Can we predict who will develop postoperative hyperkalaemia after parathyroidectomy in dialysis patients with secondary hyperparathyroidism?

Although the survival of end-stage renal disease (ESRD) patients has remarkably improved in recent years, SHPT is a common disorder in ESRD patients receiving MHD [1]. Highly elevated PTH levels in SHPT patients may result in adverse outcomes, such as mineral and bone disorders and high cardiovascular morbidity and mortality. PTX for SHPT in MHD patients was first performed in 1965. PTX continues to be a valuable option for severe SHPT patients who are refractory to medical therapy. Large observational studies have suggested that PTX can reduce the mortality risk [2, 3]. The number of PTX has been decreased in developed countries. However, PTX is required in patients with cinacalcet resistant to SHPT.

The abrupt reduction in serum PTH after PTX may provoke a series of electrolyte abnormalities, such as hypocalcaemia, hypomagnesaemia, hypophosphataemia, and hyperkalaemia [4, 5]. As a result, these patients should be closely monitored, because the immediate postoperative period is the most likely time frame for clinical manifestations of these electrolyte abnormalities [6]. Hypocalcaemia is the most widely recognized disorder and may produce weakness leading to postoperative respiratory distress [7]. Hyperkalaemia is also a complication that occurs within the first 24 h postoperatively after PTX in MHD patients, although the mechanism is not understood [8]. To control hyperkalaemia is one of important issues peri PTX and should be resolved. Hyperkalaemia occurs in 25% to 80% of patients with MHD undergoing PTX. However, this disorder is under-recognized and may lead to more devastating consequences, especially when patients have high normal or elevated baseline serum potassium levels [9‐11]. Rosenkrans reported a case of intraoperative hyperkalaemia and ventricular arrhythmia during PTX, which highlighted the under-recognized alterations in potassium homeostasis associated with PTX and underscored the importance of preoperative optimization [6].

Therefore, this retrospective study investigates how multiple perioperative risk factors can lead to postoperative hyperkalaemia in MHD patients undergoing PTX.

We enrolled 90 refractory SHPT patients with ESRD needing regular renal dialysis who prepared to receive PTX in the Peking University Aerospace School of Clinical Medicine between April 2011 and April 2016. One expertise surgeon performed all of the surgeries. The study received informed consent in written format from the patients and underwent the approval process of the Research and Ethics Committee of Aerospace Center Hospital.

All of our refractory SHPT patients received thrice weekly dialysis, and the treatment duration was 4 h. The patients were prescribed haemodialysis through a functioning fistula with a blood flow rate of >230 mL/min. The mean and median of the delivered Kt/V were 1.4 and 1.3, respectively, for the haemodialysis patients. Data included age, sex, dialysis duration, the serum creatinine (sCr), blood urea nitrogen (BUN), parathyroid hormone (PTH), alkaline phosphate (ALP),cholesterol (CH), albumin (Alb), haemoglobin (Hb), magnesium (Mg), potassium (K),sodium (Na), calcium (Ca), bicarbonate (HCO3-), phosphorus (P), triglyceride (TG),serum ferritin (SF), and serum iron (SI) levels and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) use before and after PTX. Hyperkalaemia was defined as serum K >5.3 mmol/L in our hospital.

Patients was resumed for 3 h heparin-free haemodialysis on the day before PTX surgery and on postoperative day 1. The electrolyte K concentration of the dialysate was 2.0 mEq/L. Four venous blood samples were collected before and after heparin-free dialysis, at the end of PTX surgery and pre-dialysis on postoperative day 3 for laboratory chemistry assessments.

The indications for PTX surgery in our hospital were similar to those reported in other studies [8] and included the following: (1) a persistently high PTH level (>800 pg/ml); (2) detection of enlarged parathyroid glands with more than one gland with diameter ≥1 cm on power-Doppler images, and rich in blood flow. (3) uncontrolled hypercalcaemia and hyperphosphataemia, multiple severe bone deformities or extraskeletal calcifications that refractory to medical treatment even though the PTH level was < 500 pg/ml.

MHD patients were excluded if they met one of the following criteria: (1) primary hyperparathyroidism; (2) subtotal parathyroidectomy; (3) previous parathyroid surgery; and (4) pathological diagnosis in addition to parathyroid hyperplasia.

SHPT requiring PTX occurs more commonly in patients with progressive chronic kidney disease. Successful PTX often results in a dramatic drop in the parathyroid hormone level, relief of clinical symptoms, and reduced mortality.

There is no agreed upon definition of hyperkalaemia. The above normal limit of the potassium level is 5.3mmol/L in our hospital, and therefore we define hyperkalaemia as a pre-dialysis K>5.3 mmol/L. The European Resuscitation Council recommends stratification of hyperkalaemia into minimal (5.5-5.9mmol/L), moderate (6.0-6.4mmol/L), and severe (≥6.5mmol/L) cases [21]. Due to the high associated mortality, the American Heart Association recommends ‘immediate therapy’ for patients with serum potassium >6.0mmol/L [22].

Hungry bone syndrome (HBS) following PTX surgery is most often associated with hypocalcaemia [23]. However, concomitant hyperkalaemia was also reported in dialysis patients who underwent PTX for SHPT and experienced HBS postoperatively [24]. Is hyperkalaemia a complication of PTX? Fortunately, PTX complicated with hyperkalaemia has attracted the attention of scholars in recent years. One finding suggested that ESRD patients with prior treatment with cinacalcet who were undergoing parathyroidectomy for renal hyperparathyroidism had a greater risk of acute hyperkalaemia during the intraoperative and immediate postoperative periods [17]. Serum K increased quickly since resection of the first hyperplastic parathyroid gland, which accompanied with more parathyroid glands were removed. The decrease of PTH level by parathyroidectomy in SHPT patients exposed cinacalcet can significantly diminish mobilization of skeletal calcium with concomitant hypocalcaemia and hyperkalaemia. Unfortunately, cinacalcet was not widely used until 2018 in China (as a developing country) .Almost none of the 90 patients in our study took cinacalcet. The exact mechanism of this association between hyperkalaemia and cinacalcet is unknown. However, awareness of the phenomenon is imperative for surgeons, anaesthetists and renal physicians.

Shpitz B reported that the mean serum potassium concentration increased from 4.4 mmol/L preoperatively to 6.2 mmol/L within several hours after PTX [12]. A retrospective cohort study of 22 patients who had undergone PTX for SHPT found a 27.3% incidence of hyperkalaemia after PTX. Furthermore, a male dominance of 68% was observed, and the median duration of surgery was longer in the hyperkalaemic patients [18]. A recent publication with larger numbers (204 cases) of PTX patients found that 66.7% patients suffered from hyperkalemia during or immediately after surgery [20].

Many patients routinely (even without surgery) enter dialysis with K >5.3. We needed a comparable control group of patients who did not undergo parathyroidectomy. Therefore, we measured the pre-dialysis K levels on postoperative day 3 and found that the K levels and rates of hyperkalaemia in this group were lower than those in the postoperative K group. Thus, PTX may play a role in the increase in serum potassium.

Our results first indicated that reducing the preoperative potassium levels with preoperative dialysis adequately decreased the risk of postoperative hyperkalaemia in MHD patients undergoing PTX. Preoperative serum potassium concentrations should be controlled below 3.9 mmol/L to avoid postoperative hyperkalaemia.

Additionally, we showed that patients with hyperkalaemia had lower TG levels and a shorter dialysis duration than the non-hyperkalaemia group of patients, presumably due to the patients’ poor compliance. The ALP level was high in the hyperkalaemia group, suggesting that hyperkalaemia might have a relationship with HBS. Cruz found that the rise in the potassium concentration was greater in patients who developed postoperative hypocalcaemia than in patients with normal serum potassium levels and that the highest potassium concentration appeared to be consistent with the lowest calcium concentration [4]. Unfortunately, we did not find statistical significance between the two factors in this study, probably because of the timely regular intravenous calcium supplementations after PTX surgery.

However, the mechanisms underlying the development of postoperative hyperkalaemia following PTX are not clear. A few reports have suggested a causal relationship between hyperkalaemia and HBS. The mechanism has been explained as follows. First, the physiologic calcium pump drives potassium to a location inside the cell membrane. The sharp decrease in the serum calcium levels accompanied by rapid bone absorption after removal of the high PTH levels may trigger a sudden reversal in the physiologic pump mechanism. The kidney of the MHD patient is unable to compensate for this sudden change and develops a high serum potassium level, which may be acute and serious [9]. Second, one study reported that the increase in cellular metabolism might lead to an accumulation of hydrogen and carbon dioxide production. Both of these mechanisms are adversely affected in MHD patients. Finally, PTX patients may manifest life-threatening hyperkalaemia [25]. Third, some anaesthetic drugs can induce life-threatening hyperkalaemia in operative patients, such as succinylcholine and halogenated agents [26]. Mannitol is a type of anaesthesia that usually is used to reduce intracranial pressure. Seto reported that this drug could induce hyperkalaemia and even life-threatening ventricular tachycardia [27]. Furthermore, transfusion of blood products, muscle and surrounding tissue injury, metabolic acidosis, and use of ACEIs/ARBs have all been reported to result in hyperkalaemia [28‐30].

Several limitations with regard to this study should be noted. First, parathyroidectomy was the most frequently performed operation in long-term dialysis patients, but there was a broad distribution of many different general surgical procedures, including abdominal or pulmonary resection and orthopaedic or cardiac surgery. The rates of postoperative hyperkalaemia in dialysis patients range from 9.5-24.5% [31‐36]. How do the rates of hyperkalaemia compare with those of other surgeries vs PTX? Is the rate of hyperkalaemia higher after PTX than after other surgeries? We cannot draw conclusions from our data and have not found relevant literature reports. Therefore, this issue requires further research. Second, we could not obtain the correlation between postoperative hyperkalaemia and preoperative cinacalcet. Third, this study did not obtain a correlation between postoperative hyperkalaemia and the duration of surgery and did not discover how PTX could lead to specific mechanisms of hyperkalaemia.

Briefly, this study is a large observational report of how multiple perioperative risk factors affect hyperkalaemia during the immediate postoperative period for ESRD patients who have undergone PTX for renal hyperparathyroidism. Clinicians need to be aware of the risk factors for developing postoperative hyperkalaemia after PTX in MHD patients, especially in male patients younger than 40.5 years. Preoperative severe hyperkalaemia should be monitored, and treatments such as postponing the operation, emergent HD or medication should be considered. Pre-operative serum potassium less than 3.9 mmol/L was associated with less hyperkalaemia post-operatively in end-stage renal disease (ESRD) patients undergoing PTX. This simple scheduling policy is effective at reducing both cost and unnecessary perioperative risks for patients. The relationship between postoperative hyperkalaemia and HBS after PTX needs further study.