Extreme hyperkalemia.

Abstract: Hyperkalemia is a potentially fatal condition and is defined by a serum potassium level ([K.sup.+]) of greater than 5.5 mmol/L. The associated prevalence of cardiac arrhythmia increases directly with the degree of hyperkalemia. The danger in the majority of hyperkalemia cases is cardiac dysrhythmia, and often ventricular fibrillation or asystole is the terminating event. Although there are many previous reports addressing this threatening problem and associated therapeutic maneuvers, there have not been many previous reports citing the fatal concentration of hyperkalemia irrespective of the causes. However, it is uniformly accepted that a [K.sup.+] concentration greater than 10.0 mmol/L is fatal unless urgent treatment is instituted. This report describes a case of nonfatal hyperkalemia of 14 mmol/L with intact survival and complete recovery. Potassium homeostasis is revisited, and some explanations are proffered regarding the protective mechanism against hyperkalemia, including transcellular flux, renal tubular function, and endocrine responses.

Key Words: aldosterone, homeostasis, hyperkalemia, serum potassium level

Case Report

A 55-year-old male presented with a sudden onset of chest pain and collapse while in the ward. The patient had been admitted 2 days prior with acute cholecystitis. He had been previously well with no known history of cardiac disease and was a smoker of 20 to 30 cigarettes daily. There was no prior medical, surgical, family, or allergy history. He was receiving 5,000 U subcutaneous heparin twice daily as part of thromboprophylaxis and intravenous ampicillin, gentamicin, and metronidazole.

The patient was found to be in ventricular tachycardia, with no recordable blood pressure and no cardiac output. Resuscitation was promptly instituted. The condition was intractable, with periods of ventricular tachycardia and fibrillation. Cardiopulmonary resuscitation was performed continuously for 30 minutes, including six episodes of defibrillation of increasing voltage to a maximum of 360 J, before the resumption of sinus (tachycardia) rhythm. During this time, the patient was given intravenous normal saline of 0.9% sodium chloride. No potassium or noradrenalin was given at any stage. Medications administered during the resuscitation included intravenous lignocaine and amiodarone.

His intraarrest blood samples were collected through a femoral venipuncture with a 20F gauge needle. Fortunately, his prearrest tests were available to be analyzed retrospectively. (1) Results are listed in Table 1. (2)

Progress

The patient remained in sinus tachycardia but was stable, with blood pressure of 110/80 mm Hg. He did not require any inotropic or ventilatory support but was monitored closely. His urinary output was satisfactory. An amiodarone infusion was given for the ensuing 24 hours, followed by an oral maintenance dose. His 12-lead electrocardiogram (ECG) showed sinus tachycardia with clear evidence of an inferior myocardial infarction. Surprisingly, there were no features of hyperkalemia. The extreme hyperkalemia was treated with a calcium gluconate, insulin, and glucose infusion for the following 24 hours until his potassium level normalized (see Table 1). (2) His serum troponin-1 was 15.1 ng/mL, supporting the ECG evidence of a myocardial infarction. He was treated expectantly and made a satisfactory recovery. At the 1-month review, the patient remained well, with a serum potassium ([K.sup.+]) level of 4.2 mmol/L, normal serum bicarbonate, and otherwise normal renal function. His fasting glucose level was 5.2 mmol/L.

Discussion

Hyperkalemia is not an uncommon condition in the hospitalized population, and is defined as [K.sup.+] of greater than 5.5 mmol/L. (2) To the best of my knowledge, this case demonstrates the highest recorded [K.sup.+] level survived by a patient. The highest reported [K.sup.+] level was 9.3 mmol/L, (3,4) with a fatal outcome. (3) The anomalous feature noted is the absence of ECG-related changes, together with the extreme [K.sup.+] level, raising the possibility of pseudohyperkalemia. This suspicion is further strengthened by the positive, albeit mild, hemolysis index. The true potassium concentration, however, is confirmed by the slightly lower parallel plasma measurements. Plasma [K.sup.+] levels are slightly lower than that of serum and are expected to be within the reference interval in the presence of pseudohyperkalemia. (1) The initial high value is also collected through the femoral vein, circumventing the problem with sampling at a peripheral site, such as repeated fist clenching. (5) Femoral vein samples have been shown to have lower potassium compared with forearm samples, (6) especially during critical resuscitation, where there is relative ischemia in the forearms or peripheral site. This collection site is in addition advantageous in that it excludes drip site as a possible contaminant. True [K.sup.+] values are almost always associated with other electrolyte abnormalities, as reflected by the presence of lactic and metabolic acidosis and disturbance in sodium, calcium, and phosphate homeostasis in this case. The latter two are more reflective of tissue damage and rhabdomyolysis. In the absence of marked leukocytosis and thrombocythemia, pseudohyperkalemia is very unlikely. (7,8) Finally, familial pseudohyperkalemia is excluded, given his previously normal baseline [K.sup.+].

The physiology and homeostasis of potassium have been well studied and reported previously. (6,9,10) The majority of hyperkalemia cases are renal related, without which the prevalence would probably be significantly less. These are due to either glomerular disease or failure of the distal convoluted tubules to respond to various controlling factors. Other causes are flux or redistribution of [K.sup.+] across the cellular membrane, excessive dietary loading, and potassium-affecting medications. (1)

In the case presented, the extreme hyperkalemia is multifactorial. The major factor, however, is the intracellular release of potassium from rhabdomyolysis sustained during the trauma of cardiopulmonary resuscitation and external defibrillation as well as the relatively prolonged ischemia. These are evident by the release of intracellular contents including high phosphate, urate, and creatinine kinase concentrations. Lactic metabolic acidosis would aggravate the condition. The presence of hyperglycemia, due to relative insulin resistance as indicated by the high insulin level, further compounds the situation. The hyperglycemia increases the tonicity of the extracellular space, causing necrosis and hence the release of excessive [K.sup.+] to the extracellular space. The use of heparin also contributes to the condition by way of aldosterone suppression, natriuresis, and reduced potassium excretion. The degree of heparin-induced hyperkalemia is mild to moderate however, occurring commonly on days 3 to 5 and in approximately 7% of patients. (11) Severe hyperkalemia only occurs in the presence of other exacerbating factors such as renal insufficiency or potassium-retaining drugs. It is not certain if this phenomenon is dose related, although the suppression of aldosterone production must be small in this situation in which there is an obvious "escape" producing a satisfactory aldosterone response. (10) None of the antibiotics given are known to contribute to hyperkalemia.

In counteracting the extreme hyperkalemia, potassium itself is a potent stimulator of aldosterone secretion by ways of opening up membrane voltage-dependent [Ca.sup.2+] channels, allowing an influx of [Ca.sup.2+] to stimulate aldosterone synthesis. (12) The subsequent secondary hyperreninemic hyperaldosteronism will contribute to the [K.sup.+] reduction by increasing renal tubular secretion, as indicated by the high transtubular potassium gradient and 24-hour urinary [K.sup.+] excretion. The cortisol level in excess of 1,000 nmol/L rules out Addison disease as a contributor to hyperkalemia. (13,14) In fact, such high concentration may hypothetically serve to reduce [K.sup.+] addition to aldosterone. The excess growth hormone in critical illness theoretically may also assist in lowering potassium levels by increasing cellular synthesis and tissue anabolism. This is not the case, however, in patients receiving growth hormone supplements. (15,16) The prolactin and thyrotropin responses are also consistent with the critical illness response. It is unlikely these two hormones contribute in any way to the [K.sup.+] reduction.

The patient did not have any further arrhythmias during the recovery period while the hyperkalemia was regressing. Possibilities include the adequate antihyperkalemic measures with the use of membrane stabilizing agents with lignocaine, calcium, and amiodarone. The rate of potassium reduction may also be a factor. Renal homeostasis undoubtedly assists, as illustrated by this case, as well as probably increased [K.sup.+] excretion in the colon, (17) under the influence of aldosterone but in a delayed fashion. The extreme degree of hyperkalemia also brings into question the existence of an underlying metabolic disorder, which is fully excluded by the normal electrolyte pattern before and after the event.

Conclusion

This report illustrates a case of extreme hyperkalemia in which the patient survived. Pseudohyperkalemia is fully excluded, given the markedly elevated [K.sup.+]. The patient's survival and complete recovery is probably due to a combination of satisfactory medical intervention and the patient's intact physiologic response without any underlying potassium handling disorders.

References

1. Ethier JH, Kamel KS, Magner PO, et al. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990;15:309-315.

2. Mandal AK. Hypokalemia and hyperkalemia. Med Clin North Am 1997;81:611-639.

3. Revert L. Lethal hyperkalemia associated with severe hyperglycemia in diabetic patients with renal failure. Am J Kidney Dis 1985;5:47-48.

4. Acker CG, Johnson PJ, Palevsky PM, et al. Hyperkalemia in hospitalised patients. Arch Intern Med 1998;158:917-924.

5. Burl RD, Sebastian A, Cheitlin MW, et al. Pseudohyperkalemia caused by fish clenching during phlebotomy. N Engl J Med 1990;322:1290-1292.

6. Halperin ML, Kamel KS. Potassium. Lancet 1998;352:135-140.

7. Coloussis G, Cipriani D. Pseudohyperkalemia in extreme leucocytosis. Am J Nephrol 1995;15:450-452.

8. Rodriguez-Cuartero A, Perez-Blanco F, Riera M, et al. Spurious serum hyperkalemia in essential thrombocythemia. Clin Nephrol 2004;61:229-230.

9. Lin Y-F, Lin S-H, Tsai W-S, et al. Severe hypokalaemia in a Chinese male. Q J Med 2002;95:695-704.

10. Rose B, Post T. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York, McGraw-Hill, 2001.

11. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995;98:575-586.

12. Williams JS, Williams GH. Fiftieth anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:2364-2372.

13. Le Roux CW, Meeran K, Alaghband-Zadeh J. Is a 0900-h cortisol useful prior to a short Synacthen test in outpatient assessment? Ann Clin Biochem 2002;39:148-150.

14. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727-734.

15. Hoffman DM, Crampton L, Sernia C, et al. Short-term growth hormone treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 1996;81:1123-1128.

16. Hoffman AR, Kuntze JE, Baptista J, et al. Growth hormone replacement therapy in adult-onset GH deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2003;89:2048-2056.

17. Bastl C, Hayslett JP, Binder HJ. Increased large intestinal secretion of potassium in renal insufficiency. Kidney Int 1977;12:9.

H. A. Tran, MD

From Hunter Area Pathology Service, John Hunter Hospital, Locked Bag Number 1, Hunter Mail Region Centre, New South Wales 2310, Australia.

Reprint requests to Dr. Huy A. Tran, Department of Clinical Chemistry, Hunter Area Pathology Service, John Hunter Hospital, NSW 2310. Email: [e-mail]

Accepted October 5, 2004.

RELATED ARTICLE: Key Points

* Hyperkalemia is potentially fatal and should be managed with urgency.

* Potassium level greater than 10 mmol/L is rare, and pseudohyperkalemia should be strongly considered, especially when clinically incongruent and when there is an absence of associated electrolyte abnormalities.

* Potassium homeostatic and protective mechanisms include a combination of cellular, renal, endocrine, and gastrointestinal responses. The latter is often not well appreciated.

Table. Serial electrolyte and endocrine results before and after arrest
showing extreme hyperkalemia (a,b,c,d)

                                        15 min
                              Baseline  after
                              (before   CPR (a)        60 min after
Results                       arrest)   started        CPR (a)
                                                       White cell count
                                 Hemoglobin,           11.3 X [10.sup.9]
Full blood count              134 g/L (115-165)        per L (4.0-11.0)

Sodium (137-143 mmol/L)       138         162            155
Potassium (3.5-5.5 mmol/L)
  serum                         4.3        14.0           13.2
  plasma                                   13.8           12.9
Chloride (100-108 mmol/L)      99          95             98
Bicarbonate (24-31 mmol/L)     27           8              9
Lactic acid (0.5-2.2 mmol/L)                5.9            6.2
Urea (3.6-6.8 mmol/L)           6.8         4.6            5.5
Creatinine (0.06-0.10           0.09        0.10           0.10
  mmol/L)
Calcium (2.18-2.50 mmol/L)      2.35        1.73           1.80
Phosphate (0.86-1.36 mmol/L)    1.12        7.72           7.48
Creatine kinase (<180 U/L)    188         669          8,238
Uric acid (0.20-0.40 mmol/L)    0.24        0.27           0.68
Glucose (random) (3.0-7.7       6.5        27.3           26.3
  mmol/L)
24-h urine K excretion (b)     75
                               mmol/d
Transtubular [K.sup.+]          7.0
  gradient (TTKG) (c)
24-h urine Na excretion (d)    98
                               mmol/d
Cortisol (at 8 AM: 150-450    455       1,550          1,890
  nmol/L)
Aldosterone (80-365 ng/dL)    245       2,586          3,200
Renin (0.4-2.5 ng/mL per hr)    1.1         3.8            4.9
Thyrotropin (TSH) (0.5-5.0      2.4         8.8           10.5
  mU/L)
Free tetra-iodothyronine       18           9.5            8.8
  (FT4) (11.0-25.0 pmol/L)
Free triiodothyronine (FT3)     2.3         1.8            2.0
  (2.8-5.8 pmol/L)
Prolactin (<25 [micro]g/L)     25          59             80
Insulin (6-25 mU/L)                        42             40

                              8 h after           24 h after
Results                       arrest                arrest
Full blood count              Platelet count 410 X [10.sup.9]
                                     per L (150-400)

Sodium (137-143 mmol/L)          155                  147
Potassium (3.5-5.5 mmol/L)
  serum                            9.8                  3.5
  plasma                           9.1                  3.7
Chloride (100-108 mmol/L)        101                  114
Bicarbonate (24-31 mmol/L)        10                   18
Lactic acid (0.5-2.2 mmol/L)       5.2                  1.6
Urea (3.6-6.8 mmol/L)              8.8                 18.1
Creatinine (0.06-0.10              0.11                 0.11
  mmol/L)
Calcium (2.18-2.50 mmol/L)         2.35                 2.45
Phosphate (0.86-1.36 mmol/L)       7.50                 1.13
Creatine kinase (<180 U/L)    12,588                7,250
Uric acid (0.20-0.40 mmol/L)       0.55                 0.46
Glucose (random) (3.0-7.7         18.6                 10.3
  mmol/L)
24-h urine K excretion (b)
Transtubular [K.sup.+]
  gradient (TTKG) (c)
24-h urine Na excretion (d)
Cortisol (at 8 AM: 150-450     1,586                  908
  nmol/L)
Aldosterone (80-365 ng/dL)     1,189                1,258
Renin (0.4-2.5 ng/mL per hr)       3.5                  2.5
Thyrotropin (TSH) (0.5-5.0        11.2                  8.5
  mU/L)
Free tetra-iodothyronine           9.8                 10.2
  (FT4) (11.0-25.0 pmol/L)
Free triiodothyronine (FT3)        1.9                  2.0
  (2.8-5.8 pmol/L)
Prolactin (<25 [micro]g/L)        66                   34
Insulin (6-25 mU/L)               55                   48

(a) Hemolysis index shows a hemoglobin value of 186 g/L, indicating
presence of mild/moderate hemolysis. Reference intervals are shown in
parentheses. CPR, cardiopulmonary resuscitation.
(b) Urinary K excretion depends on many factors. When conserving
[K.sup.+], normal excretion rate is <15 mmol/L daily.
(c) TTKG is calculated using formula from Reference 2. It is a
semiquantitative index of the activity of the K secretory process. In
hypokalemia of hyperaldosteronism, mean TTKG is 6.7 [+ or -] 1.3. In
normal subjects ingesting potassium chloride, the value is 13.1 [+ or -]
3.8[.sup.2].
(d) Urinary Na excretion varies with salt intake and is heavily
influenced in this case with the normal saline infusion.