High Volume Plasma Exchange in Acute Liver Failure: A Brief Review

Matthew D Rockstrom, MD¹

Jonathan D Rice, MD^1,2

Tomio Tran, MD³

Anna Neumeier, MD^1,4

¹Department of Medicine, University of Colorado School of Medicine, Aurora, CO USA

²Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO USA

³Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA USA

⁴Department of Medicine, Division of Pulmonary Sciences and Critical Care, Denver Health and Hospital Authority, Denver, CO USA

Abstract

Acute liver failure (ALF) is characterized by acute liver injury, coagulopathy, and altered mental status. Acetaminophen overdose contributes to almost half the cases of ALF in the United States. In the era of liver transplantation, mortality associated with this condition has improved dramatically. However, many patients are not transplant candidates including many who present with overt suicide attempt from acetaminophen overdose. High volume plasma exchange (HVP) is a novel application of plasma exchange. Prior research has shown that HVP can correct the pathophysiologic derangements underlying ALF. A randomized control trial demonstrated improved transplant-free survival when HVP was added to standard medical therapy. In this case, we examine a patient who presented to the intensive care unit with ALF caused by intentional acetaminophen overdose. She was denied transplant due to overt suicide attempt, was treated with HVP, and made a rapid recovery, eventually discharged to inpatient psychiatry and then home.

Abbreviations: ALF: acute liver failure: CVVH: continuous veno-venous hemodialysis; DAMPs: damage associated molecular patterns; FFP: fresh frozen plasma; HVP: high volume plasma exchange; MODS: multisystem organ dysfunction; NAC: N-acetyl cysteine; NNT: Number needed to treat; SIRS: systemic inflammatory response syndrome; SMT: standard medical therapy; TNF-α: tumor necrosis factor alpha

Introduction

Acute liver failure (ALF) is a rare, life-threatening condition. Although survival has improved in the transplant era, mortality remains high without transplantation. Here we discuss a novel therapy for ALF patients which may provide improved transplant-free mortality.

Case Report

A 21-year-old woman arrived by ambulance, found to be obtunded and hypotensive in the field, with an empty bottle of acetaminophen and a suicide note. She had a history of depression, infrequent alcohol and marijuana use, and was otherwise healthy.

Upon presentation, she was afebrile (temperature 36.5°C), tachycardic (heart rate 155 beats-per-minute) and hypotensive requiring norepinephrine of 0.1 μg/kg/min to maintain mean arterial blood pressure above 65.  Due to grade IV encephalopathy, she was intubated.  Admission lab work is shown below (Table 1). Viral hepatitis and HIV serologies were negative and ultrasound demonstrated patent vasculature and normal liver parenchyma.

Table 1: Lab work on admission, hospital day 2, and following high-volume plasma exchange therapy.

BUN: blood urea nitrogen, AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; APAP: N-acetyl-para-aminophenol

N-acetyl cysteine (NAC) was administered and transplant evaluation was obtained. Despite meeting King’s College Criterion for transplantation, she was declined due to presentation for suicide attempt. She was managed supportively with vasopressors, continuous veno-venous hemodialysis (CVVH), and high-volume plasma exchange (HVP) at a rate of 8 liters of fresh frozen plasma (FFP) daily, receiving 24 liters total. After initiation of HVP, vasopressors were immediately weaned. The following day, her encephalopathy improved, and she followed simple commands. CVVH was discontinued on hospital day 4. She was extubated on hospital day 6 and was eventually discharged home.

Clinical Discussion

ALF is a life-threatening syndrome characterized by acute liver injury, encephalopathy, and coagulopathy. In the United States, the most common etiology is acetaminophen overdose, accounting for ~46% of cases (1). Standard medical therapy (SMT) is supportive, treating the underlying etiology and mitigating manifestations of multisystem organ dysfunction (MODS). The advent of transplantation dramatically improved the mortality associated with ALF but the benefit of transplant must be balanced with high-risk surgery, lifelong immunosuppression, and organ scarcity (2). Given these risks, patients undergo evaluation including psychologic evaluation which commonly excludes patients presenting with intentional acetaminophen overdose. Without transplantation, mortality for these patients remains high.

The pathophysiology of ALF is not entirely understood but is largely driven by hepatic necrosis leading to hepatic metabolic dysfunction and release of intracellular contents. Intracellular damage associated molecular pattern (DAMPs) and Kupffer cell activation trigger the release of pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α), which result in systemic inflammatory response syndrome (SIRS) and vasodilation (3,4). Subsequent hepatic metabolic dysfunction is manifested by hyperbilirubinemia, hyperammonemia, coagulopathy, and hypoglycemia.

High volume plasma exchange (HVP) has shown promise as a new modality of treatment for patients with ALF. A new implementation of plasma-exchange therapy, patient plasma is exchanged with donor FFP. In one prospective, randomized control trial by Larsen et al, 15% of ideal body weight of FFP was exchanged daily for three days in addition to SMT. HVP plus SMT improved survival to discharge when compared to SMT alone (58.7 % versus 47.8%, respectively; number needed to treat (NNT) 9.2) (5). HVP plus SMT has been shown to reverse clinical parameters associated with ALF including INR, bilirubin, vasopressor requirements, reliance on renal replacement, hepatic encephalopathy (5-7). HVP was also shown to significantly attenuate DAMPs, including IL-6 and TNF-α, indicating an ability to attenuate the biochemical nidus of MODS (6,7). A systematic review of HVP found evidence of mortality benefit in HVP for both ALF and acute on chronic liver failure, though Larsen et al remains the only randomized prospective trial. Subsequently, HVP has become a level I, grade 1 recommendation in European guidelines for ALF (6).

There are limitations associated with HVP including utilization of FFP, concerns for precipitation volume overload, and worsening cerebral edema. Additionally, there is no clear optimal regimen for dose and duration of HVP. In a recent randomized control trial by Maiwall et al, standard volume plasma exchange was shown to improve transplant free survival using only 1.5 to 2 times calculated patient plasma volume (4).

Conclusion

In this case, a 21-year-old patient presented with ALF following acetaminophen overdose. Despite qualifying for transplantation, she was denied due to presentation for suicide attempt. She was treated with standard medical therapy and HVP and had rapid improvement in hemodynamics and mentation. While it is impossible to quantify the degree to which HVP contributed to her recovery, her clinical improvement was dramatic despite presentation with severe disease. HVP has been shown to reverse the pathophysiologic hallmarks of ALF, improve transplant-free mortality, and is now a level I recommendation according to European guidelines. More trials are necessary to determine the optimal dose and duration of this life saving modality.

References

1. Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008 May;28(2):142-52. [CrossRef] [PubMed]
2. Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology. 2008 Apr;47(4):1401-15. [CrossRef] [PubMed]
3. Chung RT, Stravitz RT, Fontana RJ, Schiodt FV, Mehal WZ, Reddy KR, Lee WM. Pathogenesis of liver injury in acute liver failure. Gastroenterology. 2012 Sep;143(3):e1-e7. [CrossRef] [PubMed]
4. Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2021 Jan 29:S1542-3565(21)00086-0. [CrossRef] [PubMed]
5. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016 Jan;64(1):69-78. [CrossRef] [PubMed]
6. Tan EX, Wang MX, Pang J, Lee GH. Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review. World J Gastroenterol. 2020 Jan 14;26(2):219-245. [CrossRef] [PubMed]
7. Larsen FS, Ejlersen E, Hansen BA, Mogensen T, Tygstrup N, Secher NH. Systemic vascular resistance during high-volume plasmapheresis in patients with fulminant hepatic failure: relationship with oxygen consumption. Eur J Gastroenterol Hepatol. 1995 Sep;7(9):887-92. [PubMed]

Cite as: Rockstrom MD, Rice JD, Tran T, Neumeier A. High Volume Plasma Exchange in Acute Liver Failure: A Brief Review. Southwest J Pulm Crit Care. 2021;22(5):102-5. doi: https://doi.org/10.13175/swjpcc009-21 PDF

June 2018 Critical Care Case of the Month

Stephanie Fountain, MD

Banner University Medical Center Phoenix

Phoenix, AZ USA

History of Present Illness

A 60-year-old native American man presented to an outside hospital with several days of nausea, vomiting and diarrhea. The patient felt weak and called emergency medical services and was taken to the emergency department.

Past Medical History

He has a history of end stage renal disease secondary to diabetes mellitus and hypertension. He received a cadaveric renal transplant in 2008 which was complicated with acute on chronic rejection and symptomatic hyponatremia.

Physical Examination

His pulse was recorded as 28 beats/min and his blood pressure was 90/60.

Which of the following should be done? (Click on the correct answer to be directed to the second of six pages)

1. Administer atropine
2. Begin transcutaneous pacing
3. Obtain a drug history
4. 1 and 3
5. All of the above 

Cite as: Fountain S. June 2018 critical care case of the month. Southwest J Pulm Crit Care. 2018;16(6):304-10. doi: http://doi.org/10.13175/swjpcc065-18 PDF 

October 2017 Critical Care Case of the Month

Margaret Ragland, MD¹

Carolyn H. Welsh, MD^1,2

Pulmonary Sciences and Critical Care Medicine

¹University of Colorado Anschutz Medical Campus and ²VA Eastern Colorado Health Care System

Denver, Colorado USA

History of Present Illness

A 42-year-old man with a history of intravenous heroin abuse and chronic hepatitis C infection presents to the emergency department (ED) with recurrent abdominal pain. The pain was dull, epigastric, and did not radiate. The pain worsened after eating, but the timing after eating that it worsened was inconsistent. He had nausea but no vomiting. His bowel movements were normal without constipation, diarrhea, or melena.   

He had presented to another ED multiple times with this same pain over the past six weeks. He does not know what the work-ups revealed, but was discharged from the emergency department each time. He received supportive care including fluids and analgesics, but the pain would always recur a few hours after returning home.

He went to a third ED a few weeks ago with bilateral testicular pain after which he was discharged home with acetaminophen for pain.

Past Medical History, Family History, and Social History

His past medical history is notable for bipolar disorder. He takes no prescribed medications and does not know his family’s medical history. He is a current every day smoker, has no history of heavy alcohol use, and uses intravenous heroin but no other recreational drugs.

Current Medications

Acetaminophen a few times a day for abdominal pain.

Review of Systems

He notes subjective fevers, poor appetite, and an 8 pound unintentional weight loss over the past six weeks.

Physical Exam

Vital signs are notable for hypertension to 158/91 mm Hg. Other vitals are within normal limits.

On exam, he is an ill appearing middle aged man who appears very uncomfortable. His abdomen is nondistended. He has normal bowel sounds and epigastric tenderness with a tender, smooth liver edge palpable just under the costal margin. He has decreased sensation to light touch in his toes with no skin changes. Toes are warm with capillary refill less than two seconds.

Laboratory Evaluation

CBC reveals a leukocytosis to 23,600 cells/mcL with 80% neutrophils; eosinophils are normal. Hemoglobin and platelet counts are normal. Sodium is 128 mmol/L with a bicarbonate of 30 mmol/L and creatinine of 0.64 mmol/L. AST 155 U/L, ALT 137 U/L, with a total bilirubin 1.1 mmol/L. Albumin is 1.8 g/L. INR is 1.9. Urinalysis showed 1+ protein.

What additional laboratory evaluation is indicated at this time? (Click on the correct answer to proceed to the second of six pages)

1. Acetaminophen level
2. Hepatitis B viral (HBV) serologies
3. Lipase
4. 1 and 3
5. All of the above

Cite as: Ragland M, Welsh CH. October 2017 critical care case of the month. Southwest J Pulm Crit Care. 2017;15(4):131-7. doi: https://doi.org/10.13175/swjpcc113-17 PDF 

December 2014 Critical Care Case of the Month: Weak for Weeks

Bhupinder Natt MD¹

Shadi Koleilat MD²

Janet Campion MD¹

¹Division of Pulmonary, Allergy, Critical care and Sleep Medicine

²Department of Neurology

University of Arizona Medical Center

Tucson, AZ

History of Present Illness

A 65 year old woman presents with weakness involving both upper and lower extremities that is intermittent over the last 3 months, but in the last 2 weeks she has also noticed increasing neck weakness, droopy eyelids and increased drooling. Prior to this she was able to walk without difficulty and ride a recumbent bike for 20 minutes, but now is having difficulty walking on her own. She denies fevers, weight loss, shortness of breath, chest pain, palpitations, LE edema, joint pain, rash, any recent or current GI/GU symptoms and no new medications.

Past Medical History, Social History, and Family History

The patient has a past history of hypertension, hyperlipidemia, diabetes mellitus Type II, GERD, obstructive sleep apnea (compliant with BiPAP), atrial fibrillation and hypothyroidism. She has a 40 pack-year history of tobacco use. Family history is noncontributory.

Medications

• Dabigatran 75mg BID
• Esomeprazole 20 mg BID
• Furosemide 30 mg BID
• Insulin glargine 50 Units BID and Lispro per sliding scale
• Levothyroxine 88 mcg per day
• Losartan 50 mg QD,
• Pregabalin 75 mg BID
• Rosuvastatin 40 mg per day

Physical Examination

Vital signs: Afebrile. Pulse 86, respiratory rate 20, PaO2 92% on room air

General: Awake, fully oriented, dysarthric speech.

HEENT: Non-icteric, ears, nares, oropharynx unremarkable; there is no neck LAD, elevated JVP or thyromegaly.

Respiratory: Normal breath sounds, no wheeze or rhonchi.

CVS: Irregularly irregular rhythm, no murmurs. Peripheral vascular exam normal.

Abdomen: Obese, soft, non-tender with normal bowel sounds. No organomegaly appreciable.

Extremities: Trace pedal edema, normal muscle bulk and tone.

CN: Ptosis bilaterally, no nystagmus, reactive pupils, extra-ocular muscles intact, sensation intact, weak cheek puff, symmetric palate excursion, normal tongue protrusion.

Motor: Neck flexion and extension 4-/5, bilateral pronator drift, no focal lower extremity weakness, no muscle atrophy, no tremors or fasciculations.

Sensation: Intact to light touch hands and feet.

Reflexes: 2+ and symmetric throughout.

Gait: Wide-based and slow, can only walk short distances before experiencing bilateral leg weakness.

Laboratory: Normal electrolytes, complete blood count, and liver function tests. Creatinine mildly elevated at 2.1 mg/dL.

EKG

Atrial Fibrillation.

What is the most likely diagnosis? (Click on the correct answer to proceed to the next panel)

1. Guillain-Barré syndrome (GBS)
2. Hypothyroidism
3. Lambert-Eaton myasthenic  syndrome (LEMS)
4. Motor neuron disease (ALS)
5. Myasthenia gravis crisis

Reference as: Natt B, Koleilat S, Campion J. December 2014 critical care case of the month: weak for weeks. Southwest J Pulm Crit Care. 2014;9(6):302-8. doi: http://dx.doi.org/10.13175/swjpcc141-14 PDF

January 2013 Critical Care Case of the Month: Different Name, Same Disease...or Is It?

Nathaniel Reyes MD (NReyes@deptofmed.arizona.edu)

Jarrod Mosier MD (JMosier@aemrc.arizona.edu)

University of Arizona- AHSC/Pulmonary

1501 N Campbell Ave.

Tucson, AZ 85724-5030

History of Present Illness

A 50-year-old female who presented with 2-weeks of worsening cough and shortness of breath.  She presented to another hospital 2-weeks prior to presentation complaining of cough productive of yellow sputum and was diagnosed with bronchitis and discharged home with a normal chest x-ray.  Her symptoms persisted and one day prior to admission she experienced one episode of hemoptysis which prompted her presentation to our emergency department.  She denied fever, chills, night sweats, and complained only of dyspnea on exertion.

PMH/SH

Granulomatous polyangitis (GPA) was diagnosed by renal biopsy in 2004. She subsequent developed end-stage renal disease and has been receiving peritoneal dialysis.  She has never required immunosuppresive therapy. There is no history of tobacco use.  She has lived in Arizona for many years.  She is retired but previously worked as an information technology manager. 

Physical Exam

Vital signs were normal except for an O2 saturation of 91% on room air.  Physical exam was significant only for pale sclerae and bilateral dry crackles.

Laboratory Data

Hemoglobin: 5.4 g/dL; Hematocrit: 17%.  BUN: 43 mg/dL; creatinine: 10.7 mg/dL.   

ABG: PaO2 75; PaCO2 39; pH 7.43 on 2L O2.

P-ANCA: Positive

Myeloperoxidase antibody titer: 83 U/mL

C-ANCA/proteinase 3 antibody titer/Anti-GBM antibodies: negative.

Imaging

Chest X-ray showed diffuse areas of consolidation (Figure 1).

Figure 1. PA Chest X-ray

Which of the following is not appropriate in her management?

1. Admit to the intensive care unit.
2. Computerized tomography of the chest.
3. High dose corticosteroids
4. Bronchoscopy
5. Coccidioidomycosis serology

The authors report no conflict of interest.

Reference as: Reyes N, Mosier J. Critical care case of the month: different name, same disease...or is it? Southwest J Pulm Crit Care 2013;6(1):5-11. PDF