Amitriptyline toxicity kills patient

Unknown North Carolina venue

A 26-year-old woman with diabetes saw a psychiatrist to manage her depression. The psychiatrist increased her amitriptyline dosage to 300 mg nightly and over 10 months added:

• alprazolam (unknown dosage, nightly)
  
• quetiapine (400 mg bid)
  
• extended-release venlafaxine (225 mg bid)
  
• and promethazine (100 mg bid).
  

The patient also took insulin for diabetes.

Several weeks later, the woman was found dead in her home. An autopsy revealed amitriptyline toxicity as the cause of death. The medical examiner noted “a much larger concentration of the metabolite nortriptyline in the liver versus the parent drug,” suggesting a metabolism problem, rather than an overdose, caused the toxic build-up.

The patient’s estate claimed that amitriptyline was cardiotoxic at the prescribed dosage and combined with the other medications used and that the patient was not properly monitored.

• A $2.3 million settlement was reached.
  

Fatal cardiac arrest after 2 concomitant antidepressants

Gwinnett County (GA) Superior Court

A 40-year-old woman was under a psychiatrist’s care for anxiety and depression. The psychiatrist continued sertraline, which the woman had been taking, and added nortriptyline. Several weeks after the patient began taking the medications together, she had a fatal cardiac arrest.

The patient’s estate argued that:

• toxic levels of the antidepressants caused her death
  
• sertraline and nortriptyline should not be taken concurrently because one drug inhibits clearance of the other
  
• the psychiatrist should have monitored the patient to make sure sertraline and nortriptyline levels remained normal.
  

The psychiatrist argued that coronary artery disease caused the patient’s death—not the combination of medications.

The medical examiner was unable to say which condition more likely led to the patient’s death.

• The defendant was awarded $3 million. A statutory capitation reduced the award to $1.65 million.
  

Dr. Grant’s observations

As these cases demonstrate, lawsuits against psychiatrists commonly include allegations of preventable prescribing missteps and drug-drug interactions^{Off-label prescribing: 7 steps for safer, more effective treatment”).
When a patient is taking multiple medications, interactions can inhibit drug metabolism and render normal doses excessive.5 When prescribing drugs known to have adverse effects with excessive dosing, such as tricyclic antidepressants and lithium, failing to monitor serum levels could be considered malpractice. In fact, the courts view actions such as prescribing doses that exceed FDA recommendations or failing to monitor levels as prima facie evidence of negligence, requiring the psychiatrist to prove otherwise.}

Amitriptyline and nortriptyline have shown cardiac toxicity in overdose,⁶ and their serum levels increase when used with other antidepressants.^7,8 Standard of care dictates serum level monitoring particularly when you use tricyclics:

• in doses higher than recommended by the FDA (300 mg/d for amitriptyline, 150 mg/d for nortriptyline)
  
• with other drugs that affect their metabolism.⁹
  

You cannot rely on pharmacy computer programs to catch potentially important drug-drug interactions. One study found that even among pharmacies with such programs, one-third of pharmacists filled prescriptions for a dangerous medication combination.¹⁰

Box

How to prevent fatal errors. Don’t shy away from using medications that require serum level monitoring. Anticipating and monitoring drug-drug interactions becomes second nature once you’ve used these medications frequently. Plus, patients benefit from a greater array of safe and effective treatment options.

The following strategies can help you avoid mistakes and malpractice claims.^1,11

Clinical practice. Obtain a comprehensive patient history and necessary examinations before prescribing medications. See patients at clinically appropriate intervals.

Ask the patient about other medications he or she is taking, including over-the-counter medications, herbal remedies, and dietary supplements. Remind the patient to report changes in medications or new medications prescribed by another physician.

Put in place a process to obtain appropriate baseline laboratory testing and to ensure that follow-up testing is completed and reviewed. Monitoring lab results becomes particularly important in cases—such as these two—when escalating levels of certain medications can cause adverse effects.

 

Communicate with the patient’s other physicians about all the medications that are being prescribed to him and about signs, symptoms, and responses to the medications.

Educate yourself by participating in continuing education programs, discussions with colleagues, and through relevant literature. Review drug manufacturer alerts.

Patient education. Educate patients about medication instructions, including the dosage and frequency, ways to identify side effects, and what to do in the event of side effects or a bad reaction. Get informed consent.

Be aware of and inform the patient about potentially lethal side effects of misusing or abusing certain medications. Address the use of street drugs and how they interact with prescription medications; make appropriate treatment assessments and referrals for addiction and dependence issues.

Documentation. Keep thorough records of medications prescribed: dosage, amount, directions for taking them, and other instructions to the patient. Document results of laboratory testing and any decisions you make based on medication serum levels.

When using polypharmacy that increases the risk of adverse interactions, document a clear rationale in patients’ charts.

Amitriptyline toxicity kills patient

Unknown North Carolina venue

A 26-year-old woman with diabetes saw a psychiatrist to manage her depression. The psychiatrist increased her amitriptyline dosage to 300 mg nightly and over 10 months added:

• alprazolam (unknown dosage, nightly)
  
• quetiapine (400 mg bid)
  
• extended-release venlafaxine (225 mg bid)
  
• and promethazine (100 mg bid).
  

The patient also took insulin for diabetes.

Several weeks later, the woman was found dead in her home. An autopsy revealed amitriptyline toxicity as the cause of death. The medical examiner noted “a much larger concentration of the metabolite nortriptyline in the liver versus the parent drug,” suggesting a metabolism problem, rather than an overdose, caused the toxic build-up.

The patient’s estate claimed that amitriptyline was cardiotoxic at the prescribed dosage and combined with the other medications used and that the patient was not properly monitored.

• A $2.3 million settlement was reached.
  

Fatal cardiac arrest after 2 concomitant antidepressants

Gwinnett County (GA) Superior Court

A 40-year-old woman was under a psychiatrist’s care for anxiety and depression. The psychiatrist continued sertraline, which the woman had been taking, and added nortriptyline. Several weeks after the patient began taking the medications together, she had a fatal cardiac arrest.

The patient’s estate argued that:

• toxic levels of the antidepressants caused her death
  
• sertraline and nortriptyline should not be taken concurrently because one drug inhibits clearance of the other
  
• the psychiatrist should have monitored the patient to make sure sertraline and nortriptyline levels remained normal.
  

The psychiatrist argued that coronary artery disease caused the patient’s death—not the combination of medications.

The medical examiner was unable to say which condition more likely led to the patient’s death.

• The defendant was awarded $3 million. A statutory capitation reduced the award to $1.65 million.
  

Dr. Grant’s observations

As these cases demonstrate, lawsuits against psychiatrists commonly include allegations of preventable prescribing missteps and drug-drug interactions^{Off-label prescribing: 7 steps for safer, more effective treatment”).
When a patient is taking multiple medications, interactions can inhibit drug metabolism and render normal doses excessive.5 When prescribing drugs known to have adverse effects with excessive dosing, such as tricyclic antidepressants and lithium, failing to monitor serum levels could be considered malpractice. In fact, the courts view actions such as prescribing doses that exceed FDA recommendations or failing to monitor levels as prima facie evidence of negligence, requiring the psychiatrist to prove otherwise.}

Amitriptyline and nortriptyline have shown cardiac toxicity in overdose,⁶ and their serum levels increase when used with other antidepressants.^7,8 Standard of care dictates serum level monitoring particularly when you use tricyclics:

• in doses higher than recommended by the FDA (300 mg/d for amitriptyline, 150 mg/d for nortriptyline)
  
• with other drugs that affect their metabolism.⁹
  

You cannot rely on pharmacy computer programs to catch potentially important drug-drug interactions. One study found that even among pharmacies with such programs, one-third of pharmacists filled prescriptions for a dangerous medication combination.¹⁰

Box

How to prevent fatal errors. Don’t shy away from using medications that require serum level monitoring. Anticipating and monitoring drug-drug interactions becomes second nature once you’ve used these medications frequently. Plus, patients benefit from a greater array of safe and effective treatment options.

The following strategies can help you avoid mistakes and malpractice claims.^1,11

Clinical practice. Obtain a comprehensive patient history and necessary examinations before prescribing medications. See patients at clinically appropriate intervals.

Ask the patient about other medications he or she is taking, including over-the-counter medications, herbal remedies, and dietary supplements. Remind the patient to report changes in medications or new medications prescribed by another physician.

Put in place a process to obtain appropriate baseline laboratory testing and to ensure that follow-up testing is completed and reviewed. Monitoring lab results becomes particularly important in cases—such as these two—when escalating levels of certain medications can cause adverse effects.

 

Communicate with the patient’s other physicians about all the medications that are being prescribed to him and about signs, symptoms, and responses to the medications.

Educate yourself by participating in continuing education programs, discussions with colleagues, and through relevant literature. Review drug manufacturer alerts.

Patient education. Educate patients about medication instructions, including the dosage and frequency, ways to identify side effects, and what to do in the event of side effects or a bad reaction. Get informed consent.

Be aware of and inform the patient about potentially lethal side effects of misusing or abusing certain medications. Address the use of street drugs and how they interact with prescription medications; make appropriate treatment assessments and referrals for addiction and dependence issues.

Documentation. Keep thorough records of medications prescribed: dosage, amount, directions for taking them, and other instructions to the patient. Document results of laboratory testing and any decisions you make based on medication serum levels.

When using polypharmacy that increases the risk of adverse interactions, document a clear rationale in patients’ charts.

Amitriptyline toxicity kills patient

Unknown North Carolina venue

A 26-year-old woman with diabetes saw a psychiatrist to manage her depression. The psychiatrist increased her amitriptyline dosage to 300 mg nightly and over 10 months added:

• alprazolam (unknown dosage, nightly)
  
• quetiapine (400 mg bid)
  
• extended-release venlafaxine (225 mg bid)
  
• and promethazine (100 mg bid).
  

The patient also took insulin for diabetes.

Several weeks later, the woman was found dead in her home. An autopsy revealed amitriptyline toxicity as the cause of death. The medical examiner noted “a much larger concentration of the metabolite nortriptyline in the liver versus the parent drug,” suggesting a metabolism problem, rather than an overdose, caused the toxic build-up.

The patient’s estate claimed that amitriptyline was cardiotoxic at the prescribed dosage and combined with the other medications used and that the patient was not properly monitored.

• A $2.3 million settlement was reached.
  

Fatal cardiac arrest after 2 concomitant antidepressants

Gwinnett County (GA) Superior Court

A 40-year-old woman was under a psychiatrist’s care for anxiety and depression. The psychiatrist continued sertraline, which the woman had been taking, and added nortriptyline. Several weeks after the patient began taking the medications together, she had a fatal cardiac arrest.

The patient’s estate argued that:

• toxic levels of the antidepressants caused her death
  
• sertraline and nortriptyline should not be taken concurrently because one drug inhibits clearance of the other
  
• the psychiatrist should have monitored the patient to make sure sertraline and nortriptyline levels remained normal.
  

The psychiatrist argued that coronary artery disease caused the patient’s death—not the combination of medications.

The medical examiner was unable to say which condition more likely led to the patient’s death.

• The defendant was awarded $3 million. A statutory capitation reduced the award to $1.65 million.
  

Dr. Grant’s observations

As these cases demonstrate, lawsuits against psychiatrists commonly include allegations of preventable prescribing missteps and drug-drug interactions^{Off-label prescribing: 7 steps for safer, more effective treatment”).
When a patient is taking multiple medications, interactions can inhibit drug metabolism and render normal doses excessive.5 When prescribing drugs known to have adverse effects with excessive dosing, such as tricyclic antidepressants and lithium, failing to monitor serum levels could be considered malpractice. In fact, the courts view actions such as prescribing doses that exceed FDA recommendations or failing to monitor levels as prima facie evidence of negligence, requiring the psychiatrist to prove otherwise.}

Amitriptyline and nortriptyline have shown cardiac toxicity in overdose,⁶ and their serum levels increase when used with other antidepressants.^7,8 Standard of care dictates serum level monitoring particularly when you use tricyclics:

• in doses higher than recommended by the FDA (300 mg/d for amitriptyline, 150 mg/d for nortriptyline)
  
• with other drugs that affect their metabolism.⁹
  

You cannot rely on pharmacy computer programs to catch potentially important drug-drug interactions. One study found that even among pharmacies with such programs, one-third of pharmacists filled prescriptions for a dangerous medication combination.¹⁰

Box

How to prevent fatal errors. Don’t shy away from using medications that require serum level monitoring. Anticipating and monitoring drug-drug interactions becomes second nature once you’ve used these medications frequently. Plus, patients benefit from a greater array of safe and effective treatment options.

The following strategies can help you avoid mistakes and malpractice claims.^1,11

Clinical practice. Obtain a comprehensive patient history and necessary examinations before prescribing medications. See patients at clinically appropriate intervals.

Ask the patient about other medications he or she is taking, including over-the-counter medications, herbal remedies, and dietary supplements. Remind the patient to report changes in medications or new medications prescribed by another physician.

Put in place a process to obtain appropriate baseline laboratory testing and to ensure that follow-up testing is completed and reviewed. Monitoring lab results becomes particularly important in cases—such as these two—when escalating levels of certain medications can cause adverse effects.

 

Communicate with the patient’s other physicians about all the medications that are being prescribed to him and about signs, symptoms, and responses to the medications.

Educate yourself by participating in continuing education programs, discussions with colleagues, and through relevant literature. Review drug manufacturer alerts.

Patient education. Educate patients about medication instructions, including the dosage and frequency, ways to identify side effects, and what to do in the event of side effects or a bad reaction. Get informed consent.

Be aware of and inform the patient about potentially lethal side effects of misusing or abusing certain medications. Address the use of street drugs and how they interact with prescription medications; make appropriate treatment assessments and referrals for addiction and dependence issues.

Documentation. Keep thorough records of medications prescribed: dosage, amount, directions for taking them, and other instructions to the patient. Document results of laboratory testing and any decisions you make based on medication serum levels.

When using polypharmacy that increases the risk of adverse interactions, document a clear rationale in patients’ charts.

The phone rang at 6 a.m. on a cold, stormy winter morning. It was a consult: Would I come see a patient in the ICU? I was in my second year of nephrology fellowship, moonlighting out on the frozen tundra of Minnesota. It was Garrison Keillor country, and—as he says about Lake Wobegon—on that day the woman was strong, but I was one man who was not looking too good. I rolled over and brought up the labs on my bedside computer. The patient’s potassium was 7.8 mmol/L; she also had a creatinine of 6.1 mg/dL, a bicarbonate of 8 mmol/L, and a blood urea nitrogen (BUN) more than 140 mg/dL.

This was a small community hospital with no dialysis facility, and my first thought was that it was time to warm up the Medevac helicopter. I could envision the flight nurses loading the patient and saying, “Welcome aboard Medevac One. Today we will be serving normal saline, insulin, and glucose. Sit back and enjoy the flight, and thank you for choosing Medevac One.” One look outside at the flying snow canceled that plan. I went to see the patient.

One of the first symptoms of uremia is anorexia, and the patient will frequently self-avert from taking protein—sort of a survival mechanism in an attempt to control uremia. I arrived in the ICU to find a woman finishing off a plate of bacon and eggs. She told me she had had a gynecologic procedure done a little over a week before. The pain had been intolerable during the past week. She had not felt like eating or drinking and had been taking a lot of ibuprofen. It was the pain that had brought her to the emergency department, and the narcotics had worked wonders. She was finally feeling well enough to eat. Her ECG was stone-cold unchanged from one obtained pre-operatively.

I treated immediately with intravenous insulin, dextrose, and sodium polystyrene sulfonate. By exam she was volume depleted, and her urine output overnight was less than 10 mL per hour. An arterial blood gas demonstrated a significant mixed acidemia; both anion and nonanion gap acidosis were present. I used a bolus of bicarbonate solution, and the urine output in one hour was 50 mL. This was better, and she had just proven to me that she could make urine. Great news for a nephrologist in training! I ordered a constant infusion of bicarbonate.

Despite these labs, she was hypertensive, so I ordered furosemide—200 mg IV—to attempt a forced diuresis. After another hour, the urine output was 200 mL, and I was much more comfortable. Hyperkalemia is much easier to control when a patient is nonoliguric, and I continued aggressive fluid administration. Within four hours, the patient’s potassium and the acidemia were much improved. By the end of my shift, the potassium was within normal range, the creatinine and BUN had also improved significantly, and the patient was transferred to the medical floor.

This patient’s story illustrates the potential difficulties involved in diagnosing and treating potassium-related problems. With these challenges in mind, here are 10 pieces of information every hospitalist should have when dealing with this type of patient.

1) Hyperkalemia in the patient with acute renal failure is usually a problem of poor perfusion; acute decreases in glomerular filtration rate (GFR) that occur in acute renal failure could lead to a marked decrease in sodium and water at the distal tubule, which might decrease distal potassium secretion.

 

When acute renal failure is oliguric, distal delivery of sodium and water is low, and hyperkalemia is a frequent problem. What to do? If respiratory status allows, add aggressive volume resuscitation to your medical management. If the patient’s urine output increases, or when acute renal failure is nonoliguric, distal delivery is usually sufficient and hyperkalemia is less of an issue. Concerned about giving IV fluids to an oliguric patient? Medical management is a temporizing measure in the oliguric patient, and hyperkalemia will always be difficult to treat; a fluid challenge might be worthwhile prior to initiating hemodialysis. Urgent dialysis might be hours away, but fluids can be started within minutes.

If hemodynamics allow, I start forced diuresis with high-dose loop diuretics in an attempt to convert to nonoliguria and promote renal potassium excretion. In life-threatening hyperkalemia all is fair, and—once a patient is nonoliguric—hyperkalemia is much easier to manage.

2) A little potassium is not always bad. There is robust evidence supporting the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in patients with chronic kidney disease with both diabetic and non-diabetic causes. In most patients, according to the National Kidney Foundation’s Clinical Guidelines, the ACE inhibitor or ARB can be continued if the GFR decline over four months is <30% from baseline value and serum potassium is equal to 5.5 mEq/L. The proper way for the inpatient physician to initiate treatment with an ACE inhibitor or ARB is to start at a low dose, with follow-up in one week for a serum potassium measurement and titration of dose as necessary.

3) During my fellowship, I had an attending who would start a discussion with the phrase “I’m just a dumb nephrologist” and then talk for 25 minutes about the physiology of, theories about, and potential therapeutic interventions for just about any type of kidney disease. I prefer a simple approach, too: insulin and dextrose. Why? Because it works well on just about all patients and is quick to administer. Just about every hospital floor in America has a supply of insulin and dextrose on hand. Give the order and, in most cases, the patient is receiving treatment in a matter of minutes.

4) Sodium bicarbonate buffers hydrogen ions extracellularly while shifting potassium intracellularly to maintain electrical neutrality. Sodium bicarbonate should be reserved for cases with severe metabolic acidosis, because effects might be delayed or unreliable, especially in patients with chronic kidney disease.

5) Beta-2 adrenergic agonists drive potassium intracellularly via the Na,K-ATPase mechanism. Albuterol is most commonly used; however, the dosage used by clinicians is frequently insufficient. A dose of albuterol that is 10–20 mg via nebulizer is required, and response time to lowering of potassium might be up to 90 minutes.1

6) I am often asked what ECG changes need to be present before I recommend treatment of hyperkalemia with calcium chloride or calcium gluconate. In a patient without central venous access the concern is that peripheral intravenous infusions of calcium might extravasate, leading to local cellular necrosis and possible loss of limb.

The answer I give is that I don’t know what exact ECG changes would benefit from treatment versus no treatment. In fact, patients with life-threatening hyperkalemia might have subtle changes on ECG.2 Therefore, I believe that every patient with electrocardiographic manifestations of hyperkalemia can be treated with calcium infusion. In my mind, the outcome of sudden cardiac death is far worse than the possible negative effects of calcium infusion.

7) If you suspect a renal cause for a potassium derangement, please check the urine electrolytes. This test is best done at the time of admission or when the patient is in a steady state. As a practicing nephrologist, I find that most of my consults for electrolyte abnormalities are for the patient with a chronic potassium abnormality. I am usually called on the second or third day, when the patient has received a multitude of IV fluids, treatment, medication changes, and so on. All too often, no urine studies have been obtained at the time of consultation. Would you consult your cardiologist for chest pain without first obtaining an ECG?

 

8) Normally, when blood is drawn and allowed to clot before centrifugation, enough potassium is released from platelets to raise the serum level by approximately 0.5 mEq/L. This is accounted for within the limits of the normal range. Excessive errors could occur, however, in the presence of marked leukocytosis or thrombocytosis. These conditions are referred to as pseudohyperkalemia. This can be confirmed by remeasuring serum potassium in a blood sample collected in a heparinized sample tube.3

9) Oral sodium phosphate is a cathartic used in bowel preparation prior to colonoscopy. This agent has been associated with changes in serum electrolyte levels that are generally within the normal range but could occasionally cause serious electrolyte disturbances. Significant hypokalemia could develop, particularly in the elderly, and is due to intestinal potassium loss.4

Other abnormalities reported include hyperphosphatemia, hypocalcemia, and hypernatremia. In addition to increased age, risk factors for these disturbances include the presence of bowel obstruction, poor gut motility, and unrecognized renal disease. Additionally, phosphate nephropathy has been well reported after administration of sodium phosphate and might cause irreversible kidney disease with histology resembling nephrocalcinosis.5

10) The most commonly used cation-exchange resin, sodium polystyrene sulfonate, is frequently used to manage hyperkalemia in patients with chronic kidney disease. Use of this resin could result in hypokalemia, hypomagnesemia, and—occasionally—metabolic alkalosis. After the oral administration of this drug, sodium is released from the resin in exchange for hydrogen in the gastric juice. As the resin passes through the rest of the gastrointestinal tract, the hydrogen is then exchanged for other cations, including potassium, which is present in greater quantities, particularly in the distal gut. Potassium binding to the resin is influenced by duration of exposure, which is primarily determined by gut transit time.

The primary potential complication of using sodium polystyrene sulfonate is the development of sodium overload. The absorption of sodium from the resin by the gut might lead to heart failure, hypertension, and occasionally hypernatremia. Because the resin binds other divalent cations, hypocalcemia and hypomagnesemia could also develop. Decreased plasma levels of magnesium and calcium are more likely to occur in patients taking diuretics or in those with poor nutrition.6 Use of the resin could also lead to metabolic alkalosis when administered with antacids or phosphate binders such as magnesium hydroxide or calcium carbonate. As magnesium and calcium bind to the resin, the base is then free to be absorbed into the systemic circulation. TH

Dr. Casey works in the Department of Internal Medicine, Section of Hospital Internal Medicine, Division of Nephrology and Hypertension at the Mayo Clinic, Rochester, Minn.

References

1. Liou HH, Chiang SS, Wu SC, et al. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure: comparative study. Am J Kidney Dis. 1994 Feb;23(2):266-271.
2. Martinez-Vea A, Bardaji A, Garcia C, et al. Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases. J Electrocardiol. 1999 Jan;32(1):45-49.
3. Stankovic AK, Smith S. Elevated serum potassium values: the role of preanalytic variables. Am J Clin Pathol. 2004 Jun;121 Suppl:S105–S112.
4. Beloosesky Y, Grinblat J, Weiss A, et al. Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med. 2003 Apr 14;163(7):803–808.
5. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colorectal cleanser. Drugs. 2004;64(15):1697-1714.
6. Chen CC, Chen CA, Chau T, et al. Hypokalaemia and hypomagnesaemia in an oedematous diabetic patient with advanced renal failure. Nephrol Dial Transplant. 2005 Oct;20(10):2271-2273.

The phone rang at 6 a.m. on a cold, stormy winter morning. It was a consult: Would I come see a patient in the ICU? I was in my second year of nephrology fellowship, moonlighting out on the frozen tundra of Minnesota. It was Garrison Keillor country, and—as he says about Lake Wobegon—on that day the woman was strong, but I was one man who was not looking too good. I rolled over and brought up the labs on my bedside computer. The patient’s potassium was 7.8 mmol/L; she also had a creatinine of 6.1 mg/dL, a bicarbonate of 8 mmol/L, and a blood urea nitrogen (BUN) more than 140 mg/dL.

This was a small community hospital with no dialysis facility, and my first thought was that it was time to warm up the Medevac helicopter. I could envision the flight nurses loading the patient and saying, “Welcome aboard Medevac One. Today we will be serving normal saline, insulin, and glucose. Sit back and enjoy the flight, and thank you for choosing Medevac One.” One look outside at the flying snow canceled that plan. I went to see the patient.

One of the first symptoms of uremia is anorexia, and the patient will frequently self-avert from taking protein—sort of a survival mechanism in an attempt to control uremia. I arrived in the ICU to find a woman finishing off a plate of bacon and eggs. She told me she had had a gynecologic procedure done a little over a week before. The pain had been intolerable during the past week. She had not felt like eating or drinking and had been taking a lot of ibuprofen. It was the pain that had brought her to the emergency department, and the narcotics had worked wonders. She was finally feeling well enough to eat. Her ECG was stone-cold unchanged from one obtained pre-operatively.

I treated immediately with intravenous insulin, dextrose, and sodium polystyrene sulfonate. By exam she was volume depleted, and her urine output overnight was less than 10 mL per hour. An arterial blood gas demonstrated a significant mixed acidemia; both anion and nonanion gap acidosis were present. I used a bolus of bicarbonate solution, and the urine output in one hour was 50 mL. This was better, and she had just proven to me that she could make urine. Great news for a nephrologist in training! I ordered a constant infusion of bicarbonate.

Despite these labs, she was hypertensive, so I ordered furosemide—200 mg IV—to attempt a forced diuresis. After another hour, the urine output was 200 mL, and I was much more comfortable. Hyperkalemia is much easier to control when a patient is nonoliguric, and I continued aggressive fluid administration. Within four hours, the patient’s potassium and the acidemia were much improved. By the end of my shift, the potassium was within normal range, the creatinine and BUN had also improved significantly, and the patient was transferred to the medical floor.

This patient’s story illustrates the potential difficulties involved in diagnosing and treating potassium-related problems. With these challenges in mind, here are 10 pieces of information every hospitalist should have when dealing with this type of patient.

1) Hyperkalemia in the patient with acute renal failure is usually a problem of poor perfusion; acute decreases in glomerular filtration rate (GFR) that occur in acute renal failure could lead to a marked decrease in sodium and water at the distal tubule, which might decrease distal potassium secretion.

 

When acute renal failure is oliguric, distal delivery of sodium and water is low, and hyperkalemia is a frequent problem. What to do? If respiratory status allows, add aggressive volume resuscitation to your medical management. If the patient’s urine output increases, or when acute renal failure is nonoliguric, distal delivery is usually sufficient and hyperkalemia is less of an issue. Concerned about giving IV fluids to an oliguric patient? Medical management is a temporizing measure in the oliguric patient, and hyperkalemia will always be difficult to treat; a fluid challenge might be worthwhile prior to initiating hemodialysis. Urgent dialysis might be hours away, but fluids can be started within minutes.

If hemodynamics allow, I start forced diuresis with high-dose loop diuretics in an attempt to convert to nonoliguria and promote renal potassium excretion. In life-threatening hyperkalemia all is fair, and—once a patient is nonoliguric—hyperkalemia is much easier to manage.

2) A little potassium is not always bad. There is robust evidence supporting the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in patients with chronic kidney disease with both diabetic and non-diabetic causes. In most patients, according to the National Kidney Foundation’s Clinical Guidelines, the ACE inhibitor or ARB can be continued if the GFR decline over four months is <30% from baseline value and serum potassium is equal to 5.5 mEq/L. The proper way for the inpatient physician to initiate treatment with an ACE inhibitor or ARB is to start at a low dose, with follow-up in one week for a serum potassium measurement and titration of dose as necessary.

3) During my fellowship, I had an attending who would start a discussion with the phrase “I’m just a dumb nephrologist” and then talk for 25 minutes about the physiology of, theories about, and potential therapeutic interventions for just about any type of kidney disease. I prefer a simple approach, too: insulin and dextrose. Why? Because it works well on just about all patients and is quick to administer. Just about every hospital floor in America has a supply of insulin and dextrose on hand. Give the order and, in most cases, the patient is receiving treatment in a matter of minutes.

4) Sodium bicarbonate buffers hydrogen ions extracellularly while shifting potassium intracellularly to maintain electrical neutrality. Sodium bicarbonate should be reserved for cases with severe metabolic acidosis, because effects might be delayed or unreliable, especially in patients with chronic kidney disease.

5) Beta-2 adrenergic agonists drive potassium intracellularly via the Na,K-ATPase mechanism. Albuterol is most commonly used; however, the dosage used by clinicians is frequently insufficient. A dose of albuterol that is 10–20 mg via nebulizer is required, and response time to lowering of potassium might be up to 90 minutes.1

6) I am often asked what ECG changes need to be present before I recommend treatment of hyperkalemia with calcium chloride or calcium gluconate. In a patient without central venous access the concern is that peripheral intravenous infusions of calcium might extravasate, leading to local cellular necrosis and possible loss of limb.

The answer I give is that I don’t know what exact ECG changes would benefit from treatment versus no treatment. In fact, patients with life-threatening hyperkalemia might have subtle changes on ECG.2 Therefore, I believe that every patient with electrocardiographic manifestations of hyperkalemia can be treated with calcium infusion. In my mind, the outcome of sudden cardiac death is far worse than the possible negative effects of calcium infusion.

7) If you suspect a renal cause for a potassium derangement, please check the urine electrolytes. This test is best done at the time of admission or when the patient is in a steady state. As a practicing nephrologist, I find that most of my consults for electrolyte abnormalities are for the patient with a chronic potassium abnormality. I am usually called on the second or third day, when the patient has received a multitude of IV fluids, treatment, medication changes, and so on. All too often, no urine studies have been obtained at the time of consultation. Would you consult your cardiologist for chest pain without first obtaining an ECG?

 

8) Normally, when blood is drawn and allowed to clot before centrifugation, enough potassium is released from platelets to raise the serum level by approximately 0.5 mEq/L. This is accounted for within the limits of the normal range. Excessive errors could occur, however, in the presence of marked leukocytosis or thrombocytosis. These conditions are referred to as pseudohyperkalemia. This can be confirmed by remeasuring serum potassium in a blood sample collected in a heparinized sample tube.3

9) Oral sodium phosphate is a cathartic used in bowel preparation prior to colonoscopy. This agent has been associated with changes in serum electrolyte levels that are generally within the normal range but could occasionally cause serious electrolyte disturbances. Significant hypokalemia could develop, particularly in the elderly, and is due to intestinal potassium loss.4

Other abnormalities reported include hyperphosphatemia, hypocalcemia, and hypernatremia. In addition to increased age, risk factors for these disturbances include the presence of bowel obstruction, poor gut motility, and unrecognized renal disease. Additionally, phosphate nephropathy has been well reported after administration of sodium phosphate and might cause irreversible kidney disease with histology resembling nephrocalcinosis.5

10) The most commonly used cation-exchange resin, sodium polystyrene sulfonate, is frequently used to manage hyperkalemia in patients with chronic kidney disease. Use of this resin could result in hypokalemia, hypomagnesemia, and—occasionally—metabolic alkalosis. After the oral administration of this drug, sodium is released from the resin in exchange for hydrogen in the gastric juice. As the resin passes through the rest of the gastrointestinal tract, the hydrogen is then exchanged for other cations, including potassium, which is present in greater quantities, particularly in the distal gut. Potassium binding to the resin is influenced by duration of exposure, which is primarily determined by gut transit time.

The primary potential complication of using sodium polystyrene sulfonate is the development of sodium overload. The absorption of sodium from the resin by the gut might lead to heart failure, hypertension, and occasionally hypernatremia. Because the resin binds other divalent cations, hypocalcemia and hypomagnesemia could also develop. Decreased plasma levels of magnesium and calcium are more likely to occur in patients taking diuretics or in those with poor nutrition.6 Use of the resin could also lead to metabolic alkalosis when administered with antacids or phosphate binders such as magnesium hydroxide or calcium carbonate. As magnesium and calcium bind to the resin, the base is then free to be absorbed into the systemic circulation. TH

Dr. Casey works in the Department of Internal Medicine, Section of Hospital Internal Medicine, Division of Nephrology and Hypertension at the Mayo Clinic, Rochester, Minn.

References

1. Liou HH, Chiang SS, Wu SC, et al. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure: comparative study. Am J Kidney Dis. 1994 Feb;23(2):266-271.
2. Martinez-Vea A, Bardaji A, Garcia C, et al. Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases. J Electrocardiol. 1999 Jan;32(1):45-49.
3. Stankovic AK, Smith S. Elevated serum potassium values: the role of preanalytic variables. Am J Clin Pathol. 2004 Jun;121 Suppl:S105–S112.
4. Beloosesky Y, Grinblat J, Weiss A, et al. Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med. 2003 Apr 14;163(7):803–808.
5. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colorectal cleanser. Drugs. 2004;64(15):1697-1714.
6. Chen CC, Chen CA, Chau T, et al. Hypokalaemia and hypomagnesaemia in an oedematous diabetic patient with advanced renal failure. Nephrol Dial Transplant. 2005 Oct;20(10):2271-2273.

The phone rang at 6 a.m. on a cold, stormy winter morning. It was a consult: Would I come see a patient in the ICU? I was in my second year of nephrology fellowship, moonlighting out on the frozen tundra of Minnesota. It was Garrison Keillor country, and—as he says about Lake Wobegon—on that day the woman was strong, but I was one man who was not looking too good. I rolled over and brought up the labs on my bedside computer. The patient’s potassium was 7.8 mmol/L; she also had a creatinine of 6.1 mg/dL, a bicarbonate of 8 mmol/L, and a blood urea nitrogen (BUN) more than 140 mg/dL.

This was a small community hospital with no dialysis facility, and my first thought was that it was time to warm up the Medevac helicopter. I could envision the flight nurses loading the patient and saying, “Welcome aboard Medevac One. Today we will be serving normal saline, insulin, and glucose. Sit back and enjoy the flight, and thank you for choosing Medevac One.” One look outside at the flying snow canceled that plan. I went to see the patient.

One of the first symptoms of uremia is anorexia, and the patient will frequently self-avert from taking protein—sort of a survival mechanism in an attempt to control uremia. I arrived in the ICU to find a woman finishing off a plate of bacon and eggs. She told me she had had a gynecologic procedure done a little over a week before. The pain had been intolerable during the past week. She had not felt like eating or drinking and had been taking a lot of ibuprofen. It was the pain that had brought her to the emergency department, and the narcotics had worked wonders. She was finally feeling well enough to eat. Her ECG was stone-cold unchanged from one obtained pre-operatively.

I treated immediately with intravenous insulin, dextrose, and sodium polystyrene sulfonate. By exam she was volume depleted, and her urine output overnight was less than 10 mL per hour. An arterial blood gas demonstrated a significant mixed acidemia; both anion and nonanion gap acidosis were present. I used a bolus of bicarbonate solution, and the urine output in one hour was 50 mL. This was better, and she had just proven to me that she could make urine. Great news for a nephrologist in training! I ordered a constant infusion of bicarbonate.

Despite these labs, she was hypertensive, so I ordered furosemide—200 mg IV—to attempt a forced diuresis. After another hour, the urine output was 200 mL, and I was much more comfortable. Hyperkalemia is much easier to control when a patient is nonoliguric, and I continued aggressive fluid administration. Within four hours, the patient’s potassium and the acidemia were much improved. By the end of my shift, the potassium was within normal range, the creatinine and BUN had also improved significantly, and the patient was transferred to the medical floor.

This patient’s story illustrates the potential difficulties involved in diagnosing and treating potassium-related problems. With these challenges in mind, here are 10 pieces of information every hospitalist should have when dealing with this type of patient.

1) Hyperkalemia in the patient with acute renal failure is usually a problem of poor perfusion; acute decreases in glomerular filtration rate (GFR) that occur in acute renal failure could lead to a marked decrease in sodium and water at the distal tubule, which might decrease distal potassium secretion.

 

When acute renal failure is oliguric, distal delivery of sodium and water is low, and hyperkalemia is a frequent problem. What to do? If respiratory status allows, add aggressive volume resuscitation to your medical management. If the patient’s urine output increases, or when acute renal failure is nonoliguric, distal delivery is usually sufficient and hyperkalemia is less of an issue. Concerned about giving IV fluids to an oliguric patient? Medical management is a temporizing measure in the oliguric patient, and hyperkalemia will always be difficult to treat; a fluid challenge might be worthwhile prior to initiating hemodialysis. Urgent dialysis might be hours away, but fluids can be started within minutes.

If hemodynamics allow, I start forced diuresis with high-dose loop diuretics in an attempt to convert to nonoliguria and promote renal potassium excretion. In life-threatening hyperkalemia all is fair, and—once a patient is nonoliguric—hyperkalemia is much easier to manage.

2) A little potassium is not always bad. There is robust evidence supporting the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in patients with chronic kidney disease with both diabetic and non-diabetic causes. In most patients, according to the National Kidney Foundation’s Clinical Guidelines, the ACE inhibitor or ARB can be continued if the GFR decline over four months is <30% from baseline value and serum potassium is equal to 5.5 mEq/L. The proper way for the inpatient physician to initiate treatment with an ACE inhibitor or ARB is to start at a low dose, with follow-up in one week for a serum potassium measurement and titration of dose as necessary.

3) During my fellowship, I had an attending who would start a discussion with the phrase “I’m just a dumb nephrologist” and then talk for 25 minutes about the physiology of, theories about, and potential therapeutic interventions for just about any type of kidney disease. I prefer a simple approach, too: insulin and dextrose. Why? Because it works well on just about all patients and is quick to administer. Just about every hospital floor in America has a supply of insulin and dextrose on hand. Give the order and, in most cases, the patient is receiving treatment in a matter of minutes.

4) Sodium bicarbonate buffers hydrogen ions extracellularly while shifting potassium intracellularly to maintain electrical neutrality. Sodium bicarbonate should be reserved for cases with severe metabolic acidosis, because effects might be delayed or unreliable, especially in patients with chronic kidney disease.

5) Beta-2 adrenergic agonists drive potassium intracellularly via the Na,K-ATPase mechanism. Albuterol is most commonly used; however, the dosage used by clinicians is frequently insufficient. A dose of albuterol that is 10–20 mg via nebulizer is required, and response time to lowering of potassium might be up to 90 minutes.1

6) I am often asked what ECG changes need to be present before I recommend treatment of hyperkalemia with calcium chloride or calcium gluconate. In a patient without central venous access the concern is that peripheral intravenous infusions of calcium might extravasate, leading to local cellular necrosis and possible loss of limb.

The answer I give is that I don’t know what exact ECG changes would benefit from treatment versus no treatment. In fact, patients with life-threatening hyperkalemia might have subtle changes on ECG.2 Therefore, I believe that every patient with electrocardiographic manifestations of hyperkalemia can be treated with calcium infusion. In my mind, the outcome of sudden cardiac death is far worse than the possible negative effects of calcium infusion.

7) If you suspect a renal cause for a potassium derangement, please check the urine electrolytes. This test is best done at the time of admission or when the patient is in a steady state. As a practicing nephrologist, I find that most of my consults for electrolyte abnormalities are for the patient with a chronic potassium abnormality. I am usually called on the second or third day, when the patient has received a multitude of IV fluids, treatment, medication changes, and so on. All too often, no urine studies have been obtained at the time of consultation. Would you consult your cardiologist for chest pain without first obtaining an ECG?

 

8) Normally, when blood is drawn and allowed to clot before centrifugation, enough potassium is released from platelets to raise the serum level by approximately 0.5 mEq/L. This is accounted for within the limits of the normal range. Excessive errors could occur, however, in the presence of marked leukocytosis or thrombocytosis. These conditions are referred to as pseudohyperkalemia. This can be confirmed by remeasuring serum potassium in a blood sample collected in a heparinized sample tube.3

9) Oral sodium phosphate is a cathartic used in bowel preparation prior to colonoscopy. This agent has been associated with changes in serum electrolyte levels that are generally within the normal range but could occasionally cause serious electrolyte disturbances. Significant hypokalemia could develop, particularly in the elderly, and is due to intestinal potassium loss.4

Other abnormalities reported include hyperphosphatemia, hypocalcemia, and hypernatremia. In addition to increased age, risk factors for these disturbances include the presence of bowel obstruction, poor gut motility, and unrecognized renal disease. Additionally, phosphate nephropathy has been well reported after administration of sodium phosphate and might cause irreversible kidney disease with histology resembling nephrocalcinosis.5

10) The most commonly used cation-exchange resin, sodium polystyrene sulfonate, is frequently used to manage hyperkalemia in patients with chronic kidney disease. Use of this resin could result in hypokalemia, hypomagnesemia, and—occasionally—metabolic alkalosis. After the oral administration of this drug, sodium is released from the resin in exchange for hydrogen in the gastric juice. As the resin passes through the rest of the gastrointestinal tract, the hydrogen is then exchanged for other cations, including potassium, which is present in greater quantities, particularly in the distal gut. Potassium binding to the resin is influenced by duration of exposure, which is primarily determined by gut transit time.

The primary potential complication of using sodium polystyrene sulfonate is the development of sodium overload. The absorption of sodium from the resin by the gut might lead to heart failure, hypertension, and occasionally hypernatremia. Because the resin binds other divalent cations, hypocalcemia and hypomagnesemia could also develop. Decreased plasma levels of magnesium and calcium are more likely to occur in patients taking diuretics or in those with poor nutrition.6 Use of the resin could also lead to metabolic alkalosis when administered with antacids or phosphate binders such as magnesium hydroxide or calcium carbonate. As magnesium and calcium bind to the resin, the base is then free to be absorbed into the systemic circulation. TH

Dr. Casey works in the Department of Internal Medicine, Section of Hospital Internal Medicine, Division of Nephrology and Hypertension at the Mayo Clinic, Rochester, Minn.

References

1. Liou HH, Chiang SS, Wu SC, et al. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure: comparative study. Am J Kidney Dis. 1994 Feb;23(2):266-271.
2. Martinez-Vea A, Bardaji A, Garcia C, et al. Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases. J Electrocardiol. 1999 Jan;32(1):45-49.
3. Stankovic AK, Smith S. Elevated serum potassium values: the role of preanalytic variables. Am J Clin Pathol. 2004 Jun;121 Suppl:S105–S112.
4. Beloosesky Y, Grinblat J, Weiss A, et al. Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med. 2003 Apr 14;163(7):803–808.
5. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colorectal cleanser. Drugs. 2004;64(15):1697-1714.
6. Chen CC, Chen CA, Chau T, et al. Hypokalaemia and hypomagnesaemia in an oedematous diabetic patient with advanced renal failure. Nephrol Dial Transplant. 2005 Oct;20(10):2271-2273.