopressin resistant – increased vasopressinase activity due to decreased

vasopressinase degradation due to hepatic disease (e.g. AFLP, HELLP, hepatitis)

DI - Diagnosis• Diagnosis during pregnancy –

– Standard water deprivation test – do not use in pregnancy because have to lose 5% of total body weight before the induced dehydration adequately stimulates vasopressin release; such dehydration can be dangerous in pregnancy and should not be used

– Use of DDAVP as a test of urinary concentrating ability is possible and is the preferred test in pregnancy; maximum urine osmolality over the 11 hours after administration of DDAVP is assessed ; any value > 700mosmol/kg is considered normal and no DI is present; <700, ADH is not being secreted or working on the kidney thus the kidney produces hypotonic urine

DI Management• Treatment of central DI in pregnancy –

– DDAVP (2-20micrograms intranasally BID) – BID due to diurnal/circadian rhythms

– DDAVP - not degraded by vasopressinase and no further adjustment is needed in patients with increased vasopressinase activity;

– Breast feeding - transfer of DDAVP to breast milk is minimal so breast feeding is ok; treatment of central DI with DDAVP in pregnancy does not pose any risk to the fetus/neonate

• Labor proceeds normally in women with central DI– surges of oxytocin can be detected during labor and peurperium;

suggests that women with central DI, although vasopressinase deficient, still secrete oxytocin normally;

• Lactation is not impaired

ADH slide

Hypothyroidism & Myxedema Coma• Hypothyroidism – inadequate thyroid hormone

production• Myxedema coma – extreme hypothyroidism• Medical emergency with 20-40% mortality rate• Very rare in pregnancy

• Pregnancy changes – no significant change in free T4 levels or free T3 levels

Myxedema coma - Diagnosis• Symptoms - Decreased mental status, hypothermia,

bradycardia, hyponatremia, hypoglycemia, hypotension

• Lab - high serum TSH, low free T4 (<0.7-1.8ng/dL)• Diagnosis - based on H&P, exclusion of other causes of

coma• Evaluation for precipitating factors such as infection,

etc (similar to thyroid storm)– Rule out MI, maternal echocardiogram– Panculture and empiric antibiotics until culture results

are known

• Treatment- supportive measures similar to thyroid storm– IV levothyroxine – 200-500mcg IV x1, give additional dose of 100-300mcg if no

response in 24 hr, continue 75-100 mcg IV daily until switched to PO (50-200mcg/day)

• Cortiocosteroids to prevent adrenal insufficiency– Draw baseline cortisol level– 100mg hydrocortisone every 8 hr until baseline cortisol level is known, then

titrate accordingly• Endotracheal intubation and ventilation – if hypercapnia (pCO2 >40mmHg) or

hypoxia (<70mmHg)• Ordinary warming (normal blankets) –avoid external re-warming devices• IV fluids and electrolytes and inotropic supportive therapy if required• IV sodium if serum sodium <120 meq/L• Liothyronine T3 replacement in young patients with low cardiovascular risk (more

likely than T4 to cause arrhythmias)• Normal T4 levels are usually obtained in 24 hrs, then get increase in T3• Hypotension, hypothermia, CO, mental status, etc improves in 24 hrs, further

improvement in 4-7 d

Myxedema coma - Management

Cardiovascular Changes of Pregnancy

• Cardiac Output Increased by 30-50%• Twin Pregnancy: Add another 15%• Starts Early and Peaks at 20 Weeks• Increase in Stroke Volume• Increase in Heart Rate• POTENTIAL MATERNAL COMPLICATIONS — Twin

pregnancy results in greater maternal hemodynamic changes than singleton pregnancy. Women carrying twins have a 20 percent higher cardiac output and 10 to 20 percent greater increase in plasma volume than women with singleton pregnancy [176,177]. Although there is also a larger rise in red cell mass in twin pregnancy, physiological anemia is common.

Sheehan syndrome p139, not ER, but poss include as

complication of PPH• Diagnosis• treatement

• Normal pregnancy –

• Glucose production increases with advancing gestational age

Creasy Ch 46

• Normal pregnancy –

• Insulin resistance increases with advancing gestational age

Creasy Ch 46

Creasy Ch 46

• Normal pregnancy –• Insulin response to glucose tolerance test• Increases with advancing gestational age

Physiology in normal pregnancy

• A1C - Glycosylated hemoglobin lower in pregnancy– Mean blood glucose level is 20% lower in

pregnant women– First 20 weeks – rise in red cell mass & slight

decrease in red cell life span– <6 = <120– >9 = >240

Lurie S Mamet Y. Red blood cell survival and kinetics during pregnancy. Eur J Obstet Gynecol Reprod Biol 2000;93:185.Bunn HF, Haney DN, Kamin S, Gabbay KH, et al. The biosynthesis of human hemoglobin A1C. Slow glycosylation of hemoglobin in vivo. J Clin Invest 1976;57:1652.

Intrapartum Maternal Glycemic Control

• Insulin Infusion Method• Intermittent Subcutaneous Injection

Method

*An option for an insulin drip• 500units of regular insulin/500cc normal saline (1unit/cc), start at

0.1 unit/kg/hr. • Blood glucose • <40 mg/dL – discontinue insulin, give glucose per 10gm IV

boluses (D50), give 20ml=10g, check glucose in next hour• 40-60mg/dL – discontinue insulin, resume monitoring• 61-80mg/dL – decrease insulin dose by 0.5 uniuts/hour • 81-110mg/dL - no change• 111-140mg/dL – increase rate by 0.5units/hour • >140 incr rate by 2u/hr• If blood glucose decreases by 50% or more, reduce insulin dose by

1/2, check blood glucose in 1 hour.• If blood glucose does not decrease by 20%, increase the rate by

20%

Intrapartum diabetes management:Blood glucose Novolog or Regular

insulin (units/hr) IVIV fluids

<80 0 D5 1/2 NS at 100-125cc/hr

80-100 0.5 D5 1/2 NS at 100-125cc/hr

101-140 1 D5 1/2 NS at 100-125cc/hr141-180 1.5 Normal saline181-220 2.0 Normal saline>220 2.5 Normal salineMonitor q 2 hr for A2GDM, q 4 hr for A1GDMMay bolus 1-4 units of insulin (novolog or regular) as neededHold AM dose of medication (insulin or glyburide), NPO after MN the night before*Subcutaneous injections as option - intermittent subcutaneous injections

l i li 2 5 it b t l l i 80 120 /dL ½ AM

Management principles• Electrolyte replacement

– K+– Check PO4 and magnesium

• Search and treat precipitating factor (infection)• ICU• Oxygen• Left lateral position• CEFM• Monitor uop

Infant of a diabetic mother

• Neonatal metabolic complications (hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, erythremia)

Diabetes Insipidus• Causes/changes in Pregnancy• Central

– Pregnancy worsening of prior DI – *placenta vasopressinase– CNS tumor (e.g., prolactinoma), Granuloma (e.g., sarcoid), Histiocytosis

X, Aneurysm, Lymphocytic hypophysitis– Sheehan syndrome

• Nephrogenic – X-linked abnormality of vasopressin V2 receptor• Transient vasopressin resistant – increased vasopressinase activity due to

decreased vasopressinase degradation due to hepatic disease (e.g. AFLP, HELLP, hepatitis)

• During pregnancy – 60% of central DI worsens, 25% improve, 15% of cases remain the same- vasopressinase increases in proportion to placental weight

Vasopressin (ADH)• Peptide (9AA)• Half life 3-6 minutes• Made in large cell bodies of hypothalamic magnocellular neurons in the

supraoptic nuclei• Transported to posterior pituitary for storage, release with long axonal tracks

extending from hypothalamus to posterior pituitary (hypothalamohypophyseal tract)

• Cleared by kidney• Minimal crossing of placenta• Vasoactive, maintains CV homeostasis in stress; high doses ADH elevates

venous pressure, decreases blood volume• Fetal hypoxia, hemorrhage, hyperosmolarity stimulate release of ADH and

ADH levels in AF increase in pts with Rhesus isoimmunization– High cord blood levels in IUGR, following fetal bradycardia, passage of

meconium; mediator of stress– Maternal indomethacin therapy decreases fetal urinary flow rates as a

result of stimulation o circulating ADH levels and enhancement of peripheral ADH effects in the fetus.

– Regulates lung liquid secretion by decreaseing the secretion rate in fetuses and increasing lung liquid resorption in neonates

Nephrogenic DI• Rare X-linked disorder• 6 mutations in this gene have been identified for carrier

detection and early prenatal diagnosis• Nonpregnant women with nephrogenic DI are usually

treated with thiazide diuretics or chlorpropamide; chlorpropamide stimulates vasopressin release and enhances its action on the renal tubule, but it may cause fetal hypoglycemia and neonatal DI and should not be used in pregnancy

• Thiazide diuretics are the treatment of choice for nephrogenic DI in pregnancy

Transient Vasopressin Resistant DI

• Most common form of DI seen in pregnancy• Caused by increased vasopressinase activity due either to

increased placental production of the enzyme or to decreased hepatic vasopressinase metabolism as a result of liver damage; transient disturbances of liver function may be seen in AFLP, HELLP, hepatitis

• Treatment is with DDAVP b/c DDAVP is not degraded by vasopressinase

• Electrolyte and fluid balance should be closely monitored during the postpartum period

• Symptoms resolve shortly after delivery when liver function returns to normal

Definitions

• Thyrotoxicosis – clinical and biochemical state resulting from over-production and exposure to thyroid hormone– Most common cause – Grave’s disease – T3 thyrotoxicosis – uncommon

• Thyroid storm – acute, severe exacerbation of hyperthyroidism

• Hypothyroidism – inadequate thyroid hormone production• Myxedema coma – extreme hypothyroidism• Thyroiditis – autoimmune inflammation of the thyroid

gland, may occur for first time postpartum

Changes in pregnancy• Thyroid gland enlarges• First trimester TSH depression due to HCG, normalized

thereafter• Increased renal iodide clearance (increased GFR) and losses to

fetus and placenta lead to decline in iodide• Increased total serum T4 and total serum T3• Normal serum free T4 (0.7-1.8ng/dL) and free T3• Fetal thyroid gland begins concentrating iodine and synthesizing

thyroid hormone after 10-12 weeks of gestation (before which is supplied by maternal supply)– link of overt failure with pregnancy complications, intellectual

impairment; not as strong with mild, subclinical disease

Common precipitants of thyroid storm

• Acute surgical emergency• Induction of anesthesia• DKA• Pulmonary embolism• Noncompliance with antithyroid medications• Myocardial infarction• Infection• Hypertension, preeclampsia• Labor and delivery • Severe anemia

• Extreme expression of severe hypothyroidism in pregnancy

• Medical emergency with 20% mortality rate

• Very rare in pregnancy

Myxedema coma

• Corticosteroids• Draw baseline cortisol level• 100mg hydrocortisone every 8 hr until baseline cortisol level is known, then titrate accordingly

• Levothyroxine sodium• IV/NG tube- oral dose is 30-50% more than the IV dose• Slow bolus IV dose 300-500 micrograms• Daily IV doses of 75-100 micrograms• Daily oral doses of 50-200 micrograms once patient is ambulatory

• Liothyronine T3 replacement in young patients with low cardiovascular risk (more likely than T4 to cause arrhythmias)

• Panculture and empiric antibiotics until culture results are known• Normal T4 levels are usually obtained in 24 hrs, then get increase in t3• Hypotension, hypothermia, CO, mental status, etc improves in 24 hrs, further improvement in 4-7

d

Myxedema coma - management

Corticotropin releasing hormone (CRH)

• Polypeptide hormone and neurotransmitter involved in stress response

• 41 amino acids; released from paraventricularneurons as well as supraoptic and arcuate nuclei and limbic system in response to stress– Stimulates anterior pituitary release of ACTH,

stimulating release of cortisol by adrenal glands• Placenta – determines in part gestation length,

involved in parturition; rapid increase in levels at the onset of parturition acting as trigger; levels decline to nonpregnancy levels 24-48 hr after birth– Placental CRH Thought to regulate the fetal HPA axis

Primary Hyperaldosteronism• Rare cause of hypertension in pregnancy• Diagnosis – high aldosterone, low renin• Can be severe, confused with preeclampsia• Can be variable and significantly worsen in the first 6 weeks postpartum• Present with HTN, hypokalemia, elevated urinary potassium levels• Biochemical diagnosis –• Before making the biochemical diagnosis – hypokalemia should be corrected as

low potassium may supress aldosterone release• When making the diagnosis – potassium replacement should be initiated, all

diuretcis should be discontinued for at least 2 weeks and high doses of beta blockers should be reduced because they reduce renin production.

• Calcium channel blockers should not be used for 2-3 hours before testing

Primary Hyperaldosteronism• Physiologic increase of aldosterone levels occurs in pregnancy; the levels measured in

normal pregnancy are often within the primary hyperaldosteronism range• Pregnant women may have less urinary potassium wasting than patients with primary

hyperaldosteronism b/c of the antagonizing effects of progesterone• Diagnosis during pregnancy can be complicated by the increase in the plasma renin

levels in pregnancy• In primary hyperaldosteronism - plasma renin levels are usually decreased and in

pregnancy the decrease may be attenuated• Outside of pregnancy – the test is a salt-loading study to confirm the autonomous

secretion of aldosterone, but during pregnancy there are concerns about volume overload, worsening of hypokalemia and the lack of specific ref ranges in pregnancy

• Test possible in pregnancy – prolonged upright posture position (which usually causes a modest increase in plasma renin activity) but in primary hyperaldosteronism, the plasma renin activity remains suppressed

Primary Hyperaldosteronism• Ultrasound and MRI to localize the tumor in pregnancy

or CT as needed• Adrenal adenoma if detected – preferred treatment is

unilateral adrenalectomy; successful cases in second trimester have been reported

• Early delivery potentially needed in third trimester since spironolactone and ACE inhibitors are avoided in pregnancy

• Treatment goals – reduce BP, replace potassium and while methyldopa, β-blockers and CCBs can be used, success is variable

Adrenal corticotropin hormone (ACTH)• 39 AA polypeptide hormone

• ½ life 10 minutes in human blood• Released in response to stress• ACTH - basophilic corticotrophs represent 20 percent of cells in anterior pituitary; ACTH is

product of proopiomelanocortin (POMC) gene; • release controlled by CRH, ADH; glucocorticoids inhibit hypothalamic release of CRH and

pituitary to inhibit release of ACTH• Stimulates cortex of adrenal gland to make and release corticosteroids (glucocorticoids,

androgens)• Longterm stimulatory effects on expression of adrenal steroidogenic enzymes, the density of

LDL receptors and the rate of de novo adrenal cholesterol synthesis• Enhances adrenal hypertrophy and hyperplasia by stimulating paracrine factors like IGF II

which induces adrenal cell division• In absence of ACTH as in anencephaly, the fetal adrenal is reduced at 15 weeks, but admin of

ACTH provides tropic/trophic• Seen in fetus by 8 weeks; pituitary corticotropes respond to CRH by 10 weeks• Involution of adrenal cortex following parturition reflects normal reduction in plasma ACTH

once influence of elevated CRH is removed (assd with parturition)

Below is long version 2-10-11

Endocrine Emergencies in Obstetrics

Darren Farley, MDClinical Assistant Professor

Division of Maternal-Fetal MedicineDept. of Obstetrics and Gynecology

University of Kansas School of Medicine – Wichita

• No financial interests to disclose.

OUTLINE• Diabetic Ketoacidosis• Thyrotoxicosis & Thyroid Storm• Pheochromocytoma• Addisonian Crisis• Hypothyroidism & Myxedema Coma• Diabetes Insipidus• Primary Hyperparathyroidism• Primary Hyperaldosteronism

• Pregnancy changes• Diagnosis• Management

Diabetic Ketoacidosis

Glucose physiology in pregnancy

• Glucose production increases with advancing gestational age

• Insulin resistance increases with advancing gestational age

• Insulin response to glucose tolerance test - increases with advancing gestational age

Incidence of DKA• Nonpregnant -

– 1-5 episodes per 100 patients / year– Mortality 5-10%

• Complicates 2-9% of diabetic pregnancies• A leading cause of fetal loss• Fetal mortality rate

– 1963 – 50-90% – Now – 10-20%

• Maternal mortality - now 1% (previously 15-50%)

Foley p 143

DKA—signs/symptoms

HyperventilationKetotic breathTachycardiaHypotensionDry MMDisorientationComa

PolyuriaPolydipsiaN/VAbdominal painWeaknessWeight loss

Factors precipitating DKA in pregnancy

• Emesis• Infection• Non-compliance• Insulin pump failure• ß-sympathomimetic drugs• Steroids• Poor management• PE

Diagnosis

• DKA -

• D –Diabetic - >180mg/dL• K –serum acetone, Ketones 1:2 or greater• A –Acidosis – arterial pH<7.3, HCO3-

<15, anion gap [Na – (Cl +HCO3)] >12

Management• Maternal Resuscitation

– IV fluids– Insulin– Search for underlying cause – infection,

noncompliance, etc – I/Os, monitoring glucose (q1-2hr), – ABG, pH, anion gap, electrolytes (q2-4hr)– Fetal monitoring*

• Withhold intervention toward delivery on behalf of the fetus until maternal metabolic disturbances are corrected

• Oxygen and correct maternal positioning while correcting disturbances

Management -

• Fluid replacement– Fluid deficit is 100cc/kg (7-10L for total deficit)

• Accurate I/Os, BUN, Creatinine• Replace 75% of deficit in 1st 24 hrs, remainder over the

hospitalization– NS (use isotonic solution to prevent rapid decline in plasma

osmolarity and resultant cellular swelling and cererbral edema)

– 1L NS in first hour, 500 mL/hr hours 2 and 3 (NS 1st 3 hrs)– LR or ½ NS at 250cc/hr in initial 24 hr until 75% of volume

deficit is replaced• LR is used to avoid further acidosis (LR pH 6.5, vs 5.0 of NS)• Sodium load with NS – possible hypernatremia, switch to LR or ½

NS if Na >150meq/L

Insulin (0.1)• Insulin therapy (inhibits lipolysis and ketogenesis,

leads to suppression of hepatic glucose production)– Loading dose 0.1U/kg regular insulin

• 50 units / 500 mL NS (1cc = 0.1units, 10 cc = 1unit)– Infusion 0.1units/kg/hour– If plasma glucose does not decrease by 10% in first hour

or by 20% in second hour – repeat loading dose or double infusion rate

– When glucose ~250mg/dL or less, add D5 to the fluids and reduce the hourly rate by 1/2

– Continue infusion of insulin until serum bicarbonate and anion gap normalize

*An option for an insulin drip• 500units of regular insulin/500cc normal saline (1unit/cc), start at

0.1 unit/kg/hr. • Blood glucose • <40 mg/dL – discontinue insulin, give glucose per 10gm IV

boluses (D50), give 20ml=10g, check glucose in next hour• 40-60mg/dL – discontinue insulin, resume monitoring• 61-80mg/dL – decrease insulin dose by 0.5 uniuts/hour • 81-110mg/dL - no change• 111-140mg/dL – increase rate by 0.5units/hour • >140 incr rate by 2u/hr• If blood glucose decreases by 50% or more, reduce insulin dose by

1/2, check blood glucose in 1 hour.• If blood glucose does not decrease by 20%, increase the rate by

20%

Insulin• Use regular insulin• Pump monitor infusion rate• Label insulin line with rate (units/volume)• IV insulin is compatble with IV magnesium and oxytocin• Mix and flush tubing and bag of insulin to prevent binding to plastic bag• Obtain blood samples from arm opposite the infusion• Glucose levels hourly during labor• Have amp of D50 at bedside for hypoglycemia• Use glucose-free solutions for boluses for hydration, anesthetics• Before discontinuation of IV insulin, give SQ dose to prevent rebound

hyperglycemia

• Insulin half lives – Regular IV – 5 min– Regular IM – 2hr– Regular SQ – 4hr

Insulin sensitivity factor – 1500 rule

• How much of a reduction in blood glucose should you expect for each 1.0 unit of insulin delivered to the patient

• 1500 rule– Insulin sensitvity factor = 1500/TDI– Ex – if TDI = 50units

• 1500/50 = 30mg/dL blood glucose drop per 1.0 unit of insulin

• To correct a patient’s blood glucose to 100mg/d:• Patient’s blood glucose -100 / 30 = Supplemental units of

insulin

Example insulin sliding scale:• Blood glucose Insulin aspart (SQ units)• <70 Hypoglycemia protocol• 70-120 zero units• 121-150 1 unit• 151-200 2 units• 201-250 3 units• 251-300 4 units• 301-350 5 units• 351-400 6 units• >400 7 units, call MD

Switching to subcutaneous insulin and insulin pump

• Patient should be tolerating a full diet• Total daily dose needed after resolution of DKA• Classic split – NPH and regular

– AM 2/3 total daily dose (2/3 NPH, 1/3 regular)– PM 1/3 total daily dose (1/2 regular dinner, ½ NPH HS)

• NPH and humalog/novolog– NPH (60%), 2/3 AM, 1/3 HS– Novolog (40%), 1/3 with each meal

• Glargine/detimir & novolog/humalog• If switching to pump – reduce TDI by 25%

– 50% basal dose / 24hr to get hourly basal rate– 50% is bolus dose with meals (1/3 with each meal)

Insulin preparations & pharmacokinetics Creasy p977

Insulin Peak onset (h)

Duration (h)

Comments

Lispro (Humalog)

1 2 OOA 10 min; no need to delay meal intake

Aspart (Novolog)

1 2 OOA 10 min; no need to delay meal intake

Regular 2 4 Good coverage of individual meals if injected 20 min preprandial; postprandial hypoglycemia

NPH 4 8 Intermediate acting control, give upon wakening and at bedtime, risk of 3AM hypoglycemia

Glargine (Lantus)Detimir

5 24 Less peak, limited pregnancy experience, increased risk of nocturnal hypoglycemia or undertreatment

Potassium administration• Anticipated potassium deficit in a pregnant patient with DKA is 5-10 meq/kg• Replacement usually delayed for the first 2-4hr of therapy, since K+ is usually

elevated until patient diureses has been established (at least 0.5cc/kg/h). • Once IV fluids and insulin therapy are started serum K+ may drop quickly as a

result of urinary loss and intracellular shift. When K+ is <5 and adequate diuresis has been established (0.5cc/kg/h) then K administration should begin

• 40-60meq KCl/liter of NS• If K+ is ≥4, give 10-20meq• If K+ is <4, give 30-40 meq• Replace K cautiously, watching UOP and serum K+ frequently, every 4hr• Replace entire K+ deficit (5-10meq/kg) over the span of the patient’s entire

hospitalization• Alternatively – with DKA induced maternal phosphate deficiency, K2PO4

(KPhos) may be given as K replacement instead of KCL

Bicarbonate therapy

• Only if arterial pH <6.9-7.0 and HCO3 < 5meq/L

• Rapid undiluted correction of metabolic acidosis with NaHCO3 is unwarranted and may lead to severe hypokalemia, hypernatremia, impaired oxygen delivery, and a paradoxical fall in CSF pH

Infant of a diabetic mother

• Neonatal metabolic complications (hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, erythremia)

Diabetes Insipidus

Diabetes Insipidus• Causes in Pregnancy• Central

– Pregnancy worsening of prior DI– CNS tumor (e.g., prolactinoma)– Granuloma (e.g., sarcoid)– Histiocytosis X– Aneurysm– Lymphocytic hypophysitis– Sheehan syndrome

• Neprhogenic – X-linked abnormality of vasopressin V2 receptor• Transient vasopressin resistant – increased vasopressinase

activity due to decreased vasopressinase degradation due to hepatic disease (e.g. AFLP, HELLP, hepatitis)

Diabetes Insipidus• Caused by abnormality in vasopressin secretion, an abnormality of vasopressin action

or vasopressin degradation• Polydypsia, polyuria, dehydration• Central – caused by decreased production of vasopressin by the paraventricular nuclei

of the hypothalamus• 1 in 5000 deliveries• Most commonly presents before conception arising from a pituitary tumor or another

invasive disease such as histiocytosis X• Often worsens during pregnancy due to an increase in the clearance of endogenous

vasopressin by placental vasopressinase• Vasopressinase concentration increases during pregnancy in proportion to the placental

weight• Vasopressinase is Metabolized by the liver, thus increased in liver disease• Subclinical central DI may be unmasked for the first time during rpegnancy, because

the need for vasopressin release, low serum osmolality and because of increased clearance of vasopressinase

• During pregnancy – 60% of central DI worsens, 25% improve, 15% of cases remain the same

Diabetes Insipidus

• Diagnosis during pregnancy – seen following development of Sheehan syndrome and as a result of the enlargement of a prolactinoma, histiocytosis X, and lymphocytic hypophysitis, and complication of ventriculoperitoneal shunt during pregnancy

• Standard water deprivation test – do not use in pregnancy b/c have to lose 5% of total body weight before the induced dehydration adequately stimulates vasopressin release; such dehydration can be dangerous in pregnancy and should not be used

• Use of DDAVP as a test of urinary concentrating ability is possible and is the preferred test in pregnancy; maximum urine osmolality over the 11 hours after administration of DDAVP is assessed ; any value > 700mosmol/kg is considered normal and no DI is present; <700, ADH is not being secreted or working on the kidney thus the kidney produces hypotonic urine

Diabetes Insipidus

• Treatment of central DI in pregnancy – DDAVP (2-20micrograms intranasally BID) due to diurnal/circadian rhythms; can be given IV after cesarean but IV dosing is 5-20fold more potent than the intranasal spray and the does should be adjusted accordingly, therefore just give intranasally; DDAVP is not degraded by vasopressinase and no further adjustment is needed in patients with increased vasopressinase activity; transfer of DDAVP to breast milk is minimal so breast feeding is ok; treatment of central DI with DDAVP in pregnancy does not pose any risk to the fetus/neonate

• Labor proceeds normally in women with central DI; surges of oxytocin can be detected during labor and peurperium; suggests that women with central DI, although vasopressinase deficient, still secrete oxytocin normally; lactation is not impaired

Vasopressin (ADH)• Peptide (9AA)• Half life 3-6 minutes• Made in large cell bodies of hypothalamic magnocellular neurons in the

supraoptic nuclei• Transported to posterior pituitary for storage, release with long axonal tracks

extending from hypothalamus to posterior pituitary (hypothalamohypophyseal tract)

• Cleared by kidney• Minimal crossing of placenta• Vasoactive, maintains CV homeostasis in stress; high doses ADH elevates

venous pressure, decreases blood volume• Fetal hypoxia, hemorrhage, hyperosmolarity stimulate release of ADH and

ADH levels in AF increase in pts with Rhesus isoimmunization– High cord blood levels in IUGR, following fetal bradycardia, passage of

meconium; mediator of stress– Maternal indomethacin therapy decreases fetal urinary flow rates as a

result of stimulation o circulating ADH levels and enhancement of peripheral ADH effects in the fetus.

– Regulates lung liquid secretion by decreaseing the secretion rate in fetuses and increasing lung liquid resorption in neonates

Nephrogenic DI

• Rare X-linked disorder• 6 mutations in this gene have been identified for carrier detection

and early prenatal diagnosis• Nonpregnant women with nephrogenic DI are usually treated

with thiazide diuretics or chlorpropamide; chlorpropamide stimulates vasopressin release and enhances its action on the renal tubule, but it may cause fetal hypoglycemia and neonatal DI and should not be used in pregnancy

• Thiazide diuretics are the treatment of choice for nephrogenic DI in pregnancy

Transient Vasopressin Resistant DI

• Most common form of DI seen in pregnancy• Caused by increased vasopressinase activity due either to

increased placental production of the enzyme or to decreased hepatic vasopressinase metabolism as a result of liver damage; transient disturbances of liver function may be seen in AFLP, HELLP, hepatitis

• Treatment is with DDAVP b/c DDAVP is not degraded by vasopressinase

• Electrolyte and fluid balance should be closely monitored during the postpartum period

• Symptoms resolve shortly after delivery when liver function returns to normal

Thyroid

Changes in pregnancy• Thyroid gland enlarges

– Goiter-minimal in regions of iodine deficiency; 30% increase in size in regions with dietary iodine deficiency

• First trimester TSH depression due to HCG, normalized thereafter

• Increased renal iodide clearance (increased GFR) and losses to fetus and placenta lead to decline in iodide

• Increased total serum T4 and total serum T3• Normal serum free T4 (.7-1.8ng/dL) and free T3

– estrogen-mediated increase in circulating levels of TBG (major transport protein for thyroid hormone)

• fetal thyroid gland begins concentrating iodine and synthesizing thyroid hormone after 10-12 weeks of gestation (before which is supplied by maternal supply)– link of overt failure with pregnancy complications, intellectual

impairment; not as strong with mild, subclinical disease

Definitions• Thyrotoxicosis – clinical and biochemical state resulting from

over-production and exposure to thyroid hormone– Most common cause in preg is Grave’s disease (autoimmune

condition, production of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone binding inhibitory immunoglobulin (TBII) that act on TSH receptor to mediate thyroid stimulation or inhibition or both

• Thyroid storm – acute, severe exacerbation of hyperthyroidism• Hypothyroidism – inadequate thyroid hormone production• Myxedema coma – extreme hypothyroidism• Thyroiditis – autoimmune inflammation of the thyroid gland,

may occur for first time postpartum– Usually painless, may present at de novo hypothyroidism,

transient thyrotoxicosis, initial hyperthyroidism followed by hypothyroidism within 1 yr postpartum

Free T4 concentrations remain within nonpregnant reference range (0.7-1.8ng/dL) throughout pregnancy

Thyrotoxicosis & Thyroid Storm

Thyroid storm

Thyroid storm• Exacerbation of hyperthyroidism/thyrotoxicosis• Heart failure from excessive thyroxine is more common in

pregnant women• Diagnosis is clinical

• Hypermetabolism - Fever, perspiration, warm, flushed skin

• Cardiovascular - Tachycardia, atrial fibrillation, CHF• CNS - Irritability, agitation, tremor, mental status change

(delirium, psychosis, coma)• GI - Nausea, vomiting, diarrhea, jaundice• Dehydration• Supporting laboratory evidence

– Leukocytosis, elevated LFTs, hypercalcemia, low TSH, high free T4, and/or T3

Common precipitants of thyroid storm

• Acute surgical emergency• Induction of anesthesia• DKA• Pulmonary embolism• Noncompliance with antithyroid medications• Myocardial infarction• Infection• Hypertension, preeclampsia• Labor and delivery • Severe anemia

Thyroid storm• Medical management coordinated with supportive

measures in intensive care unit setting• IV fluids, electrolytes• Cardiac monitoring• Cooling measures (blanket, sponge bath, Tylenol)• Oxygen therapy with serial ABGs if oxygenation is an issue• No salicylates (increased T4)• NG tube if patient is unable to swallow (may need for PTU

admin described next)• Consideration of PA catheter for central hemodynamic

monitoring to guide β-blocker therapy during hyperdynamic cardiac failure)

Thyroid storm

• Supportive measures while instituting medical management (block, inhibit, block, block)

• Workup for inciting causes, maternal echocardiography

Thyroid storm• Treatment• PTU – 1gm PO, then 200mg q6hr• Sodium iodide 500 mg or 10gtts of oral Lugol’s

solution q 8 hrs – start 1 hr after PTU load to inhibit thyroid release of T3 and T4– if iodine allergy, give lithium carbonate 300mg q6hr

• Dexamethasone 2mg IV q6hr x4 to block peripheral conversion of T4 to T3

• Labetalol 200mg po q8hr for HR >120• Phenobarbital 300mg IV q8hr prn agitation

Thyroid storm

• Admit to intensive care unit, L & D• BLOCK –

– Propylthiouracil – 1 gram PO or crushed in NG tube, then 200mg PO q 6 hrs

– blocks synthesis of T3 by BLOCKING conversion of T4 to T3

• Inhibit• Block• Block

Thyroid storm• Block• INHIBIT – after 1 hour of initial PTU load (to

prevent inadvertent release of T4 as a result of this therapy) – iodide is given to INHIBIT release of T4 and T3 by the thyroid gland– Na iodide 500-1000 IV q 8hr– SSKI 5 drops PO q 8hr– Lugol’s solution 10 drops PO q 8hr– *Lithium carbonate 300mg q6hr (if history of iodine

induced anaphylaxis)• Block• Block

Thyroid storm

• Block• Inhibit• BLOCK – Dexamethasone (or

corticosteroid equivalent) 2mg IV q6hr x 4 doses – this therapy BLOCKS further peripheral conversion of T4 to T3

• Block

Thyroid storm

• Block• Inhibit• Block• BLOCK – beta-BLOCKERS

(propranolol 20mg PO/IV q 8hr; labetalol 200 mg PO q 6hr; esmolol) to treat tachycardia (rate control of <120 bpm)

Hypothyroidism & Myxedema Coma

Myxedema coma• Symptoms = Decreased mental status, Hypothermia,

Bradycardia, Hyponatremia, Hypoglycemia, Hypotension, Precipitating illness

• Lab - high serum TSH, low free T4 (<.7-1.8ng/dL)• Diagnosis = based on H&P, exclusion of other causes of

coma• Evaluation – workup of precipitating factors such as

infection, etc (similar to thyroid storm)• Mortality rate = 30-40%• Treatment- supportive measures similar to thyroid storm

– IV levothyroxine – 200-500mcg IV x1, give additional dose of 100-300mcg if no response in 24 hr, continue 75-100 mcg IV daily until switched to PO

• Extreme expression of severe hypothyroidism in pregnancy

• Medical emergency with 20% mortality rate• Very rare in pregnancy

Myxedema coma

• Tx –• Supportive • Cortiocosteroids to prevent adrenal insufficiency• Endotracheal intubation and ventilation – if hypercapnia (pCO2 >40mmHg) or

hypoxia (<70mmHg)• Ordinary warming (normal blankets) –avoid external re-warming devices• IV fluids and electrolytes and inotropic supportive therapy if required• IV sodium if serum sodium <120 meq/L

• Cardiac monitoring• ECG, troponin and CPK levels to rule out MI• BP monitoring

• Corticosteroids

Myxedema coma

• Corticosteroids• Draw baseline cortisol level• 100mg hydrocortisone every 8 hr until baseline cortisol level is known, then titrate accordingly

• Levothyroxine sodium• IV/NG tube- oral dose is 30-50% more than the IV dose• Slow bolus IV dose 300-500 micrograms• Daily IV doses of 75-100 micrograms• Daily oral doses of 50-200 micrograms once patient is ambulatory

• Liothyronine T3 replacement in young patients with low cardiovascular risk (more likely than T4 to cause arrhythmias)

• Panculture and empiric antibiotics until culture results are known• Normal T4 levels are usually obtained in 24 hrs, then get increase in t3• Hypotension, hypothermia, CO, mental status, etc improves in 24 hrs, further improvement in 4-7

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Myxedema coma - management

Hyperparathyroidism

• More common in women than men (3:1)• Avg age dx 55yo• 145 cases reported during pregnancy• Symptoms – weakness, fatigue, kidney stones, bone pain, pancreatitis,

mental disturbances; most found incidentally • Diagnosis – elevated levels of ionized calcium in the presence of elevated

PTH• Majority of calcium is bound to albumin; reduced serum albumin levels in

pregnancy, acquisition by the fetus of 25-30g of calcium, increase in GFR and the expanded extracellular fluid volume result in an overall decrease in total serum calcium levels by 0.5mg/dL

• Ionized calcium levels are not affected• PTH levels stay the same or slightly decrease• Primary hyperparathyroidism - ~90% due to parathyroid adenoma (9%

with parathyroid hyperplasia, 2% parathyroid cancer)• 20% have nephrolithiasis

Hyperparathyroidism

• Definitive treatment is surgical removal of the glands• Only 25% of asymptomatic patients have progressive disease (decrease of

bone mass)• Treat during pregnancy to reduce risk of neonatal tetany, miscarriage

and stillbirth seen with maternal hypercalcemia; fetal testing• Mithramycin and bisphosphonates contraindicated during pregnancy –

details of why*****• If asymptomatic with mild hypercalcemia – monitoring acceptable with

surgery after pregnancy• If symptomatic and not a surgical candidate - Oral phosphate

therapy1.5g/day TID; only if serum phosphate is <3mg/dL, phosphate administration should be adjusted to maintain serum phosphate <4mg/dL

• Furosemide – increases excretion of calcium in the urine, can be given orally to help decrease Ca2+

• Symptomatic pt, progressive, hypercalcemia (>12mg/dL) or if there is a deterioration of renal function – surgery by experienced parathyroid surgeon; do not defer because of the pregnancy if she is symptomatic and has hypercalcemia

• Hypercalcemia crisis• Hypercalcemia crisis – progressive hypercalcemia with hypovolemia,

renal insufficiency, altered mentation, pancreatitis, seizures (can mimic eclampsia

• -hydration with NS (2-3L over 3-6hr)• -correct electrolyte abnormalities• -furosemide (decreases distal tubular calcium reabsorption) 10-40mg IV

every 2-4 hrs to maintain UOP at 200mL• -calcium restriction

• -persistent hypercalcemia –• calcitonin (100-400 units/day), effective, tachyphylaxis occurs in 4-6 days• Glucocorticoids – can decrease GI calcium absorption, dexamethasone

2mg IV q6hr; hydrocortisone 100mg IV q8; prednisone 1mg/kg

• Neonatal hypocalcemia – predictable, preventable• Transient neonatal tetany should not be associated with long-term

sequelae

Hyperparathyroidism

Adrenal

Pheochromocytoma

• Rare tumor of catecholamine-secreting chromaffin cells• Most pheochromocytomas occur sporadically-90%, 10% occur as part of a syndrome• Maternal mortality – 2% (16% in 1980), fetal loss – 11% (26% in 1980), due to earlier

diagnosis (83% diagnosed antenatally now vs 52% in 1980) – Ahlawat 1999, Hermayer 1999, Almog 2000

• Plasma metanephrines – best test – 99% sensitivity, 89% specificity• Clonidine suppression test – helpful in distinguishing beteween elevated blood levels of

norepinephrine due to increased sympathetic nerve stimulation from that due to pheochromocytoma; clonidine inhibits neurally mediated catecholamine release; after an overnight fast, a heparin lock is placed at least 30min prior to baseline levels being drawn; plasma catecholamine levels are sampled at baseline and hourly for 3 hours after the patient is given clonidine (0.3mg per 70kg body weight)

• normal response is a decrease of >50% in plasma norepinephrine levels or minimal norepinephrine of 500pg/mL or less

• false positives can occur if pt on diuretics and particularly tricyclic antidepressants

• MRI to localize the tumor – 90% of tumors arise in adrenal glands; after delivery –radioactive iodine-labeled metiodobenzylguanidine scintigraphy offers greater than 95% specificity in detection

Pheochromocytoma –Symptoms/signs

• Symptomatic hypertension - severe, fluctuating, paroxysmal– HA, perspiration, palpitations, tachycardia– Excessive truncal sweating

• Postural hypotension• Different from preeclampsia – no

proteinuria, hyperuricemia, edema

Pheochromocytoma• Management• Pharmacologic control of HTN and tachycardia• Alpha adrenergic receptor blockade • Phenoxybenzamine – 20mg BID and gradually increase (10mg qod) to max

dose (20-40mg bid/tid) • Phentolamine 5-10mg IV/IM, reserved for emergency or preoperative

situations• Prazosin – 1mg PO BID/TID, increase to max daily dose of 6-15mg divided in

BID/TID• Labetalol – 100mg BID, increase by 100mg BID every 2 weeks, max

2400mg/day; if discontinuing, taper dose over 1-2 weeks• IV boluses – 20mg IV over 2 minutes, increase by 20mg every 10min until

BP is controlled, max dose of 300mg IV acutely (within 6 hours)• infusion – 2mg/min until BP control, switch to oral dosing – 200-400mg

every 6-12 hours• Nitroprusside – 0.25micrograms/kg/min IV infusion to control BP; max

infusion rate is 10microgram/kg/min• Metyrosine may be used if HTN is still uncontrolled

Pheochromocytoma• *Beta blockade – use if tachycardia or arrhythmia, predominately adrenaline secreting tumors;

selective/short acting agents preferred• *Use only after α-blockade has been started because unopposed α-adrenergic activity may lead

to vasoconstriction and a marked increase in BP• Metoprolol – 50-200mg BID PO• Atenolol – 50mg PO every day and increase after 10-14 days to a max of 100mg every day• Propranolol – only use if adequate alpha blockade has been started; 40mg PO BID, increase

every 3-7 days to a max of 480mg daily, BID

• Fluid management

• Surgical management • Timing depends on medical control, tumor size, risk of malignancy, stage of pregnancy (best in

second trimester), laparoscopy vs laparotomy• Third trimester – C/S after confirmation of lung maturity with adrenalectomy OR vaginal

delivery and laparoscopic removal of the tumor postpartum• Magnesium sulfate has been used (4g bolus, 2g/hr) has been used in nonpregnant patients for

operative control during surgical removal of pheochromocytoma

Dildy p429

Addisonian Crisis

Adrenal corticotropin hormone (ACTH)

• 39 AA polypeptide hormone• ½ life 10 minutes in human blood• Released in response to stress• ACTH - basophilic corticotrophs represent 20 percent of cells in anterior pituitary;

ACTH is product of proopiomelanocortin (POMC) gene; • release controlled by CRH, ADH; glucocorticoids inhibit hypothalamic release of

CRH and pituitary to inhibit release of ACTH• Stimulates cortex of adrenal gland to make and release corticosteroids

(glucocorticoids, androgens)• Longterm stimulatory effects on expression of adrenal steroidogenic enzymes, the

density of LDL receptors and the rate of de novo adrenal cholesterol synthesis• Enhances adrenal hypertrophy and hyperplasia by stimulating paracrine factors

like IGF II which induces adrenal cell division• In absence of ACTH as in anencephaly, the fetal adrenal is reduced at 15 weeks,

but admin of ACTH provides tropic/trophic• Seen in fetus by 8 weeks; pituitary corticotropes respond to CRH by 10 weeks• Involution of adrenal cortex following parturition reflects normal reduction in

plasma ACTH once influence of elevated CRH is removed (assd with parturition)

Normal Plasma Total and Free Cortisol, Urinary Free Cortisol and ACTH Levels in Normal Pregnancy

Nonpregnant Third trimesterTotal cortisol 0900 11.3 ± 3.5mg/mL

324 ± 100nmol/L36.0 ± 7mg/mL1029 ± 200nmol/L

Total cortisol 2400 3.6 ± 2.6 mg/mL103 ± 76nmol/L

23.5 ± 4.3 mg/mL470 ± 124nmol/L

Plasma free cortisol0900

0.6±0.3 mg/mL18 ± 9nmol/L

1.3 ± 0.4 mg/mL32 ± 12 nmol/L

Plasma free cortisol2400

0.2 ± 0.1mg/mL6 ± 4 nmol/L

0.6 ± 0.2mg/mL17 ± 5 nmol/L

Urinary free cortisol 4.7-9.5mg/day13-256nmol/day

82.4-244.8mg/day229-680nmol/day

Plasma ACTH 15-70pg/mL3.3-15.4pmol/L

20-120pg/mL4.4-26.4pmol/L

Foley p132

Addisonian Crisis• Incidence –• Diagnosis-• Acute adreno-cortical insufficiency in pregnancy• Can occur in pregnancy when a patient with chronic adrenal insufficiency is

Massive bilateral adrenal hemorrhage stressed or in one who is undiagnosed• May result from an OB complications that results in DIC, such as severe

preeclampsia or eclampsia, abruptio placenta, amniotic fluid embolus, postpartum hemorrhage

• can occur and cause an emergency• Presents with n/v, abdominal pain, shock, frequently fatal (similar

presentation to acute pyelonphritis, gram negative bacillemia, fulminant meningococcal infection (Waterhouse-Friderichsen syndrome)

• Early recognition

Addisonian Crisis• Treatment – IV bolus of hydrocortisone succinate 200mg

followed by 100mg hydrocortisone succinate in 1liter of NS over 30minutes; then put 100 mg of hydrocortisone succinate in each liter of NS that is infused until the patient is adequately hydrated; may take up to 5 liters

• Hypoglycemia may be prevented by instituting a 50-gm glucose infusion

• Since the patient will receive up to 600mg of hydrocortisone succinate with this protocol, no added mineralocorticoid is needed

Corticotropin releasing hormone (CRH)

• Polypeptide hormone and neurotransmitter involved in stress response

• 41 amino acids; released from paraventricular neurons as well as supraoptic and arcuate nuclei and limbic system in response to stress– Stimulates anterior pituitary release of ACTH, stimulating

release of cortisol by adrenal glands• Placenta – determines in part gestation length, involved in

parturition; rapid increase in levels at the onset of parturition acting as trigger; levels decline to nonpregnancylevels 24-48 hr after birth– Placental CRH Thought to regulate the fetal HPA axis

Primary Hyperaldosteronism• Rare cause of hypertension in pregnancy• Diagnosis – high aldosterone, low renin• Can be severe, confused with preeclampsia• Can be variable and significantly worsen in the first 6 weeks postpartum• Present with HTN, hypokalemia, elevated urinary potassium levels• Biochemical diagnosis –• Before making the biochemical diagnosis – hypokalemia should be corrected as

low potassium may supress aldosterone release• When making the diagnosis – potassium replacement should be initiated, all

diuretcis should be discontinued for at least 2 weeks and high doses of beta blockers should be reduced because they reduce renin production.

• Calcium channel blockers should not be used for 2-3 hours before testing

Primary Hyperaldosteronism• Physiologic increase of aldosterone levels occurs in pregnancy; the levels measured in

normal pregnancy are often within the primary hyperaldosteronism range• Pregnant women may have less urinary potassium wasting than patients with primary

hyperaldosteronism b/c of the antagonizing effects of progesterone• Diagnosis during pregnancy can be complicated by the increase in the plasma renin

levels in pregnancy• In primary hyperaldosteronism - , plasma renin levels are usually decreased and in

pregnancy the decrease may be attenuated• Outside of pregnancy – the test is a salt-loading study to confirm the autonomous

secretion of aldosterone, but during pregnancy ther are concerns ab out volume overload, worsening of hypokalemia and the lack of specific ref ranges in pregnancy

• Test possible in pregnancy – prolonged upright posture position (which usually causes a modest increase in plasma renin activity) but in primary hyperaldosteronism, the plasma renin activity remains suppressed

Primary Hyperaldosteronism• Ultrasound and MRI to localize the tumor in pregnancy

or CT as needed• Adrenal adenoma if detected – preferred treatment is

unilateral adrenalectomy; successful cases in second trimester have been reported

• Early delivery potentially needed in third trimester since spironolactone and ACE inhibitors are avoided in pregnancy

• Treatment goals – reduce BP, replace potassium and while alphamethyldopa, b blockers and CCBs can be used, success is variable