Grand Rounds Grant Kennedy CCFP, EM R3
CASE • Otherwise healthy 31 yo female presents with N/V, abdominal pain, and “difficulty taking a breath in”.
CASE • O/E: • HR 115. Other “VSS”. • “Diffusely tender abdomen”. • Bedside U/S in ED showing Free Fluid in Morrison’s Pouch.
CASE • Beta-hCG + (205 IU/L) • Hgb 169 (elevated) • Platelets 474 (elevated) • WBC 16.9 (elevated) • Lytes Normal • No AG • Creatinine Normal • UA = ketones
Differential Diagnosis? • Ectopic pregnancy • Ovarian torsion • Ruptured/hemorrhagic cyst • Appendicitis • PID • Sepsis
CASE • Background Hx: • 2.5 yrs of primary infertility • Attending Fertility Clinic • Clomid x 3 cycles • In-vitro Fertilization (IVF) for 1 cycle
CASE • Most recently underwent oocyte retrieval, IVF and embryo transfer 2 weeks prior. • Most Likely Diagnosis????
Ovarian Hyperstimulation Syndrome • OBJECTIVES: • Definition • Complications • Classifications • Pathophysiology • Epidemiology • Risk Factors • Treatment • Prevention • Disposition
Ovarian Hyperstimulation Syndrome (OHSS) • What is it? • OHSS is a potentially life-threatening complication of controlled ovarian stimulation and ovulation induction for the purpose of treating infertility. • In its severe form it is characterized by massive ovarian enlargement and third spacing of fluid leading to hemoconcentration and hypovolemic shock.
OHSS Complications Ovarian Torsion Ascites Pleural/Pericardial effusions Electrolyte abnormalities (hypoNat, hyperK) Hypovolemic shock Acute Renal Failure Thromboembolic events DIC ARDS DEATH
OHSS Grading System • At least 5 different grading systems have been introduced over time. • Each system classified OHSS into grades of severity (mild, moderate, severe) based on a combination of symptoms, signs, lab values and ultrasonographic findings. • The first system (Rabau et al. 1967) used 24 hr urine and blood hormone levels, whereas more recent systems (Golan et al. 1989; Rizk and Aboulghar 1999) have incorporated ultrasonographic findings.
Grade I (mild) • Bilateral ovarian enlargement with multiple cysts measuring up to 5 x 5cm. • Abdominal distention/discomfort • Nausea, vomiting, diarrhea
Grade II (moderate) • Mild PLUS… • Ovarian enlargement with cysts measuring up to 12 x 12 cm • Sonographic evidence of ascites
Grade III (severe) • Moderate PLUS… • Ovarian enlargement with cysts measuring > 12 x 12 cm • Clinical Ascites • +/- complications… • Pleural effusions, lyte abnormalities, ARF, DIC, thromboembolic events, shock, ARDS etc.
Typical Lab Values in Severe OHSS • WBC > 25 (though I’m told every pt has a count >20 for up to a week post egg retrieval) • Hct > 55% • Creatinine Clearance < 50mL/min • Albumin < 20
Pathophysiology Exogenous Gonadotropin Cycles • (FSH, hCG) • Clomiphene (rare) Endogenous Gonadotropin Cycles • Spontaneous multifollicular development in PCOS or hypothyroidism secondary to LH surge (case reports) Congenital Predisposition • FSH receptor mutations allow for hyperstimulation by endogenous hCG during pregnancy
Pathophysiology • Why is it most common to develop OHSS from exogenous gonadotropin administration??? • The answer is in the difference between spontaneous ovulatory cycles and induced ovulation.
Pathophysiology • In spontaneous ovulatory cycles, the hypothalamic-pituitary-ovarian feedback mechanisms limit follicle recruitment to a small number of early antral follicles • Full development is generally restricted to a single leading follicle that will ovulate in response to the midcycle luteinizing hormone (LH) surge
Pathophysiology In contrast… • Ovarian stimulation and ovulation induction involves administration of exogenous gonadotropins, thus overriding the normal H-P-O axis feedback mechanisms. • Result is recruitment of large number of antral follicles. • Multiple follicles are sustained and capable of luteinization and ovulation.
Pathophysiology • The goal of controlled ovarian hyperstimulation is to optimize the number of oocytes available for retrieval while keeping ovarian response within safe limits. • Essentially OHSS can be thought of as the loss of control over the intended therapeutic hyperstimulation of the ovaries
In Vitro Fertilization Steps occur over approx 2 weeks = 1 IVF cycle • STEP 1. • Stimulate ovaries with fertility meds (Clomiphene, FSH, hCG + GnRH analog) and induce ovulatory cascade (hCG, LH) when follicles deemed ‘mature’. • STEP 2. • Aspirate multiple oocytes from the stimulated follicles • STEP 3. • Fertilize the oocytes “in vitro” • STEP 4. • Transfer fertilized oocytes (embryo) into the uterine cavity and support through luteal phase (progesterone)
Pathophysiology of OHSS Multiple follicles recruited into functional cohort • Sustained development of large follicles until… • Luteinization/ovulation • Excessive production of VEGF by the follicles • Perifollicular neovascularization • Leakage of follicular fluid/blood/VEGF into peritoneum and subsequent absorption into systemic circulation • Impairment of blood vessels systemically leads to a “vascular leak syndrome” • Worsening third space accumulation systemically leading to ARF, hypovolemic shock, etc.
Pathophysiology • Vascular Endothelial Growth Factor: • Glycoprotein • Promotes angiogenesis • Increases capillary permeability • VEGF levels correlate with both the presence and severity of OHSS (Abramov et al. 1997; McClure et al 1994).
Natural History For the majority of patients OHSS is a self-limiting illness. • After several days, pts begin to mobilize third spaced fluid, reversing hemoconcentration. Natural vigorous diuresis ensues which is the hallmark of the resolution of the illness. • Resolution of symptoms 14-21 days from onset of symptoms. • Onset of resolution when the cysts become smaller on two consecutive ultrasound examinations and symptoms start to recede (though not actually done in practice).
RED FLAGS On the contrary, the following suggest a worsening course of illness: • continuous weight gain (up to 2 lbs/day) • increasing severity of existing symptoms • appearance of new symptoms (N/V/D, dyspnea, etc.) • early presentation • pregnancy confirmed
Epidemiology • Variable incidence reported due to differing classification schemes • 1-3% of all US births are secondary to Assisted Reproductive Technologies (Paulson 2009) • Mild OHSS occurs in approx 20% to 33% of IVF cycles. • Moderate OHSS in approx 6% of IVF cycles. • Severe forms in approx 2% of IVF cycles. (Delvigne et al. 2002) • In CALGARY: Severe OHSS ranges from 1-3% of IVF cycles; approximately 1000 egg retrievals/year = 10-30 pts / year.
Risk Factors Delvigne A, and Rozenberg S. 2002 • Age < 35 • Low BMI • PCOS • Rapidly increased estradiol levels during ovarian stimulation • Prior OHSS • Increased # of developing follicles & oocytes (>15 = + risk; >25 = +++ risk) • Use of hCG for ovulation + luteal support • Pregnancy (95% of patients who get really sick in Calgary; also prolongs the course)
Vaginal Examination = Dangerous? “Abdominal and pelvic examinations are contraindicated due to extremely fragile ovaries that are at high risk of rupture or hemorrhage” (Tintinalli, 2004). Recurring theme in the literature is the suggestion to avoid vaginal exams in OHSS patients (Budev et al. 2005; Rutkowski et al. 1999; Dourron et al. 1996; Golan et al. 1995).
Searching under OVID, Medline, Pubmed • Using a combination of search terms: • “examination” “pelvic examination” “vaginal examination” “causing” “cyst rupture” “ovarian hyperstimulation syndrome” • Did not find any case report in which cyst rupture had occurred due to examination
Regardless, what will the vaginal exam add? • We know the ovaries will be enlarged. • Vaginal U/S is okay • Gentle abdominal exam is okay • Rare for ovaries to rupture, they are more likely to tort
Prevention of OHSS • It is the immature follicles that are responsible for OHSS • If large number of immature follicles they will “coast” by holding FSH in hopes of degenerating immature follicles prior to admin of hCG • Use lower doses of hCG on patients at risk or simply cancelling the cycle (no hCG = no OHSS) • Aspiration of follicles at 35 hours post administration of the hCG (by reducing the mass of luteinized granulosa cells) • Not transferring the embryo to the uterus
Workup in the ED • Baseline labs: • CBC, lytes, BUN, Creatinine • Albumin • PTT/INR • Liver Enzymes • Serum beta-hCG (can get false positive up to 10 days post embryo transfer) • No utility to estradiol • VEGF correlates with severity but cannot get level here.
Workup in the ED • FAST exam • +/-ECG • +/- CXR if examination suggestive of pleural effusion/pneumonia etc. • Formal Ultrasound (increased risk of heterotopic pregnancy)
Treatment of OHSS • Only multiple case reports in the Emergency Literature. • No RCTs. • Most studies in Obstetrics literature have focused on prevention. • To date, there is no treatment that will shorten the course of illness.
Treatment Of OHSS • Most cases are managed as outpatients • ASK: can they keep themselves hydrated orally? Will they be able to cope at home? • Often will only need simple IV rehydration, analgesics and anti-emetics in the ED prior to discharge • Local IVF clinic is open 7 days/week • IV hydration and ultrasound guided paracentesis performed right in the clinic
Treatment of OHSS • Depends on the Grade/Severity • Grade I: • Analgesics, anti-emetics, IV hydration if needed • Treatment is supportive with close follow up by IVF clinic (as early on, unable to predict who is en route to developing severe OHSS) • Ultrasound if concerned. • Daily weight, daily abdominal girth, record fluid intake (for all grades).
ED Treatment of OHSS • Grade II: • ABCs • Analgesics, anti-emetics • IV fluids as needed • Correction of lyte abnormalities, r/o ARF etc. • Ultrasound • Paracentesis if confirmed symptomatic ascites • +/- DVT prophylaxis
ED Treatment of OHSS • Grade III: • ABCs • Treatment is focused on restoration of blood volume, correction of electrolyte imbalances • Assessing for and treating any secondary complications (pleural effusions, pericardial effusions etc.)
ED Treatment of OHSS • Grade III: • IV NS boluses • Foley (Ins + Outs) • +/- albumin • +/- central line • Paracentesis • Thoracentesis • Heparinization for VTE prophylaxis • Daily labs
ED Treatment of OHSS • Call the IVF MD on call • More than happy to help triage the patient and establish a disposition • Recall, still need to r/o Torsion, Ectopic etc. • Consider sepsis especially if FEBRILE. (RARE but possible to have intra-abdominal sepsis in pts having undergone egg retrieval).
Treatment of Complications Ovarian enlargement: • Grade III ovarian cysts are extremely large and brittle • Recommended surgery avoided unless torsion or rupture w/ hemorrhage • In the 50s, attempts at cystectomy would inevitably lead to oophorectomy
Treatment of Complications Ascites: • Initial weight gain of >3kg following hCG admin is a warning that OHSS is developing • Women can gain as much as 20kg over 5 days!!
Treatment of Complications Ascites: Leads to multitude of complications • Pain (can be severe) • Hypovolemia • Decrease diaphragmatic excursion • Compression of Renal Vessels • (essentially abdominal compartment syndrome)
Treatment of Complications • Ascites: • Paracentesis has been shown in several studies to reduce symptoms of pain and dyspnea, and improve renal function (Levin et al. 2002; Borenstein et al. 1989; Thaler et al. 1981)
Paracentesis • Effect of paracentesis of ascitic fluids on urinary output and blood indices in patients with severe ovarian hyperstimulation syndrome. • Ishai Levin, M.D., B. Pharm., Benny Almog, M.D., Amiram Avni, M.D., Amiram Baram, M.D., Joseph B. Lessing, M.D., and Ronni Gamzu, M.D., Ph. D. • Fertility and Sterility 2002 77: 986
Paracentesis • Retrospective Interventional Study • N = 30 consecutive pts with ‘severe’ OHSS • Severe = massive ascites, WBC > 15,000, Hct >45%, oliguria • Intervention: abdominal paracentesis • Outcome measures: Urinary output/24 hrs; BUN levels
Paracentesis • Mean volume of 3,653 +/- 310 mL • Volume of colloid/crystalloid solutions used day before and day after procedure was not statistically significant • 24 hour urinary output was significantly increased following paracentesis; 1,889 +/- 128 mL to 2,660 +/- 225 mL (P=.002). • BUN also significantly decreased from 8.9 +/- 0.6 mg/dL to 7.8 +/- 0.5 mg/dL (P=<.01)