HELLP Syndrome

This CE activity is approved by EMS World Magazine, an organization accredited by the Continuing Education Coordinating Board for Emergency Medical Services (CECBEMS) for 1 CEU. To take the CE test that accompanies this article, go to www.rapidce.com to take the test and immediately receive your CE credit. Questions? E-mail editor@EMSWorld.com.

Objectives

• Define HELLP syndrome.
• Discuss the pathophysiology of HELLP syndrome.
• Differentiate HELLP syndrome from the other liver disorders of pregnancy.
• Identify the signs and symptoms of HELLP syndrome.
• Discuss prehospital management of the patient with HELLP syndrome.

A 33-year-old female presents supine in bed approximately 24 hours after giving birth. She responds to painful stimuli by opening her eyes, and she is noticeably disoriented and lethargic when asked questions. Her only complaint is of abdominal pain. A primary exam reveals a patent airway, adequate though rapid breathing, and a strong and rapid radial pulse. Her skin is cool, pale and dry.

The patient’s husband and a doula are on scene. They report the patient gave birth at home yesterday with the doula’s help. This was the patient’s fifth pregnancy and fifth vaginal birth. The pregnancy was complicated by the development of gestational hypertension in the third trimester; it was treated with labetalol. The patient checked her blood pressure daily during the remainder of her pregnancy, and both the doula and husband agree she experienced no further episodes of hypertension. The patient started having contractions yesterday around 0700 hours and had an uncomplicated childbirth at 1100. The intact placenta delivered without complications, and some mild hemorrhage secondary to a minor external vaginal tear stopped on its own with the application of direct pressure. The neonate was vigorous at birth and has been in good health since.

The husband says the patient initially complained of an acute onset of upper right quadrant abdominal pain that woke her at about 0600. She described the pain as sharp, nonradiating and reproducible with palpation. She also complained of nausea and vomited twice. At no time did she experience syncope or complain of chest pain or pressure or discomfort, difficulty breathing, dizziness, weakness, back pain or headache. The husband noticed she became increasingly drowsy during the next few hours but thought she was tired from the delivery. He used an automated blood pressure cuff previously purchased from a pharmacy to take the patient’s blood pressure, which was 154/100 mmHg. He called the doula at approximately 1000 hours. The doula also noted the patient’s vaginal tear had started lightly bleeding again. That’s when they called EMS.

The husband reports the patient has no other significant medical history, takes no medications except the labetalol and has no allergies. Your clinical exam finds pupils that are 3–4 mm, equal and reactive to light bilaterally; no JVD; and mild bilateral rales (crackles). She winces and opens her eyes with palpation of her upper right abdominal quadrant. Her uterus is palpable, but there’s no abdominal mass or rigidity present. She has not been incontinent of feces or urine, and you note capillary bleeding from a small external vaginal tear. The husband says the tear occurred during the childbirth. The patient is drowsy but follows commands and moves all her extremities with no apparent motor deficits. Distal circulation and sensation are intact and appear to be normal on all extremities. She appears puffy, with +3 pitting edema noted to all four extremities.

The patient’s vital signs are as follows: HR, 90/min. and regular; BP, 188/124 mmHg; RR, 24/min. with adequate tidal volume; SpO₂, 90% on room air; and EtCO₂, 28 mmHg with a normal waveform. The lead II ECG reveals a normal sinus rhythm, and the 12-lead ECG is nondiagnostic for any acute changes.

What are you initial concerns with this patient? What does your differential diagnosis include? What is your management plan?

HELLP Syndrome

HELLP is an acronym created to describe a syndrome characterized by hemolysis (rupture or destruction of red blood cells), elevated liver enzymes and low platelet count.¹ It is a not-uncommon life-threatening complication of pregnancy thought to be a variant or complication of preeclampsia. Both of these conditions usually occur during the third trimester or soon after childbirth. HELLP is a multisystem disease that results in generalized vasospasm, microthrombi formation and coagulation defects. Untreated, HELLP syndrome can lead to maternal end-organ failure as well as fetal demise.

HELLP syndrome occurs in approximately 0.1%–0.8% of all pregnancies and in 10%–20% of women with severe preeclampsia or eclampsia.² Up to 30% of women who develop HELLP syndrome do so after childbirth, typically within 48 hours.

A previous history of preeclampsia, eclampsia or HELLP syndrome is a risk factor for HELLP, as is a family history of it. One study found about 7% of women who experienced the syndrome developed HELLP in a subsequent pregnancy, 18% developed preeclampsia, and 18% developed gestational hypertension.³ Half or more of pregnant females affected by the syndrome have had multiple childbirths.

The pathophysiology of HELLP syndrome is poorly understood. What is known is that the activation of the coagulation cascade, secondary to influence from the placenta, plays a major role.

When activated by thrombin, fibrinogen polymerizes into strands of fibrin, which form meshlike barriers in small blood vessels such as the arterioles, capillaries and venules. These fibrin barriers act like strainers through which red blood cells are forced, resulting in their destruction. This results in the microangiopathic (small blood vessel) hemolytic anemia characteristic of the syndrome. Platelets adhere to the fibrin structures, particularly in the liver, leading to low platelet counts. Clot formation in the hepatic vasculature leads to decreased hepatic perfusion and subsequent ischemia and, if uncorrected, infarction and liver failure. Liver dysfunction and failure result in the elevated liver enzymes characteristic of HELLP syndrome. Uncorrected, liver failure will lead to fetal death if the patient has not yet delivered and maternal death unless the problem is corrected or a liver transplant performed.

Additional complications associated with HELLP include disseminated intravascular coagulation (DIC), abruptio placentae, acute renal failure, pulmonary edema, liver infarction and liver hematoma or rupture with hemorrhage.⁵

Other liver disorders unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia and acute fatty liver of pregnancy (see sidebar).⁶ These disorders have characteristic clinical features and timing of onset and may also progress to severe liver dysfunction.⁷

Table 1: Liver Disorders of Pregnancy, Timing and Clinical Findings

Disorder                                                 Timing                                        Clinical Findings

Hyperemesis gravidarum                         First trimester                              Nausea, vomiting, weight loss

Intrahepatic cholestasis of pregnancy        Second and third trimesters          Pruritis (itching; worse at night), jaundice, fatigue, anorexia, abdominal pain, steatorrhea

HELLP syndrome and preeclampsia         Third trimester                             Abdominal pain, nausea, vomiting, malaise, headache, visual changes, edema, jaundice

Acute fatty liver of pregnancy                  Third trimester                             Nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice

Signs and Symptoms

The signs and symptoms of HELLP typically appear in the third trimester of pregnancy, between 28–36 weeks’ gestation. That said, second-trimester or even postpartum onset of HELLP is not uncommon. In one study, 70% of all cases of HELLP occurred peripartum (close to the end of pregnancy), and 30% occurred postpartum.⁵

Symptoms characteristic of HELLP include epigastric or upper right quadrant abdominal pain (the most common symptom), malaise, nausea and vomiting.^8,9 These symptoms make it easy to mistake HELLP syndrome for other etiologies of abdominal pain, including cholecystitis, pancreatitis, pyelonephritis and gastroenteritis. Any pregnant patient beyond 20 weeks’ gestation or postpartum who presents to the ED complaining of abdominal pain should be evaluated for HELLP syndrome.¹⁰ Less-common symptoms include headache, visual changes, edema with significant weight gain, and jaundice.²

Hypertension (blood pressure more than 140/90 mmHg) and proteinuria (protein in the urine) occur in about 85% of cases but, unlike preeclampsia, need not be present in patients with severe HELLP syndrome.

When HELLP is suspected based on clinical findings, the diagnosis is confirmed based on the presence of all the laboratory abnormalities that make up its acronym: hemolysis, elevated liver enzymes and low platelet count. A typical workup in an emergency department would include an ultrasound of the right upper quadrant to rule out cholecystitis, of the kidney to rule out hydronephrosis, and a fetal examination. A urinalysis would help rule out urinary tract infection and kidney stones. The laboratory workup would include at a minimum:¹¹

• Complete blood count with platelet count;
• Peripheral blood smear;
• Chemistry profile;
• Aspartate transaminase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase and lipase;
• Coagulation profile and fibrinogen.

Management

Before discussing prehospital management of the patient with HELLP syndrome, it may be useful to understand the typical inpatient and outpatient management a woman with the syndrome will receive. After a diagnosis of HELLP syndrome is made, the initial steps in patient management include stabilizing the mother if necessary, assessing the condition of the fetus and deciding if immediate delivery is required.²

HELLP syndrome with maternal hypertension is controlled with medications such as labetalol, nifedipine and hydralazine in both the outpatient and inpatient settings. In patients admitted to labor and delivery units between 24–32 weeks’ gestation, magnesium sulfate is administered to prevent maternal seizures, though its use  as seizure prophylaxis is controversial . In addition to seizure prophylaxis, magnesium sulfate offers neuroprotective properties in the developing fetus and neonate and can decrease the incidence and severity of cerebral palsy in preterm infants.¹⁰

In a healthy individual platelet levels are considered normal between 150,000–400,000 mm³. Platelet replacement is indicated when a patient with HELLP syndrome has platelets below 20,000 mm³ prior to a vaginal delivery or below 50,000 mm³ prior to a cesarean section. This practice is controversial; the problem is that the administered platelets will be destroyed in the same fashion as the patient’s own platelets were. Critical care transport teams should be sure to determine the patient’s baseline and most recent platelet counts and consider early platelet administration.

The final treatment for HELLP syndrome is delivery of the fetus, and it is considered the only effective treatment.² Immediate delivery is indicated when the pregnancy is greater than 34 weeks’ gestation, there are signs of fetal stress, or with severe maternal complications such as DIC, multiorgan dysfunction, liver failure or hemorrhage, renal failure, pulmonary edema or abruptio placentae.

In the prehospital setting, initial management of the patient with HELLP syndrome centers on airway, breathing and circulation. Place patients with an altered level of consciousness in a position that facilitates an open airway, most commonly supine or semi-Fowler’s. When positioning a pregnant female supine, take care to prevent the gravid uterus from compressing the vena cava, preventing blood return to the heart and creating supine hypotensive syndrome. Prevent this by tilting the patient onto her left side by padding under the right hip.

Patients experiencing pulmonary edema may be hypoxic, requiring the administration of supplemental oxygen with a delivery device (nasal cannula, nonrebreather mask) with a flow rate adequate to improve SpO₂ to greater than 94%. Continuous positive airway pressure (CPAP) can be considered in patients with pulmonary edema who have no contraindications for use of the device. Patients in respiratory failure who are breathing inadequately should be ventilated with a bag-mask device and receive endotracheal intubation if they cannot be adequately ventilated via a BLS airway. Bag-mask ventilation of a pregnant female can be made more difficult by the need for greater airway pressures, as the gravid uterus prevents normal, unobstructed diaphragm movement. In addition, obstructed diaphragm movement also results in a decrease in tidal volume, requiring smaller tidal volumes and a higher respiratory rate to achieve an adequate minute volume.

Patients who present in the field with acute, severe hypertension secondary to HELLP syndrome may be candidates for treatment with antihypertensives depending on factors such as clinical presentation, the availability of antihypertensive agents and transport times. While there is no standard, various sources suggest initiating antihypertensive medications in patients with systolic blood pressures greater than 160 or 170 mmHg and signs of end-organ failure such as headache, visual disturbances, AMS, chest discomfort or AMI and pulmonary edema.¹³

Regarding specific antihypertensive agents, a 2013 Cochrane review of drugs for treatment of high blood pressure in pregnancy concluded that the “choice of antihypertensive should depend on the clinician’s experience and familiarity with a particular drug, with consideration of its adverse effects and patient preferences.” It also said nimodipine, diazoxide and ketanserin were probably best avoided.¹⁴ That said, the average paramedic will most likely have one antihypertensive drug available in their formulary, and will have limited experience and familiarity with using it in pregnant females with hypertension. Accordingly, medical control should be consulted prior to the administration of any antihypertensive medication in a pregnant or postpartum female.

Options for specific antihypertensives in the prehospital environment include labetalol, hydralazine and magnesium sulfate. Hydralazine is a smooth muscle relaxant and often considered the drug of choice for initial blood pressure care because it has no effect on a patient’s heart rate or respiratory rate. Typically hydralazine is administered IV in 10–20 mg doses over five minutes and can be repeated once. Magnesium sulfate is another good option. However, it requires an initial 2–6-gram IV bolus administered over 20–30 minutes. This requires the use of an IV pump to ensure it’s not delivered too fast. A rapid magnesium infusion is likely to cause hypotension as well as depression of the patient’s respirations and mental state, and can lead to flaccid paralysis and death.

The onset of seizures in the patient with suspected HELLP syndrome should be managed with 2 grams IV magnesium sulfate administered over 5–10 minutes; this has been shown to be more effective than benzodiazepines for prevention of recurrent seizures.^13,15 Magnesium sulfate should not only be used to treat active seizures but with the permission of medical control can also be administered as seizure prophylaxis in patients with HELLP syndrome. The suggested dosing regimens for magnesium sulfate vary, with loading doses ranging from 4–6 grams IV over 30 minutes and maintenance doses from 1–3 grams per hour. A common regimen involves a loading dose of 6 grams IV over 20–30 minutes followed by 2 grams per hour as a continuous infusion.¹³ Recurrent seizures in patients receiving magnesium sulfate prophylaxis can be treated with an additional 2 grams of the drug administered over 5–10 minutes.

Providers administering magnesium sulfate should be familiar with the signs and symptoms of hypermagnesemia. Mild hypermagnesemia can manifest with diminished deep tendon reflexes, headache, lethargy, drowsiness, nausea and flushing. Moderate hypermagnesemia can present with absent deep tendon reflexes, somnolence, ECG changes, bradycardia and hypotension. Severe hypermagnesemia will progress to paralysis, respiratory failure and apnea, heart block and cardiac arrest.

Proper kidney function is important in maintaining appropriate plasma magnesium concentrations, so pay particular attention to patients with renal insufficiency or failure. Patients with mild to moderate kidney disease can be treated with the administration of normal saline and a loop diuretic such as furosemide. Patients with kidney failure will require dialysis. Patients who are severely symptomatic with hypermagnesemia can also be treated with calcium gluconate 10-20 mL of 10% solution IV over 3 minutes, or calcium chloride bolus in the setting of cardiac arrest.

If magnesium sulfate is not available or seizures don’t respond to it, benzodiazepines such as diazepam, midazolam or lorazepam can be administered, preferably IV, though the intramuscular route can be utilized if IV access is unobtainable. A caution, though: All benzodiazepines are considered category D pregnancy drugs. Suggested dosing regimens are as follows, though always follow your protocol and/or consult directly with medical control:

• Diazepam: 5–10 mg IV every 5–10 mins. at a rate of 5 mg/min. or less and a maximum dose of 30 mg.
• Midazolam: 1–2 mg bolus IV at a rate of 2 mg/min. Repeat every five minutes until seizures stop, to a maximum of 2 mg/kg .
• Lorazepam: 4 mg IV at maximum rate of 2 mg/min.

Because of the risk of heart failure and acute myocardial infarction, patients with HELLP syndrome should have a 12-lead ECG performed and their cardiac rhythm monitored.

Liver Disorders of Pregnancy

Hyperemesis gravidarum (HG) is characterized by intractable nausea and vomiting during pregnancy. Nausea and vomiting occur to some degree in 50%–90% of all live births.^16–18 HG occurs in about 0.3%–2% of all live births, with onset typically beginning between the fourth and 10th week of gestation and resolving by the 20th week.^18,19 Uncontrolled persistent vomiting can lead to electrolyte imbalance, weight loss and nutritional deficiency that can require hospitalization.

Intrahepatic cholestasis of pregnancy (ICP) is a rare complication of pregnancy that occurs in the second and third trimesters and has a prevalence between 0.32%–5.6% in the United States.^20,21 Its exact cause is unknown, but cholestasis (slowing or stopping of the flow of bile from the liver and gallbladder) results in an elevation in serum bile concentration. The most common and noticeable clinical manifestation is pruritis, most commonly localized in the palms and soles of the feet.

Preeclampsia is a disorder characterized by hypertension, edema and proteinuria that occurs after 20 weeks’ gestation. It affects about 5%–10% of all pregnant woman and typically occurs late in the third or late second trimester and can also occur postpartum.²² It is thought to occur secondary to abnormalities in placental development that result in widespread vasoconstriction. Severe preeclampsia is characterized by the onset of edema and neurologic symptoms such as headaches and visual disturbances, nausea and vomiting. The onset of grand mal seizures in a woman with preeclampsia indicates eclampsia is present.

Acute fatty liver of pregnancy (AFLP) is a rare but potentially fatal complication of pregnancy that occurs in the third trimester. Occurring in approximately one in every 7,000–15,000 pregnancies, AFLP has a maternal mortality rate of 18% and a fetal mortality rate of 23%.^23,24 The disease is the result of a defect in the gene that controls mitochondrial fatty acid beta-oxidation. When the defect is present, fetal fatty acids accumulate in the mother’s liver, leading to hepatic dysfunction.

Conclusion

The patient is placed on the gurney in a semi-Fowler’s position and administered oxygen via nonrebreather mask at 15 lpm. The crew considers CPAP but rules it out due to the patient’s decreased level of consciousness and mental status. A 16-gauge IV catheter is placed and a 1,000-mL bag of normal saline with a macro drip set attached is administered KVO.

Upon arrival at the ED, the patient is intubated, the 12-lead ECG repeated and a Foley catheter placed. A chest radiograph reveals bilateral pulmonary edema. Laboratory findings include increased serum creatinine and aminotransferases, thrombocytopenia, decreased platelets, increased serum bilirubin and hemolysis. The patient is determined to be suffering from postpartum HELLP syndrome complicated by DIC and is administered fresh frozen plasma, packed red blood cells and platelets. No urine output is collected from the Foley catheter, and the patient is determined to be in renal failure. Dialysis is planned after the administration of Lasix fails to induce diuresis.

The initial presentation of HELLP syndrome can be subtle and mimic the clinical presentation of a benign viral or bacterial infection. HELLP syndrome develops in less than 1% of all pregnancies but in 10%–20% of pregnancies with preeclampsia, and up to 30% of women who develop HELLP syndrome do so after childbirth, typically within 48 hours. Outcomes for mothers with HELLP syndrome who are identified and receive prompt medical attention are usually good, but complications such as liver dysfunction or failure, renal failure, pulmonary edema and abruptio placentae can occur and contribute to maternal, and possibly fetal, morbidity and mortality. EMS providers should remember this potentially fatal complication of pregnancy in patients both pregnant and recently postpartum.

References

1. Stone JH. HELLP syndrome: hemolysis, elevated liver enzymes, and low platelets. JAMA, 1998; 280: 559.

2. Sibai BM. HELLP syndrome. UpToDate.com, www.uptodate.com/contents/hellp-syndrome.

3. van Oostwaard MF, Langenveld J. Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis. Am J Obstet Gynecol, 2015; 215(5): 624e1–624e17.

4. Lachmeijer AM, Arngrímsson R, et al. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet, 2001; 9(10): 758.

5. Sibai BM, Ramadan MK, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol, 1993; 169(4): 1,000.

6. Hepburn IS, Schade RR. Pregnancy-associated liver disorders. Dig Dis Sci, 2008 Sep; 53(9): 2,334–58.

7. Kondrackiene J, Kupcinskas L. Liver diseases unique to pregnancy. Medicina (Kaunas), 2008; 44(5): 337–45.

8. Lee NM, Brady CW. Liver disease in pregnancy. WJG, 2009; 15(8): 897–906.

9. Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol, 1990; 162: 311.

10. Simhan HN, Himes KP. Neuroprotective effects of in utero exposure to magnesium sulfate. UpToDate.com, www.uptodate.com/contents/neuroprotective-effects-of-in-utero-exposure-to-magnesium-sulfate.

11. Echevarria MA, Kuhn GJ. Chapter 104: Emergencies After 20 Weeks of Pregnancy and the Postpartum Period. In: Tintinalli JE, et al., eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7^th ed. New York, NY: McGraw-Hill, 2011.

12. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol, 2004; 103: 981.

13. August P. Management of hypertension in pregnant and postpartum women. UpToDate.com, www.uptodate.com/contents/management-of-hypertension-in-pregnant-and-postpartum-women.

14. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev, 2013; 7: CD001449.

15. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol, 2013; 122(5): 1,122.

16. Lacasse A, Rey E, et al. Nausea and vomiting of pregnancy: what about quality of life? BJOG, 2008; 115(12): 1,484.

17. Lee NM, Saha S. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am, 2011; 40(2): 309.

18. Matthews A, Haas DM, et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev, 2014; 3: CD007575.

19. Bailit JL. Hyperemesis gravidarium: Epidemiologic findings from a large cohort. Am J Obstet Gynecol, 2005; 193(3 Pt 1): 811.

20. Laifer SA, Stiller RJ, et al. Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. J Matern Fetal Med, 2001; 10(2): 131.

21. Lee RH, Goodwin TM, et al. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol, 2006; 26(9): 527.

22. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet, 2005 Feb 26; 365(9,461): 785–99.

23. Mjahed K, Charra B, et al. Acute fatty liver of pregnancy. Arch Gynecol Obstet, 2006; 274(6): 349–53.

24. Castro MA, Fassett MJ, et al. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol, 1999; 181(2): 389–95.

Scott R. Snyder, BS, NREMT-P, is a faculty member at the Public Safety Training Center in the Emergency Care Program at Santa Rosa Junior College, CA. He is also a paramedic with AMR: Sonoma Life Support in Santa Rosa, CA. E-mail scottrsnyder@me.com.

Sean M. Kivlehan, MD, MPH, NREMT-P, is the emergency medicine chief resident at the University of California San Francisco and was a New York City paramedic for 10 years. Contact him at sean.kivlehan@gmail.com.

Kevin T. Collopy, BA, FP-C, CCEMT-P, NREMT-P, WEMT, is an educator, e-learning content developer and author of numerous articles and textbook chapters. He is also the performance improvement coordinator for AirLink/VitaLink in Wilmington, NC, and a lead instructor for Wilderness Medical Associates. Contact him at kcollopy@colgatealumni.org.