Naidu, Ramana K. MD*; Richebe, Philippe MD, PhD†
From the *Department of Anesthesiology and Perioperative Care, Division of Pain Medicine, University of California–San Francisco, San Francisco, California; and †Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, Seattle, Washington.
Accepted for publication April 4, 2013.
Funding: The authors received no funding for this submission.
The authors declare no conflicts of interest.
Address correspondence to Ramana K. Naidu, MD, Department of Anesthesiology and Pain Medicine, University of California–San Francisco, 2255 Post St., San Francisco, CA 94115. Address e-mail to email@example.com.
Acute fatty liver of pregnancy (AFLP) is a rare mitochondrial disease that manifests in the latter stages of gestation with potentially fatal consequences to both mother and child. According to a 2008 United Kingdom cohort study, the incidence of AFLP is 5.0 per 100,000 maternities.1 Although the mortality rates have much decreased since the disease was described in 1940 by Sheehan, the estimated maternal mortality is still approximately 10%.2 AFLP appears in the third trimester of pregnancy and appears to be a result of the build-up of long-chain 3-hydroxyacyl metabolites from inherited maternal defects in long-chain 3-hydroxyacyl coenzyme A dehydrogenase. The metabolites accumulate leaving microvesicular infiltrates or steatosis in hepatocytes that will likely result in severe hepatic dysfunction. There is no medical treatment of AFLP; delivery of the fetus abates the disease.
Postoperative pain control is an important aspect of patient care that is particularly challenging in these patients. Because of the pathology, clinicians are advised not to give opioids which can worsen mental status when metabolism and excretion is impaired. Acetaminophen is relatively contraindicated given the acute and severe hepatic dysfunction. Nonsteroidal anti-inflammatory drugs are also relatively contraindicated because of platelet aggregation inhibition in the postsurgical setting, as well as the likelihood of acute kidney disease often seen with AFLP. In 1 case, inherent coagulopathy was a major risk factor for the development of epidural hematoma with neuraxial anesthesia.3
Transversus abdominis plane (TAP) block is a suitable method of postoperative analgesia after cesarean delivery to avoid the toxicities and side effects related to acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids. McDonnell et al.4 reported a morphine-sparing effect in women who benefited from a bilateral TAP block after cesarean delivery. In this case report, we present complications associated with TAP blocks in a woman with severe AFLP.
Consent was obtained from the patient for publication of this case.
A 25-year-old G2P0 woman at 37 0/7 weeks of gestation presented in labor with cervical dilation of 4 cm. Her symptoms included a history of 3 weeks of nausea/vomiting, somnolence, mild hypertension (140/85 mm Hg), and clinical jaundice. She was diagnosed with hyperemesis gravidarum at an outside hospital 2 weeks before her admission to our unit. Although she comprehended questions and was oriented to situation, time, and place, she was lethargic and was a grade 2 per the West Haven Criteria for hepatic encephalopathy.5
The patient weighed 51 kg, and her height was 150 cm (body mass index = 22.7 kg/m2). Initial laboratory tests showed white blood count 20,000/µL, hematocrit 41%, platelets 141,000/µL, international normalized ratio 4.1, fibrinogen 50 mg/dL, a 2+ proteinuria, elevated creatinine 2.1 mg/dL, hypoglycemia 48 mg/dL, direct bilirubinemia 9.0 mg/dL, aspartate aminotransferase/alanine aminotransferase 59/63 U/L, alkaline phosphatase 1000 IU/L, and ammonia 101 mg/dL.
The initial differential diagnosis for this patient included preeclampsia, HELLP syndrome, and AFLP. Given the clinical presentation and laboratory values, AFLP was the lead diagnosis.
After stabilizing the coagulopathy with cryoprecipitate and fresh frozen plasma, an urgent cesarean delivery was necessary because of late decelerations on fetal heart monitoring and the mother’s tenuous status. General anesthesia was provided with a rapid sequence induction with fentanyl (150 mcg), propofol (100 mg), lidocaine 2% (60 mg), and succinylcholine (70 mg). Intubation with a 6.5 oral endotracheal tube and a Macintosh #3 laryngoscope blade while holding cricoid pressure was uneventful. Maintenance of anesthesia involved isoflurane and then a transient administration of nitrous oxide. At the end of the cesarean delivery, the trachea was extubated and she was taken to postanesthesia care unit. The child was a healthy male, with an APGAR (5 minutes) of 8, weighing 2879 g.
Due to her fluctuating mental status, opioids for postoperative analgesia were withheld. She was able to follow commands and communicate, but was intermittently lethargic, similar to her predelivery status. After numerous options were considered, it was decided that a TAP block would be optimal in this particular situation. Using ultrasound guidance (Sonosite, Bothell, WA), 20 mL of bupivacaine 0.375% was injected on each side 3 cm anteromedial to the point midway between the iliac crest and costal margin along the midaxillary line using a 5-cm needle (B-Braun Medical USA, Bethlehem, PA). The international normalized ratio was 2.1, and fresh frozen plasma was given during the procedure. Pain scores decreased from 9 of 10 down to 3 of 10 twenty minutes after the procedure and remained less than 5 of 10 for 12 hours. The patient was transferred to the intensive care unit (ICU) for closer postoperative monitoring and frequent neurological assessment.
After 12 hours, the patient began to complain of increasing pain in the vicinity of her abdominal incision. We agreed to perform a second TAP block given the time interval since the first block, and because of the relief the first block achieved. Fifteen hours after the first TAP block, a second TAP block with the same doses was uneventfully provided. Her visual analog scale score decreased from 10 of 10 to 6 of 10 five minutes after the block.
Thirty minutes after the TAP block a seizure was observed; lorazepam 1.5 mg IV was administered. The trachea was intubated after administration of propofol and rocuronium. Intralipid 20% (1.5 mL/kg) was given IV to prevent bupivacaine cardiotoxicity. No electrocardiogram interval changes were noted, and she remained hemodynamically stable through her entire period in the ICU. While intubated, she was initially receiving propofol infusion without any opioids. Twelve hours after her seizure, it was agreed that a remifentanil infusion at 0.1 mcg/kg/min would be the safest analgesic option in this complex patient. Her trachea was extubated within 48 hours of intubation; on her first sedation holiday, her mental status was deemed to be unsuitable to protect her airway. On hospital day #4, she was transitioned to a remifentanil patient-controlled analgesia: she was pleasant, conversing, and had no recall of the events after her delivery. Her pain score was 1 to 2 of 10. She was discharged from the ICU on hospital day #6. She continued to progress back to her functional baseline at the follow-up at 3 months after her cesarean delivery.
The differential diagnosis for the seizure included eclampsia, posterior reversible encephalopathy syndrome, hypomagnesaemia, hypoglycemia, hepatic encephalopathy, intracranial bleeding, and, due to the temporal relationship of events with the seizure occurring within 30 minutes of a second TAP block, local anesthetic systemic toxicity (LAST). Tsen et al.6 reported that parturients, in general, may be at higher risk for LAST because of an increased free fraction of plasma bupivacaine. In AFLP, third trimester liver dysfunction leads to a decreased production of serum proteins that bind to local anesthetics such as bupivacaine. Bupivacaine, in particular, is approximately 95% protein-bound. Therefore, in patients with decreased serum albumin and α-1-glycoprotein, the free fraction of bupivacaine is augmented making an individual more susceptible to LAST. Our patient’s impaired renal function also contributed to a decreased threshold for LAST.
Pharmacokinetics of other local anesthetics have been studied in patients receiving TAP blocks. Kato et al.7 described peak plasma concentrations 15 minutes after 400 mg of lidocaine via bilateral TAP blocks; Griffiths et al.8 noted peak plasma concentrations of ropivacaine at 30 minutes after injection for bilateral TAP blocks. Although no formal studies have been performed with bupivacaine, the onset to LAST in this patient is within the range of onset for other amide local anesthetics.9
The interval between the first and second blocks was 15 hours. The estimated terminal half-life of bupivacaine is 2.7 ± 2 hours per AstraZeneca, the pharmaceutical company that makes bupivacaine in the United States (Astra insert). In a study of bupivacaine pharmacokinetics after axillary blocks, the terminal half-life for bupivacaine was 11.5 hours.10 Although we do not have data regarding the terminal half-life of bupivacaine in TAP blocks, we would usually wait 5 half-lives for elimination of the drug; given this patient’s condition, 15 hours might have been not enough time to expect >96% metabolism and excretion. Further studies involving the pharmacokinetics of sequential TAP blocks would help elucidate the appropriate interval.
The TAP block has been recently described as a safe and useful postcesarean analgesic modality. In this patient, however, the threshold for local anesthetic toxicity was likely reduced and while providing a second TAP block to provide analgesia seemed appropriate, this resulted in LAST. To our knowledge, this is the first report of the use of Intralipid 20% (1.5 mL/kg) to treat bupivacaine toxicity after a repeat TAP block. Future studies should be conducted on the pharmacokinetics of local anesthetics in TAP blocks in parturients. Providing good analgesia after cesarean delivery in patients with AFLP remains a challenge; decreased liver and renal function, encephalopathy, coagulopathy, and increased local anesthetic toxicity are complicating factors.
1. Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst PUK Obstetric Surveillance System. . A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57:951–6
2. Bacq Y, Assor P, Gendrot C, Perrotin F, Scotto B, Andres C. Recurrent acute fatty liver of pregnancy. Gastroenterol Clin Biol. 2007;31:1135–38
3. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107(Suppl 1):i96–106
4. McDonnell JG, Curley G, Carney J, Benton A, Costello J, Maharaj CH, Laffey JG. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg. 2008;106:186–91 , table of contents
5. Ferenci P. Therapy of acute and chronic hepatic encephalopathy in patients with liver cirrhosis. Z Gastroenterol. 1998;36:909–16
6. Tsen LC, Tarshis J, Denson DD, Osathanondh R, Datta S, Bader AM. Measurements of maternal protein binding of bupivacaine throughout pregnancy. Anesth Analg. 1999;89:965–8
7. Kato N, Fujiwara Y, Harato M, Kurokawa S, Shibata Y, Harada J, Komatsu T. Serum concentration of lidocaine after transversus abdominis plane block. J Anesth. 2009;23:298–300
8. Griffiths JD, Barron FA, Grant S, Bjorksten AR, Hebbard P, Royse CF. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth. 2010;105:853–6
9. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology. 2002;96:1427–34
10. Vainionpää VA, Haavisto ET, Huha TM, Korpi KJ, Nuutinen LS, Hollmén AI, Jozwiak HM, Magnusson AA. A clinical and pharmacokinetic comparison of ropivacaine and bupivacaine in axillary plexus block. Anesth Analg. 1995;81:534–8