Third in a series on hyperkalemia: current views on the treatment of hyperkalemia

Keywords

Aldosterone antagonist (AA)

Angiotensin converting enzyme inhibitors (ACEI)

Angiotensin receptor blocker (ARB)

Arrhythmia

Asystole (absence of cardiac activity)

Bradycardia

Chronic kidney disease (CKD)

Congestive heart failure (CHF)

Critical care unit (CCU)

Diabetes mellitus (DM)

Hyperkalemia

Hypertension (HTN)

Renin angiotensin aldosterone system (RAAS)

Introduction

About 1-10% of all hospitalized patients presenting at the emergency department (ED) are diagnosed with hyperkalemia [3]. Treatment requires quick and prompt diagnosis and the institution of different pharmacotherapeutic measures as early as possible. An extreme level of alertness on the part of the medical team is of the utmost importance. The drug effect should be assessed constantly with great attentiveness using a cardiac monitor (an ECG) for both cardiac rate and rhythm. The other clinical parameters, such as frequent blood biochemistry, reports on the decline of the values of serum potassium. Associated comorbidities, should also be frequently evaluated. The objectives should always revolve around major issues such as:

(a) proper and thorough clinical assessment of the patients as a whole in the ED;

(b) administration of the most appropriate pharmacotherapeutic measures;

(c) response of the patient to the treatment in a favorable manner;

(d) addressing the comorbid medical or other factors, based on clinical presentation (case history and physical examination).

This article will focus on how rapidly hyperkalemia can be treated with highly effective therapeutic agents, thus saving the life of the victim through the team effort of cardiac clinicians, paramedics and dependable laboratory equipment and personnel.

Although the exact statistics on the number of casualties for hyperkalemic patients are not known, a large number of the patients survive using the simple pharmacologic agents which have remained the same for the last couple of decades. It is uncertain what level of serum potassium above 5.5 mmol/l is going to bring about undesired catastrophic events, hence, any patient whose serum potassium ranges between 5.5 to 6 mmol/l or above should be considered very seriously. Although most studies have revealed life-threatening hyperkalemia to be in the range of 6.5 to 7 mmol/l and above, some unfortunate events have been observed with potassium values close to 6 mmol/l. Fortunately, clinicians are taking appropriate measures whenever they find a patient presenting with serum values a little over 5.0 mmol/l in order to prevent hyperkalemia, primarily by modifying their therapeutic modalities for patients with CHF, HTN, DM, CKD, etc. Although acute hyperkalemia treatment has remained more or less the same, as mentioned earlier, recurrence or new onset cases in susceptible patients should be prevented. Amongst all the new drugs, two are very promising and fall into the category of ion-exchange resins. Particularly, sodium zirconium cyclosilicate (ZS-9) and patiromer sorbitex calcium. Zirconium cyclosilicate, in particular, is very effective, rapid acting and well tolerated. These two new drugs are a welcome addition to the already available and frequently applied FDA-approved sodium or calcium polystyrene sulfonate resins. 

Symptoms and diagnosis

Surprisingly, the majority of the patients have very subtle symptoms, although onset is sudden and abrupt. Symptoms involve chest pain mimicking myocardial infarction, along with sweating, nausea, vomiting, extreme lethargy, weakness and giddiness. The “chest pain”, or precordial pain at presentation in the ED, is at times a very striking symptom. Most of the patients arrive in the CCU within an hour or two of the symptom onset. Most patients show severe brady-arrhythmia, although muscle paralysis is also seen. A large proportion of patients remain totally asymptomatic until the development of acute symptoms. The following diagnostic tools should be used for immediate evaluation:

• Twelve-lead ECG
• Serum Electrolytes (Sodium, Potassium, Magnesium, Calcium)
• Blood biochemistry for kidney function (Serum Creatinine, S. Urea, BUN, etc.)
• Doppler echocardiography
• Troponins in blood (Trop-I)
• Creatine phosphokinase (CPK)
• Arterial blood gas analysis (ABG)

Most patients are found to be suffering from more than one medical disorder, namely CHF, DM, HTN and CKD, in varying proportions and severity, and may be taking potassium-retaining medications such as ACEIs, ARBs, and AAs. In the majority of cases, the ECG will show an abnormality, which will drive the initial therapeutic intervention before obtaining the laboratory reports (blood biochemistry). Later supportive laboratory confirmation of “hyperkalemia” and other abnormal findings of co-existing illnesses should be examined. The ECG on arrival of the patient at the ED always remains a very sensitive indicator of the presence of hyperkalemia. This always triggers the medical team response in initiating ED treatment.

Apathy of patients, or the poor guidance from cardiac clinicians for hyperkalemic emergencies

The probability of hyperkalemia is increasing due to ACEI or ARB administration in virtually all diabetics, newly diagnosed or old, for the “reno-protective effect” of these classes of medicine. These agents are also vital in patients with CHF for balanced preload and afterload reductions, as well as being also frequently used for HTN. Unfortunately, it has been often observed that a large number of clinicians do not provide proper guidance to patients by, for example, proposing they receive intermittent serum potassium blood level estimations. This advice is highly necessary for the reason that most of these medicines have the side effect of potassium retention, something which can be easily corrected without facing any fatal consequences. On the other hand, there is also a serious fault on the part of patients, in terms of very infrequent medical consultations or deliberately not following the doctor’s advice.

This may lie on the complexity of the disorders and the number of medicines administered for chronic heart failure (CHF) management, blood pressure (BP) reduction, etc. The failure to understand renal compromise (both for the clinician and the patient) while receiving ACEIs, ARBs, AAs, which are the key medicines for these diseases, has been found to be the most common cause among this patient group when they arrive in the ED for “acute and abrupt” complications singularly related to hyperkalemia.

As expected, there has been increasing cardiovascular (CV) morbidity and mortality. It is essential to educate these patients and their families about the disease processes and offer periodic screening for hyperkalemia. The chances of hyperkalemia are enormous when “potassium sparing diuretics” are used for CHF, HTN or in any edematous condition. This gives rise to dangerously high levels of serum potassium when combinations of ACEIs or ARBs are made with an aldosterone antagonist, namely spironolactone, eplerenone, etc., particularly in the context of the treatment of CHF of any etiology [4]. Renal impairment at some stage is observed in all those cases, particularly in patients with reduced cardiac systolic function in terms of “ejection fraction” (EF), at levels of EF equal to 45% or less.

A serious inertia has been observed in almost all cases, either on the part of the physician or the patient themselves for a fatal result due to hyperkalemia. Chest pain in a known CV patient should arouse the suspicion of life-threatening hyperkalemia alongside the probability of acute coronary syndrome (ACS). The exact periodicity of serum potassium estimation has not been clearly defined as compared to HbA1c for DM, and this remains the crucial factor for CHF, HTN and DM patients facing a life-threatening situation. Thus, the basic objective of treating these patients with the target of prolonging quality of life becomes virtually useless, futile and risky when faced with the development of hyperkalemia, which brings life to an end in an unexpected and abrupt manner.

Treatment involved for hyperkalemia

Virtually every patient with hyperkalemia presents at the ED in an acutely ill condition. During the process of diagnosing the case, the moment it become obvious that the sole reason for the acute condition lies with hyperkalemia along with other comorbidities all measures should be taken to bring the patient into the normokalemic range. In order to achieve this objective, all treatment measures available such as calcium gluconate injection, IV glucose (25% or 50%), IV soluble (rapid) insulin, beta-agonists (salbutamol) nebulization, IV loop diuretics, IV sodium bicarbonate, potassium binding resins, polystyrene sulfonate (PSF), etc., should be brought into the management protocol. In fact, in most cases, all pharmacologic agents at your disposal will be required to be used. However, adequate attention should be given to the basic etiology of hyperkalemia such as, for instance, CHF versus CKD, problematic drug combinations, hypovolemic versus hypervolemic status, in order to create a balance between these first line management strategies. Most importantly, there should be an emphasis on salbutamol nebulized inhalations versus IV 25%-50% glucose with or without soluble insulin administration. The result and challenge of pharmacologic interventions is found to be largely dependent on such factors as oliguric versus non-oliguric status, availability of a median time of more than 1 to 4 hours of continuous monitored medications, the severity of heart failure with tolerability of glucose (fluid) administration, etc. Acute therapy may include all of these measures or only some of them, depending on the availability of pharmacologic agents, but it is very encouraging to know that their hypokalemic effects are additive [5].

This involves a wide range of measures which comprise the treatment options for acute hyperkalemia. We should consider the treatment protocol employing a “three-way” objective. The first category of cases are those who present with severe hyperkalemia with a potassium value of more than 7 mmol/l. The second category are those with moderate severity having values of between 6 to 7 mmol/l, and the third category, those with mild severity with a potassium value of 5.5 to 6 mmol/l [6]. For the first category of patients we need to employ extremely urgent medications, those which work within minutes (0-30 mins), which are required to save lives in severe cases. For the second group, we can move towards the reduction of potassium load lying in the moderate range with agents which have a hypokalemic effect in 1-2 hours, and finally, for the mild group, we can aim at bringing serum potassium to normokalemia in 3-4 hours or more. Finally, the “fourth dimension” of our treatment modality should focus on measures for the prevention of the recurrence of hyperkalemia since, as we mentioned earlier, the patient with “chronic hyperkalemia” does not survive. Details of the different medications are given below and Table 1 provides an “at a glance” guide for the treatment of hyperkalemia [7].

Rapid acting agents for severe hyperkalemia

1. Calcium gluconate injection: 10 ml of 10% IV to be given rapidly over 3-4 mins, except for those who patients who are on cardiac glycosides (digoxin). This agent does not lower the potassium level, but decreases the cardiac myocytes membrane excitability (membrane stabilizing effect) so as to prevent any deleterious effect in the form of preventing arrhythmias. Its action is short-lived and repeat doses may be required in less than half an hour. It is noteworthy that rapid IV delivery of calcium gluconate in other situations is detrimental, and 10 ml should be administered slowly over 10 to 15 mins; otherwise, it may cause vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope and cardiac arrest. Intravenous administration of calcium should be avoided in patients receiving cardiac glycosides although the recommendations allow for very slow infusion over 20-30 minutes diluted with 5D of 100-200 ml; hence, if necessary, calcium should be given slowly in small amounts because its deleterious effect on cardiac rhythm, particularly when it is known to potentiate cardiac toxicity of digoxin. The outcome of this treatment can be very satisfying, but it is only applied to tide you over the acute crisis preventing death from cardiac arrhythmias in moderate to severe hyperkalemia cases. Careful selection of cases is very important as far as calcium gluconate injection is concerned [8].
2. Glucose-insulin infusion: 25% to 50% of dextrose of 100 ml mixed with 10-20 units of soluble insulin, to be infused (slowly in CHF patients or in cases of hypervolemic state). This measure is highly effective in obtaining results within minutes. Here the potassium value falls due to a shift of the cation from the extracellular to the intracellular space. This effect is temporary and hence requires a slow continuous infusion and frequent capillary blood glucose (CBG) monitoring. This measure efficient in lowering serum potassium to the range of 0.5 to 1.5 mmol/l as compared to the pre-treatment value. Uncontrolled diabetic patients with a CBG level higher than 300-350 mg% need only a soluble insulin infusion through a syringe pump at a rate of 5-6 units per hour with a bolus of 10 units at the outset and, in order to prevent hypoglycemia, concomitant dextrose (10%-25%) administration when the CBG level falls below 150 -200 mg. Only the infusion of 100 ml 50% glucose has been compared with 100 ml 50% glucose and 10 units of soluble insulin which has been observed to produce a clinically significant decrease in serum potassium without episodes of hypoglycemia [9]. The outcome is very encouraging with this modality of treatment.
3. Beta2-adrenergic agonists: this is another highly effective measure for prompt potassium decline to prevent arrhythmias. The recommended and widely used agent is salbutamol (albuterol), nebulized solutions or inhalation formulations. The widely used form is nebulized aerosols of salbutamol at a dose of 10-20 mg diluted in 4 ml of normal saline, either intermittent inhalations at 10-15 minute intervals or continuous inhalation with a lower dosage or further diluted (this is an approximately 4-8 times higher dosage is required as compared to its use in broncho-spastic disorders). The reason for the slow continuous inhalation is related to its short-lasting action, usually approximately 2 hours. Serum potassium falls rapidly by the same mechanism as that of glucose-insulin, i.e., a cation shift from extracellular to intracellular, there is virtually no potassium removal from the body in both approaches. The hypokalemic potential is in the range of 0.5 to 1.5 mmol/l compared to the pre-treatment level. Because of the additive effect, a beta-agonist inhalation and glucose-insulin infusion combination always proves more effective than either alone and should be considered when hyperkalemia is severe [10]. Some authorities believe this has a very poor effect in hyperkalemia in the cases of very advanced CKD. In other clinical situations, and for all practical purposes, beta-agonist treatment outcome is excellent.
4. Sodium bicarbonate injection: use of 25% sodium bicarbonate (50-100 mEq dose at a time) intravenously, acts with the same mechanism of transcellular shift as that of glucose, insulin, and salbutamol. This agent is effective only when plasma acidosis is predominant, mostly in advanced CKD patients. Action is slow and the duration is short, mostly 1-2 hours [8].

Second line agents for moderate to mild hyperkalemia

1. Loop diuretics: Frusemide injection, at a dose of 40 to 80 mg intravenously is invaluable in removing potassium load from the system in non-oliguric states. Renal potassium excretion is the definitive goal while addressing this situation. Frusemide is highly effective when renal function is preserved, hence this will be of no benefit in an extreme oliguric condition (ARF, ESRD). The onset of hypokalemic action is 30-60 minutes and potassium removal is variable depending on kidney function status. Excellent results are possible in those cases where drug-induced (ACEIs, ARBs, AAs) hyperkalemia develops. Repetition of dosing is required at 2-4 hourly intervals depending upon hemodynamic status or until such a time as normokalemic status has been achieved. For maintenance of normokalemia, diuretics are continued in oral form after the acute phase is over. The untoward effects of this agent are hypotension, hyponatremia, hypokalemia, volume depletion, etc. However, if adequate attention is paid to the side effects, then diuretics should be an integral part of disease management, such as in HTN, CHF, DM and early CKD where ACEI, ARB or AA were seen the sole reason for the hyperkalemic crisis.

2. Cation-exchange resins: Calcium polystyrene sulfonate (CPS, K-bind powder) and sodium polystyrene sulfonate (SPS, kayexalate powder) are still considered to be very important agents in the removal of excess potassium from the body. This class of drugs works in the GI tract, exchanging potassium for calcium and sodium respectively. The action is slow, onset time 2-4 hours or more. The recommended dose is 15 gm four times a day. The initial bolus may be given as 60 gm granules dissolved in sorbitol (1:4 dilution), either orally or rectally (as a retention enema). Constipation is the major side effect and hence an addition of sorbitol is needed. The major threat in using these combinations are bowel necrosis or perforation in patients with abnormal bowel function or patients who have undergone recent bowel surgery. This is especially true with kayexalate (SPS). Another negative effect is hypokalemia when the treatment with resins is continued with variable dosage, once or twice daily. The efficiency of potassium removal is approximately 1 mEq per 1 gm of resin, but effectively 1 mEq of potassium is removed per day. These are the most suited agents for all stages of CKD including end stage renal damage (ESRD).

The two newer and promising drugs targeting the colon as the site of potassium removal are Sodium zirconium cyclosilicate (ZS 9) and patiromer sorbitex calcium. These two new oral potassium-exchanging compounds were shown to effectively normalize elevated serum potassium and chronically maintain potassium homeostasis in hyperkalemic patients treated with RAAS blockers (ACEIs, ARBs, and AAs). Both agents exhibit good tolerability and have not been associated with serious adverse effects. These drugs are promising in terms of lowering the risks of the incidence of hyperkalemia associated with RAAS blockade in people with CHF or DM who have CKD. They also provide the opportunity to test whether patients who could not previously receive RAAS blockade for fear of hyperkalemia, may benefit from their cardio- and reno-protective effects.

Microporous zirconium cyclosilicate compound (ZS-9), one of the most very rapid and sustained acting agent amongst all resins, can selectively entrap monovalent cations, including excess potassium and ammonium ions, in the GI tract. Furthermore, in acute hyperkalemia, it has the potential of becoming an important clinical option by rapidly lowering potassium levels, thus delaying or potentially averting the need for emergency dialysis. It could play a promising role in both acute and chronic management of hyperkalemia, as it does not swell in the GI tract, thus limiting GI symptoms. In the acute phase, a significant change in potassium compared with base (−0.2 mEq/L) was noted 1 hour after the first 10 gram dose. At 2 and 4 hours after the first dose, mean change in potassium was −0.4 mEq/L and −0.5 mEq/L, respectively, for both time points. The maintenance phase demonstrated that all three doses (5, 10 and 15 grams) maintained mean potassium at lower levels, maintaining normokalemia. The most common adverse effects experienced were constipation, anemia, hypokalemia and, infrequently, nasopharyngitis and upper respiratory tract infections. Zirconium (ZS-9), which is presently undergoing a phase III clinical trial, seems to be a promising alternative to sulfonates (SPS), one that does not induce diarrhea or colonic necrosis. Longer-term safety and tolerability studies are required for FDA approval which is expected in the first half of 2016 [11,12,13,14,15].

The FDA has approved patiromer to treat hyperkalemia (October 21, 2015), making it the first agent approved for this condition. Patiromer sorbitex calcium consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer. In the colon, patiromer exchanges calcium for potassium, thus causing a fall in serum potassium. Trials have shown that patiromer reduces serum potassium in patients with mild, moderate and moderate to severe hyperkalemia to the normal range. It has also been used successfully in patients with chronic kidney disease and/or heart failure. It has also permitted the use of the mineralocorticoid antagonist spironolactone in full dosage in patients with chronic kidney disease and/or heart failure who were already receiving an RAAS inhibitor. Adverse effects have mostly been gastrointestinal in nature and have not caused patients to discontinue treatment in unacceptable numbers. The drug is not absorbed and it is ten times more powerful than kayexalate (SPS). Constipation is the main side effect observed with this drug. Another important issue is that it is not suitable for use in acute hyperkalemia treatment as the drug has a slow onset in its action [16,17].

3. Hemodialysis: Although a very effective way of removing excess serum potassium, is not frequently applied. It is reserved for patients with advanced CKD and those who remain unresponsive to conservative measures, as discussed above. While hemodialysis is very effective (the potassium removal rate is nearly 25-50 mmol/l per hour), at times it is very difficult to use for hyperkalemia therapy as the equipment is neither compact nor easily portable and necessitates an expert paramedical staff to operate. However, this remains the primary therapeutic option in ESRD, not only for dangerous hyperkalemia but also for patient survival when renal transplant is the final target. Hemodialysis is also invaluable in selective cases of acute renal failure (ARF) for multiple reasons, and the outcome of this short-term hemodialysis is extremely positive and long lasting.

The fourth dimension in the treatment of hyperkalemia involves adequate preventive measures for those who have faced or are prone to develop hyperkalemia. These are the patients suffering from HTN, CHF, DM, CKD (Stage I to IIIb or higher) and receiving ACEIs, ARBs, AAs to control their diseases. Both clinicians and patients should be sufficiently aware concerning the threat to life caused by moderate to severe hyperkalemia. The modalities require modifying or reducing the dosage of the offending drugs, with frequent estimations of the serum electrolytes, frequent doctor/patient interactions, dietary modifications (avoiding high potassium-containing foods notably molasses, nuts, wheat cereal, banana, kiwis, oranges, mangoes), promoting urinary excretion with diuretics, as well as augmenting colonic potassium loss with cation-binding resins (SPF, ZS9, patiromer, etc.) or administering mineralocorticoids or fludrocortisone particularly in cases with hypoaldosteronism

Table 1. Treatment of hyperkalemia at a glance (Adapted from reference [7])

Correlation of serum potassium values and the outcome

In the author’s own experience, the outcome of treatment could never be predicted based on the absolute serum potassium value at admission. No correlation was found between the values and cardiac arrest (asystole). Patients with serum values of 5.8 mmol/l and 6.2 mmol/l succumbed while receiving treatment at the CCU, despite the utmost care and the most appropriate pharmacologic measures, in a span of 1-2 hours. On the other hand, a good number of patients survived who had values of more than 6.5 to 7.5 mmol/l with the same measures, by virtue of not developing malignant arrhythmia over a longer period of time (>3-4 hours). Due to the availability of more time, there was progressive decline of potassium with consequent changes in ECG configurations, rate and rhythm. This was observed as a favorable change where the patients ultimately reached a normokalemic range with excellent recovery based on the disappearance of ECG changes, one by one, until regular sinus rhythm and normal QRS-T configuration was achieved. Hence, the predictability of outcome was never possible with absolute serum potassium values exceeding normokalemic range.

Conclusion

The potassium concentration within human cells is approximately 140 mmol/l and the extracellular potassium concentration is normally 3.5 to 5.5 mmol/l. Whatever the hyperkalemic status might be, whether the plasma potassium levels are from 5.5 to 5.9 mmol/l, or 6.0 to 7 mmol/l, or 7.0 mmol/l and above, it may lead to life-threatening cardiac arrhythmias. These arrhythmias occur at times so abruptly that each of these patient groups must be given similar attention in the ED in terms of therapeutic response. The only exception remains in patients with potassium in high normal values of 5 to 5.5 mmol/l, where careful monitoring and the avoidance of a high intake of a potassium-rich diet along with modification of their existing current therapies which might be increasing their potassium levels is perhaps all that is required.

With the future availability of two highly effective oral agents, we may be entering a new era (the colonic era) for the treatment of hyperkalemia. This is particularly relevant for use with those agents which are needed for the adequate control of certain disease processes but where a fear of hyperkalemia precluded their use. Nonetheless, proper knowledge and understanding of individual drugs, their effects and side effects for treating acute hyperkalemic emergencies remain invaluable and the existing older medications are still adequate to save the victim’s life. Of those agents we reviewed, , salbutamol aerosol inhalations and IV insulin-dextrose appear to be the most effective in reducing serum potassium. There is limited evidence to support the use of others, such as IV sodium bicarbonate or aminophylline, particularly in the acute phase. The effectiveness of potassium binding resins in particular has not been tested in randomized control trials and requires further study before firm recommendations for clinical practice can be made [18].

Lastly, a dedicated team should devote the utmost care in dealing with this potentially treatable lethal clinical condition. All that is required to saving a precious life is the judicious application of all pharmacologic measures by a thoroughly experienced medical team. The clinician’s proper guidance and education and the patient’s adequate understanding and adherence to medical advice should make hyperkalemia extremely rare in the near future.