Hyponatremia and Liver Transplantation: A Narrative Review.

Abstract:

Hyponatremia is a common electrolyte disorder in patients with end-stage liver disease (ESLD) and is associated with increased mortality on the liver transplantation (LT) waiting list. The impact of hyponatremia on outcomes after LT is unclear. Ninety-day and one-year mortality may be increased, but the data are conflicting. Hyponatremic patients have an increased rate of complications and longer hospital stays after transplant. Although rare, osmotic demyelination syndrome (ODS) is a feared complication after LT in the hyponatremic patient. The condition may occur when the serum sodium (sNa) concentration increases excessively during or after LT. This increase in sNa concentration correlates with the degree of preoperative hyponatremia, the amount of intraoperative blood loss, and the volume of intravenous fluid administration. The risk of developing ODS after LT can be mitigated by avoiding large perioperative increases in sNa concentration. This can be achieved through measures such as carefully increasing the sNa pretransplant, and by limiting the intravenous intra- and postoperative amounts of sodium infused. SNa concentrations should be monitored regularly throughout the entire perioperative period.

Comments made by Cale Kassel M.D., FASA  

Summary:

Anesthesiologists encounter hyponatremia in LT patients frequently. This review outlines the multiple factors that contribute to the development and management of hyponatremia.[1] While the risk of hyponatremia is well-known for patients on the waiting list, the effect on post-operative outcomes remains unclear. A few early studies on hyponatremia in LT showed increased 90-day mortality but more recent studies listed show no difference. However, some research does show increased ICU length of stay and morbidity. Of note, one study of over 40,000 patients did show increased mortality for patients with serum sodium less than 120 mmol/L indicating perhaps serve or profound hyponatremia may carry more risk.

Osmotic demyelination syndrome (ODS) is the biggest concern with rapid serum sodium correction. This potentially lethal condition can occur when serum sodium is increased more than 8 mmol/L in 24 hours. Incidence of ODS is 0.8-1.4% in LT patients compared to 0.6% in the general population and carries a higher risk of morbidity and mortality (77% for LT patients vs. 45% for non-LT patients).

Perioperative management of hyponatremia requires attention from the pre-operative evaluation through the post-operative period. While time is often limited pre-LT, there are a few options to increase serum sodium. Holding loop diuretics, free-water restriction, and high-concentration albumin (25%) can be used. Consulting with the nephrology team can be of great value as well.

Intra-operative management certainly can be challenging. Close monitoring is essential and understanding the sodium concentration of the fluids, medications, and blood products use can guide your treatment. The use of viscoelastic testing should be considered to limit the use of blood products such as plasma (with a sodium concentration of 172 mmol/L). The use of CRRT can typically uses a dialysate solution with 140 mmol/L of sodium so in patients with hyponatremia, discussion with the nephrologists is needed to explore ways to decrease sodium concentration. The authors cite a suggestion that adds sterile water (in predefined amounts) to create hyponatremic dialysate solutions.

Many solutions and blood products we administer contain significant sodium concentrations. The authors provide a great table with the recommended amount of D5W you can add to reduce the sodium concentration to 125 mmol/L. For example, a liter of normal saline would require the addition of 232 mL of D5W. In lieu of fresh frozen plasma or cryoprecipitate, the use of factor concentrates can help improve the coagulation profile without significant increases in sodium concentration.

Post-operatively, continued monitoring is important as the fluid shifts can continue despite the new graft. Again, limiting the increase of serum sodium to less than 4-6 mmol/L per 24 hours is important as is monitoring for signs of ODS.

Overall, this review was a great summary of the current state of knowledge while also providing several useful clinical suggestions for anesthesiologists.

References:

[1] Verbeek TA, Saner FH, Bezinover D. Hyponatremia and Liver Transplantation: A Narrative Review. Journal of cardiothoracic and vascular anesthesia 2022;36(5):1458-1466. DOI: https://doi.org/10.1053/j.jvca.2021.05.027.

Markmann JF, et al. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surg. 2022 Mar 1;157(3):189-198.

Abstract

“Importance: Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.

Objective: To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs).

Design, setting, and participants: This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list.

Interventions: Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital.

Main outcomes and measures: The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant.

Results: Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.

Conclusions and relevance: This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.”

Comments by Scott Byram M.D.

Summary:

Normothermic machine perfusion (NMP) is a relatively novel liver preservation strategy as an alternative to the standard, ischemic cold storage (ICS).    In NMP, the donor liver is harvested, the hepatic artery, portal vein, and supra-hepatic cava are cannulated.  Using type specific blood, the portable machine delivers oxygenated blood flow to both the portal and arterial circulations.  The machine and donor organ are then transported to the recipient location for transplantation after several hours of perfusion.   During the perfusion time, oxygenation, arterial and portal pressures, and lactate levels are measured.   NMP may be a viable or even superior method for preservation compared to ICS.  NMP may have the potential to both expand the pool of acceptable organs for transplant, as well as lower the incidence of post-transplant, ischemia-induced cholangiopathy and early allograft dysfunction (EAD). 

                The PROTECT trial¹ is a multi-center, randomized clinical trial comparing these two different liver preservation strategies, NMP and ICS.  NMP was accomplished using the Organ Care System (OCS).    The donor inclusion criteria were preselected to capture organs particularly vulnerable to ICS induced damage.  These risk factors included DBD > 40 years old, DCD, macrosteatosis, and expected prolonged ischemic time.  After organ allocation, the donor liver was randomly assigned to either OCS or ICS.  Ultimately, 293 recipients were included in the analysis (151 OCS, 142 ICS).   The groups were similar with the exception of significantly more DCD donors existed in the OCS group.  This potentially reflects that certain marginal grafts were placed on the OCS, which would have been discarded had they been assigned to ICS.  In fact, more than twice as many organs were discarded during procurement in the ICS group due to “clinical judgement” of the surgeon.   The organs in the OCS group were perfused a mean of 276 minutes.  The primary endpoint (EAD) was significantly reduced in the OCS group (18% vs. 31%, p=0.01).  Additionally, ischemic biliary complications were lower in the OCS group compared with the ICS group at 6 months (1.3%vs 8.5%; P = .02) and 12 months (2.6%vs 9.9%; P = .02).  Finally, the authors state that reperfusion syndrome was more severe in the ICS group.  However, this claim was based on post reperfusion lactate levels rather that any hemodynamic parameters. 

                The PROTECT trial is the first trial assessing the superiority of NMP over the standard ICS.  In this study, the authors found that NMP was associated with a lower incidence in early allograft dysfunction and ischemic biliary complications at 6 and 12 months.  Additionally, the use of NMP was associated with an increased number of DCD organs acceptable for transplant.  More studies are warranted; however, NMP appears to be a promising liver graft preservation strategy.

References

1. Markmann JF, Abouljoud MS, Ghobrial RM, Bhati CS, Pelletier SJ, Lu AD, Ottmann S, Klair T, Eymard C, Roll GR, Magliocca J, Pruett TL, Reyes J, Black SM, Marsh CL, Schnickel G, Kinkhabwala M, Florman SS, Merani S, Demetris AJ, Kimura S, Rizzari M, Saharia A, Levy M, Agarwal A, Cigarroa FG, Eason JD, Syed S, Washburn WK, Parekh J, Moon J, Maskin A, Yeh H, Vagefi PA, MacConmara MP. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surg. 2022 Mar 1;157(3):189-198. doi: 10.1001/jamasurg.2021.6781. PMID: 34985503; PMCID: PMC8733869.

Intraoperative Intracardiac Thrombus in Liver Transplant: A 9-year Retrospective Review Focusing on Treatment and Outcomes

 

“This study characterizes incidence and outcomes surrounding intracardiac thrombosis (ICT) during liver transplantation over 9 years at a single center before and after the routine use of transesophageal echocardiography (TEE). Adult liver transplantation patients from 2011 to 2020 were divided into eras based on routine TEE use. ICTs were identified by querying anesthetic records for search terms. Descriptive statistics included counts and proportions for baseline recipient, donor, intraoperative, and postoperative characteristics. Outcome data were based on date of hospital discharge and date of death. The incidence of ICT increased in the TEE era (2016-2020) compared with the pre-TEE era (2011-2015; 3.7% [25/685] vs. 1.9% [9/491]; p < 0.001). Patients with ICT had significantly higher Model for End-Stage Liver Disease-sodium (MELD-Na) scores, pretransplant hospitalization, malignancy, drug-induced liver injury, hypertension, deep vein thrombosis, reperfusion syndrome, transfused platelets and cryoprecipitate, and use of hemostatic medications. A higher proportion of patients in the ICT group underwent simultaneous liver-kidney transplantation. The patients with ICT were similar, except patients in the pre-TEE era had higher MELD-Na scores and incidences of hepatitis C virus and lower incidences of encephalopathy. In the pre-TEE era, all ICTs presented as intraoperative cardiac arrest, and the 30-day mortality in the setting of ICT was 66.7% (6/9). During the TEE era, 80% of ICTs were diagnosed incidentally or attributed to hemodynamic instability (p = 0.002). The 30-day mortality rate was 36% (9/25) in the TEE era (p = 0.25). ICT incidence increased in the TEE era, yet the mortality rate was lower, suggesting that routine intraoperative TEE may lead to the early detection of ICT prior to hemodynamic collapse.”

 

Comments made by Cara Crouch, MD  

Intracardiac thrombus (ICT) is a rare but devastating complication during orthotopic liver transplantation (OLT). This study evaluates the incidence of ICT before and after TEE use during OLT became standard at a single institution. As expected, there was a higher incidence of ICT found once TEE use became standard practice, however, an important point to note from this article is the lower mortality rate during the TEE era (36% vs 66.7% in the pre-TEE era). The authors point out that earlier detection of thrombi via TEE may allow for more prompt treatment prior to the progression to full cardiovascular collapse.

This article also provides a thorough review of a single institutions experience with ICT over a 9-year period and the authors provide extensive baseline characteristics of the patients who developed this complication. The authors found that patients undergoing simultaneous liver-kidney transplant (SLK) seemed to have a higher incidence of ICT, though the use of intraoperative renal replacement therapy (non-heparinized circuit) was higher in patients undergoing SLK and the authors question if this may be the reason. Patients who experienced ICT were more likely to have post-reperfusion syndrome, platelet and cryoprecipitate transfusion, as well as administration of recombinant factor VII, tranexamic acid and desmopressin. This article offers good support for the standardization of intraoperative TEE use in patients undergoing liver transplantation. However, it is understood that this may not be feasible at some institutions, the authors also highlight several intraoperative factors that appear to be correlated with the development in ICT. This information may prove useful in helping to determine which patients may benefit from TEE probe placement given that they are higher risk for this potentially fatal complication.

References:

1. Fagelman E, Wang R, Tomlinson A, Romano D, Schlichting N, Zerillo J, DeMaria S, Smith N. Intraoperative Intracardiac Thrombus in Liver Transplant: A 9-year Retrospective Review Focusing on Treatment and Outcomes. Liver Transplantation. April 2022.