EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The increased number of liver transplants in Egypt has increased the focus on perioperative complications in live donors. An important but not yet well-investigated complication is electrolyte disturbances, which are common in such patients, need intervention, and affect the outcome. We retrospectively analyzed data of perioperative calcium, magnesium, and phosphorus levels in live liver donors at our center.

Materials and Methods: We collected perioperative laboratory results from 44 living donors for liver transplant who were at our center from February 2009 to August 2013. We analyzed results of perioperative calcium, magnesium, and phosphorus levels before transplant, on the day of transplant (defined as day 0), and at 1 and 2 days after the surgical procedure.

Results: Mean serum calcium level was 2.31 mmol/L before transplant, 1.97 mmol/L on day 0, and 1.99 mmol/L on day 1, and 2.05 mmol/L on day 2 after transplant. Serum calcium level was significantly reduced at day 0 and on postoperative days 1 and 2 (P ˂ .0001). Mean magnesium level was 0.8 mmol/L before transplant, 0.58 mmol/L on day 0, and 0.83 mmol/L on day 1, and 0.79 mmol/L on day 2 after the surgical procedure. The day 0 level was significantly reduced versus before transplant (P ˂ .0001). Mean phosphorus level was 1.23 mmol/L before transplant, 1.11 mmol/L on day 0, and 0.97 mmol/L on day 1, and 0.76 mmol/L on day 2 after transplant, with significant declines on day 0 and on postoperative days 1 and 2 (P ˂ .0001).

Conclusions: Living liver donors showed significantly decreased levels of calcium and phosphorus on day 0 and on postoperative days 1 and 2, whereas magnesium level was significantly decreased on day 0 only.

Key words : Electrolyte disturbance, Donor, Liver transplant

Egypt has a high prevalence of patients with hepatitis C and hepatitis B, with an increasing number of patients in need of liver transplant. Because of legal aspects, liver transplant is only available from living related donors in Egypt. The number of centers and number of liver transplants continue to increase, requiring analysis of relevant data and complications. However, concerns regarding donor issues have received less attention than concerns regarding recipient issues.

The number of right lobe living-donor liver transplants performed each year has recently increased. Despite the success of this procedure, the risk of morbidity and mortality in otherwise healthy donors is the main disadvantage. Right lobectomy for adult living transplant donors involves removing approximately 60% of the hepatic mass.^2,3Other surgeons remove approximately 70% of the liver mass in an extended right hepatectomy.⁴ Resection induces liver dysfunction, which persists for several days or weeks depending on the size of resection. Several studies have reported significant changes in serum electrolyte levels, particularly in magnesium and phosphorus levels as a result of liver resection.^5-7 The depletion of electrolytes such as calcium, magnesium, and phosphorus can result in a variety of clinical disorders. Electrolyte disturbances can lead to neuromuscular dysfunction and severe arrhythmias, the risk of which increases by the deficiency of more than 1 electrolyte.⁸

We conducted a retrospective analysis of the perioperative data of 44 living related donors who underwent right lobe hepatectomy for liver transplant at our center to characterize the incidence of hypocalcemia, hypomagnesemia, and hypophosphatemia among these patients.

Materials and Methods

After approval by the Ethical Review Committee of our Institute, with all protocols conforming to the ethical guidelines of the 1975 Helsinki Declaration, we retrospectively analyzed the perioperative data of 44 donors who underwent right lobe donation from February 2009 to August 2013 at Cairo University Hospital. All donors underwent thorough medical and psychiatric evaluations before surgery including blood tests, viral serology analyses, and imaging studies. An evaluated graft-to-recipient weight ratio of at least 0.8% with a residual liver volume of at least 30% was considered acceptable for right lobe donation. Donor graft weight and residual liver volume values were estimated using helical computed tomographic scans with 3-dimensional renderings.

We induced general anesthesia using 2 mg/kg propofol, 2 μg/kg fentanyl, and 0.15 mg/kg cisatracurium, with anesthesia maintained with sevoflurane and an intravenous infusion of 3 μg/kg/min cisatracurium. All donors had received epidural analgesia. We cannulated the left radial artery for continuous invasive monitoring of blood pressure. We cannulated the right internal jugular vein with a triple lumen catheter using the Seldinger technique for continuous monitoring of central venous pressure. We administered prophylactic antibiotics (piperacillin-tazobactam) with anesthetic induction. For deep vein thrombosis prophylaxis, we used pneumatic compression stockings. Intraoperative fluid replacement was achieved by the infusion of Ringer acetate at a rate of 8 to 10 mL/kg/h. Ringer acetate is a crystalloid fluid with an osmolarity of 273.4 mosm/L and contains 130 mEq/L sodium, 4 mEq/L potassium, 2.7 mEq/L calcium, 108.7 mEq/L chloride, and 28 mEq/L acetate. Hydroxyethyl starch 6% solution (130/0.4) was used when necessary. Central venous pressure was maintained below 5 cm H2O to avoid liver congestion and to reduce blood loss during liver resection. At the end of surgery, all donors were extubated in the operating room and transferred to the surgical intensive care unit.

Donors received initial care in the intensive care unit for 48 hours after the surgical procedure and then were transferred to a regular surgical ward. On admission to the intensive care unit (defined as day 0), full laboratory investigations including blood counts, coagulation profile, liver and kidney functions, and serum electrolytes were conducted and then repeated daily. Maintenance intravenous fluids (60% glucose and 10% and 40% amino acids) were supplied to donors at a rate of 100 mL/h until donors resumed oral intake. According to the protocol followed at our institution, magnesium sulfate is added to glucose infusion at a concentration of 2 mg/mL. We also supplemented the infusion with calcium and phosphorus as needed but not routinely.

Collected data included time length of surgical procedure, urine output, and the total amount of crystalloids and colloids administered. We obtained results of calcium ion, magnesium ion, and phosphorus ion levels in patient serum before transplant, at day 0, and at postoperative days 1 and 2. Average range of serum calcium is 2.2 to 2.5 mmol/L, average range of serum magnesium is 0.7 to 1 mmol/L, and average range of phosphorus is 0.8 to 1.6 mmol/L. All data are presented as means ± standard deviation.

Forty-four patients (mean age, 30.13 ± 3.90 y; mean weight, 78.54 ± 5.88 kg) were included in our analyses, with male-to-female ratio of 35 to 9. All donors were classified as American Society of Anesthesiologists Physical Status I. Mean time from start of anesthesia induction to extubation was 457.8 ± 50.16 minutes. Mean perioperative urine output was 1.10 ± 0.30 mL/kg/h. None of our donors required intraoperative or postoperative blood transfusion, and none received any diuretics either intraoperatively or postoperatively.

All patients had normal values of serum phosphate on before the surgical procedure. Three patients (6.8%) had preoperative serum magnesium levels below 0.7 mmol/L, and 2 patients had preoperative calcium levels below 2.0 mmol/L. Donors had a mean calcium level of 2.3 mmol/L, magnesium level of 0.8 mmol/L, and phosphorus level of 1.23 mmol/L before the surgical procedure (Figures 1-2-3).

Mean level of postoperative serum calcium was 1.97 mmol/L on day 0, 1.99 mmol/L on postoperative day 1, and 2.05 mmol/L on postoperative day 2. Calcium levels were significantly reduced on days 0, 1, and 2 versus the preoperative level (P < .0001) (Table 1). Mean level of serum magnesium was 0.58 mmol/L on day 0, 0.83 mmol/L on postoperative day 1, and 0.79 mmol/L on postoperative day 2. Magnesium level was significantly less at day 0 only (P < .0001) (Table 2). Regarding serum phosphorus level, mean was 1.11 mmol/L on day 0, 0.97 mmol/L on postoperative day 1, and 0.76 mmol/L on postoperative day 2. Phosphorus levels were significantly decreased days 0, 1, and 2 versus preoperative level (P < .0001) (Table 3).

In conclusion, living donors for liver transplant at our center had significant reductions in calcium and phosphorus levels on day 0 and at postoperative days 1 and 2 versus the preoperative value. Magnesium levels were significantly decreased on day 0 only versus the preoperative level. No clinically significant complications were detected as a result of electrolyte disturbances.

Our results indicate that right lobe living donors are at risk for the development of hypomagnesemia, hypocalcemia, and hypophosphatemia in the postoperative period. Magnesium level decreased despite intravenous magnesium supplementation.

The decline in levels of serum electrolytes can be due to decreased intake, increased requirements, or increased losses. Decreases in magnesium, calcium, and phosphorus levels have been previously reported in patients after cardiopulmonary bypass surgery.⁹ These decreases were explained by significant increases in postoperative urinary electrolyte excretion, which may have been as a result of postoperative renal tubular dysfunction or frequent use of diuretics in cardiac surgery patients. However, our study group included young healthy donors with normal renal function, no significant hemodynamic variations, and without excessive use of diuretics during the surgical procedure. Thus, the postoperative decrease in serum electrolyte levels cannot be explained solely by a renal mechanism.

The development of postoperative electrolyte disturbances after major surgery may be in part induced by the stress response to trauma during surgery.¹⁰ Major surgery induces the release of catecholamines and various other stress hormones, including insulin, glucagon, and cortisol. The decline in phosphorus levels may be due to an intracellular shift, with precipitation of phosphorus into skeletal muscles inducing hypophosphatemia.¹⁰ Severe hypophosphatemia has been studied as a marker of a more intense acute phase response.¹¹ Similarly, catecholamines increase the uptake of magnesium into adipose cells.¹² An intracellular shift of magnesium ion could have contributed to the change in serum magnesium level. Some experimental data have suggested that the movement of magnesium into cells may be rapid and extensive.¹³ These mechanisms^10-13 could explain the results in our patients.

Few studies have addressed the changes in serum magnesium after hepatic resection. In their report on 7 patients who underwent liver resection for tumors, Kulpmann and associates⁵ found that both total and ionized magnesium levels declined during surgery. In addition, they reported that citrate concentration showed a modest increase during hepatic resection even in patients with no citrate administered in the form of blood products. Citrate is a chelating agent for both magnesium and calcium that is mainly metabolized in the liver. As concluded by Kulpmann and associates,⁵ increased citrate levels in the absence of high citrate load reflects reduced hepatic function.

However, the patients in these 2 investigations^5,9 are different from our group of normal healthy right lobe donors. A similar mechanism may at least in part explain the postoperative decrease in serum magnesium and calcium levels observed in our study. Right lobe donors experience a form of transient hepatic dysfunction after liver resection as evidenced by marked elevation of serum transaminases and a decrease in the prothrombin concentration. These derangements reach a maximum in the first 24 hours after surgery and then start to normalize slowly over the next few postoperative days.¹⁴

In our study, serum calcium levels showed the greatest decrease on day 0 compared with preoperative values, with a trend toward mild gradual elevation on postoperative days 1 and 2. Hypocalcemia in our study population was mild. We did not observe any visible symptoms of hypocalcemia, and no donor-required treatment.

We observed that serum calcium and phosphorus levels were significantly decreased on day 0 and on postoperative days 1 and 2, whereas the magnesium level showed a significant decline on day 0 only. Postoperative glucose infusions are administered to all donors until resumption of oral intake, which usually occurs after 24 to 48 hours. The protocol followed at our institution includes the addition of magnesium sulfate preparation to the glucose infusion at a concentration of 2 mg/mL. Thus, donors receive an average of 2 to 3 g of magnesium per day during the early postoperative period. This practice may have contributed to the normalization of serum magnesium levels on days 1 and 2.

Phosphorus homeostasis is a complex process involving multiple organs, including the liver, kidney, gastrointestinal tract, and skeletal system. Hypophosphatemia has many causes, including chronic alcoholism, malnourishment, alcoholic pancreatitis, gram-negative sepsis, recovery from diabetic ketoacidosis, respiratory alkalosis, total parenteral nutrition with inadequate phosphorus supplementation, glucose loading, and the use of aluminum-based antacids. These abnormalities are frequently present among patients in an intensive care unit setting, making hypophosphatemia a frequent occurrence, although not in the case of healthy donors. Adverse effects resulting from hypophosphatemia include cerebral and myocardial effects, hemolysis, thrombocytopathy, renal impairment, and diminished muscle contraction.¹⁵ Despite these potential harmful effects, hypophosphatemia usually does not become clinically significant in most pathologic states due to a large phosphate reserve in humans.^16,17

Hypophosphatemia often occurs after partial hepatectomy. The mechanism of hypophosphatemia after hepatectomy is still not entirely clear. Hypophosphatemia after liver resection has long been attributed to the increased uptake of phosphorus into the regenerating hepatocytes.^6,18 However, liver regeneration continues for several weeks after resection, whereas hypophosphatemia usually starts to resolve by the fourth to fifth postoperative day, making this assumption questionable.

A different mechanism for hypophosphatemia after liver resection has been demonstrated in a study by Salem and Tray.¹⁹ This study included 20 patients undergoing resection of at least 2 hepatic segments for primary or secondary tumors. The hypophosphatemia reported in this study was associated with profound isolated hyperphosphaturia as evidenced by increased fractional excretion of phosphate. The authors found fractional excretion of phosphate to be highest on postoperative day 2 in association with the greatest drop in serum phosphate, which then started to fall as phosphate levels rose. A similar finding was observed in a more recent study by Nafidi and associates.²⁰ Again, hypophosphatemia after liver resection was associated with hyperphosphaturia due to increased fractional excretion of phosphate. In these 2 studies, liver resection was carried out in patients with primary or metastatic liver tumors, and all patients had normal preoperative renal function. Whether this phenomenon of hyperphosphaturia can explain the occurrence of hypophosphatemia in healthy right lobe donors is unknown and needs to be elucidated in future studies.

All donors demonstrated statistically significant hypophosphatemia compared with preoperative values. In most patients, the hypophosphatemia was moderate. Only 2 patients suffered profound hypophosphatemia (serum magnesium < 0.32 mmol/L), requiring replacement with intravenous phosphate preparation. We did not report any serious complications or increase in donor morbidity as a consequence of hypophosphatemia.

Limitations
A potential limitation of our study is that we did not measure the levels of ionized magnesium and ionized calcium in our patients. We did not measure urinary concentrations of the studied electrolytes. We included healthy donors with normal perioperative values of plasma proteins and albumin. Hence, we cannot assume the presence of significant effects to protein binding.

Hypocalcemia, hypomagnesemia, and hypophosphatemia were frequently shown in our right hepatic lobe living donors for liver transplant. The mechanism appears to be multifactorial and may involve the stress response to surgery, hepatic dysfunction after liver resection, and a renal mechanism. However, we did not encounter significantly increased complications or donor morbidity as a consequence of these electrolyte deficiencies. We recommend electrolyte supplements during the postoperative period in living donors for liver transplant.

Volume: 13 Issue: 6 December 2015

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