Steven Lippmann, MD

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

CASE 1

A 94-year-old white woman, who had been in excellent health (other than pernicious anemia, treated with monthly cyanocobalamin injections), suddenly developed gastrointestinal distress 2 weeks earlier. A work-up performed by her physician revealed advanced pancreatic cancer.

Over the next 2 weeks, she experienced pain and nausea. A left-sided fistula developed externally at her flank that drained feces and induced considerable discomfort. An indwelling drain was placed, which provided some relief, but the patient’s dyspepsia, pain, and nausea escalated.

One month into her disease course, an oncologist reported on her potential treatment options and prognosis. Her life expectancy was about 3 months without treatment. This could be extended by 1 to 2 months with extensive surgical and chemotherapeutic interventions, but would further diminish her quality of life. The patient declined further treatment.

Her clinical status declined, and her quality of life significantly deteriorated. At 3 months, she felt life had lost meaning and was not worth living. She began asking for a morphine overdose, stating a desire to end her life.

After several discussions with the oncologist, one of the patient’s adult children suggested that her mother stop eating and drinking in order to diminish discomfort and hasten her demise. This plan was adopted, and the patient declined food and drank only enough to swish for oral comfort. At 4 months, she reported less physical discomfort and an improved mood. She died otherwise uneventfully 2 weeks later.

CASE 2

An 83-year-old woman with advanced Parkinson’s disease had become increasingly disabled. Her gait and motor skills were dramatically and progressively compromised. Pharmacotherapy yielded only transient improvement and considerable adverse effects of choreiform hyperkinesia and hallucinations, which were troublesome and embarrassing. Her social, physical, and personal well-being declined to the point that she was placed in a nursing home.

Despite this help, worsening parkinsonism progressively diminished her physical capacity. She became largely bedridden and developed decubitus ulcerations, especially at the coccyx, which produced severe pain and distress.

Continue to: The confluence of pain...

The confluence of pain, bedfastness, constipation, and social isolation yielded a loss of interest and joy in life. The patient required assistance with almost every aspect of daily life, including eating. As the illness progressed, she prayed at night that God would “take her.” Each morning, she spoke of disappointment upon reawakening. She overtly expressed her lack of desire to live to her family. Medical interventions were increasingly ineffective.

After repeated family and physician discussions had focused on her death wishes, one adult daughter recommended her mother stop eating and drinking; her food intake was already minimal. Although she did not endorse this plan verbally, the patient’s oral intake significantly diminished. Within 2 weeks, her physical state had declined, and she died one night during sleep.

Adequate hydration is stressed in physician education and practice. A conventional expectation to normalize fluid balance is important to restore health and improve well-being. In addition to being good medical practice, it can also show patients (and their families) that we care about their well-being.^1-3

Do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.

Treating dehydration in individuals with terminal illness is controversial from both medical and ethical standpoints. While the natural tendency of physicians is to restore full hydration to their patients, in select cases of imminent death, being fully hydrated may prolong discomfort.^1,2 Emphasis in this population should be consistently placed on improving comfort care and quality of life, rather than prolonging life or delaying death.^3-5

Continue to: A multifactorial, patient-based decision

Years ago, before the advent of hospitalizing people with terminal illnesses, dying at home amongst loved ones was believed to be peaceful. Nevertheless, questions arise about the practical vs ethical approach to caring for patients with terminal illness.² Sometimes it is difficult to find a balance between potential health care benefits and the burdens induced by medical, legal, moral, and/or social pressures. Our medical communities and the general population uphold preserving dignity at the end of life, which is supported by organizations such as Compassion & Choices (a nonprofit group that seeks to improve and expand options for end of life care; https://www.compassionandchoices.org).

Allowing for voluntary, patient-determined dehydration in those with terminal illness can offer greater comfort than maintaining the physiologic degrees of fluid balance. There are 3 key considerations to bear in mind:

• Hydration is usually a standard part of quality medical care.¹
• Selectively allowing dehydration in patients who are dying can facilitate comfort.^1-5
• Dehydration may be a deliberate strategy to hasten death.⁶

When is dehydration appropriate?

Hydration is not favored whenever doing so may increase discomfort and prolong pain without meaningful life.³ In people with terminal illness, hydration may reduce quality of life.⁷

The data support dehydration in certain patients. A randomized controlled trial involving 129 patients receiving hospice care compared parenteral hydration with placebo, documenting that rehydration did not improve symptoms or quality of life; there was no significant difference between patients who were hydrated and those who were dehydrated.⁷ In fact, dehydration may even yield greater patient comfort.⁸

Case reports, retrospective chart reviews, and testimonials from health care professionals have reported that being less hydrated can diminish nausea, vomiting, diarrhea, ascites, edema, and urinary or bowel incontinence, with less skin breakdown.⁸ Hydration, on the other hand, may exacerbate dyspnea, coughing, and choking, increasing the need for suctioning.

Continue to: A component of palliative care

A component of palliative care. When death is imminent, palliation becomes key. Pain may be more manageable with less fluids, an important goal for this population.^6,8 Dehydration is associated with an accumulation of opioids throughout body fluid volumes, which may decrease pain, consciousness, and/or agony.² Pharmacotherapies might also have greater efficacy in a dehydrated patient.⁹ In addition, tissue shrinkage might mitigate pain from tumors, especially those in confined spaces.⁸

Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients.

Hospice care and palliative medicine confirm that routine hydration is not always advisable; allowing for dehydration is a conventional practice, especially in older adults with terminal illness.⁷ However, do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.⁸ Facilitate oral care in the form of swishing fluids, elective drinking, or providing mouth lubrication for any patients selectively allowed to become dehydrated.^3,8

The role of the physician in decision-making

Patients with terminal illness sometimes do not want fluids and may actively decline food and drink.¹⁰ This can be emotionally distressing for family members and/or caregivers to witness. Physicians can address this concern by compassionately explaining: “I know you are concerned that your relative is not eating or drinking, but there is no indication that hydration or parenteral feeding will improve function or quality of life.”¹⁰ This can generate a discussion between physicians and families by acknowledging concerns, relieving distress, and leading to what is ultimately best for the patient.

Implications for practice: Individualized autonomy

Physicians must identify patients who wish to die by purposely becoming dehydrated and uphold the important physician obligation to hydrate those with a recoverable illness. Allowing for a moderate degree of dehydration might provide greater comfort in select people with terminal illness. Some individuals for whom life has lost meaning may choose dehydration as a means to hasten their departure.^4-6 Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients. It can be difficult for caregivers, but it is medically indicated to comply with a patient’s desire for comfort when death is imminent.

Providing palliation as a priority over treatment is sometimes challenging, but comfort care takes preference and is always coordinated with the person’s own wishes. Facilitating dehydration removes assisted-suicide issues or requests and thus affords everyone involved more emotional comfort. An advantage of this method is that a decisional patient maintains full control over the direction of their choices and helps preserve dignity during the end of life.

CORRESPONDENCE
Steven Lippmann, MD, Department of Psychiatry, University of Louisville School of Medicine, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; sblipp01@louisville.edu

CASE 1

A 94-year-old white woman, who had been in excellent health (other than pernicious anemia, treated with monthly cyanocobalamin injections), suddenly developed gastrointestinal distress 2 weeks earlier. A work-up performed by her physician revealed advanced pancreatic cancer.

Over the next 2 weeks, she experienced pain and nausea. A left-sided fistula developed externally at her flank that drained feces and induced considerable discomfort. An indwelling drain was placed, which provided some relief, but the patient’s dyspepsia, pain, and nausea escalated.

One month into her disease course, an oncologist reported on her potential treatment options and prognosis. Her life expectancy was about 3 months without treatment. This could be extended by 1 to 2 months with extensive surgical and chemotherapeutic interventions, but would further diminish her quality of life. The patient declined further treatment.

Her clinical status declined, and her quality of life significantly deteriorated. At 3 months, she felt life had lost meaning and was not worth living. She began asking for a morphine overdose, stating a desire to end her life.

After several discussions with the oncologist, one of the patient’s adult children suggested that her mother stop eating and drinking in order to diminish discomfort and hasten her demise. This plan was adopted, and the patient declined food and drank only enough to swish for oral comfort. At 4 months, she reported less physical discomfort and an improved mood. She died otherwise uneventfully 2 weeks later.

CASE 2

An 83-year-old woman with advanced Parkinson’s disease had become increasingly disabled. Her gait and motor skills were dramatically and progressively compromised. Pharmacotherapy yielded only transient improvement and considerable adverse effects of choreiform hyperkinesia and hallucinations, which were troublesome and embarrassing. Her social, physical, and personal well-being declined to the point that she was placed in a nursing home.

Despite this help, worsening parkinsonism progressively diminished her physical capacity. She became largely bedridden and developed decubitus ulcerations, especially at the coccyx, which produced severe pain and distress.

Continue to: The confluence of pain...

The confluence of pain, bedfastness, constipation, and social isolation yielded a loss of interest and joy in life. The patient required assistance with almost every aspect of daily life, including eating. As the illness progressed, she prayed at night that God would “take her.” Each morning, she spoke of disappointment upon reawakening. She overtly expressed her lack of desire to live to her family. Medical interventions were increasingly ineffective.

After repeated family and physician discussions had focused on her death wishes, one adult daughter recommended her mother stop eating and drinking; her food intake was already minimal. Although she did not endorse this plan verbally, the patient’s oral intake significantly diminished. Within 2 weeks, her physical state had declined, and she died one night during sleep.

Adequate hydration is stressed in physician education and practice. A conventional expectation to normalize fluid balance is important to restore health and improve well-being. In addition to being good medical practice, it can also show patients (and their families) that we care about their well-being.^1-3

Do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.

Treating dehydration in individuals with terminal illness is controversial from both medical and ethical standpoints. While the natural tendency of physicians is to restore full hydration to their patients, in select cases of imminent death, being fully hydrated may prolong discomfort.^1,2 Emphasis in this population should be consistently placed on improving comfort care and quality of life, rather than prolonging life or delaying death.^3-5

Continue to: A multifactorial, patient-based decision

Years ago, before the advent of hospitalizing people with terminal illnesses, dying at home amongst loved ones was believed to be peaceful. Nevertheless, questions arise about the practical vs ethical approach to caring for patients with terminal illness.² Sometimes it is difficult to find a balance between potential health care benefits and the burdens induced by medical, legal, moral, and/or social pressures. Our medical communities and the general population uphold preserving dignity at the end of life, which is supported by organizations such as Compassion & Choices (a nonprofit group that seeks to improve and expand options for end of life care; https://www.compassionandchoices.org).

Allowing for voluntary, patient-determined dehydration in those with terminal illness can offer greater comfort than maintaining the physiologic degrees of fluid balance. There are 3 key considerations to bear in mind:

• Hydration is usually a standard part of quality medical care.¹
• Selectively allowing dehydration in patients who are dying can facilitate comfort.^1-5
• Dehydration may be a deliberate strategy to hasten death.⁶

When is dehydration appropriate?

Hydration is not favored whenever doing so may increase discomfort and prolong pain without meaningful life.³ In people with terminal illness, hydration may reduce quality of life.⁷

The data support dehydration in certain patients. A randomized controlled trial involving 129 patients receiving hospice care compared parenteral hydration with placebo, documenting that rehydration did not improve symptoms or quality of life; there was no significant difference between patients who were hydrated and those who were dehydrated.⁷ In fact, dehydration may even yield greater patient comfort.⁸

Case reports, retrospective chart reviews, and testimonials from health care professionals have reported that being less hydrated can diminish nausea, vomiting, diarrhea, ascites, edema, and urinary or bowel incontinence, with less skin breakdown.⁸ Hydration, on the other hand, may exacerbate dyspnea, coughing, and choking, increasing the need for suctioning.

Continue to: A component of palliative care

A component of palliative care. When death is imminent, palliation becomes key. Pain may be more manageable with less fluids, an important goal for this population.^6,8 Dehydration is associated with an accumulation of opioids throughout body fluid volumes, which may decrease pain, consciousness, and/or agony.² Pharmacotherapies might also have greater efficacy in a dehydrated patient.⁹ In addition, tissue shrinkage might mitigate pain from tumors, especially those in confined spaces.⁸

Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients.

Hospice care and palliative medicine confirm that routine hydration is not always advisable; allowing for dehydration is a conventional practice, especially in older adults with terminal illness.⁷ However, do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.⁸ Facilitate oral care in the form of swishing fluids, elective drinking, or providing mouth lubrication for any patients selectively allowed to become dehydrated.^3,8

The role of the physician in decision-making

Patients with terminal illness sometimes do not want fluids and may actively decline food and drink.¹⁰ This can be emotionally distressing for family members and/or caregivers to witness. Physicians can address this concern by compassionately explaining: “I know you are concerned that your relative is not eating or drinking, but there is no indication that hydration or parenteral feeding will improve function or quality of life.”¹⁰ This can generate a discussion between physicians and families by acknowledging concerns, relieving distress, and leading to what is ultimately best for the patient.

Implications for practice: Individualized autonomy

Physicians must identify patients who wish to die by purposely becoming dehydrated and uphold the important physician obligation to hydrate those with a recoverable illness. Allowing for a moderate degree of dehydration might provide greater comfort in select people with terminal illness. Some individuals for whom life has lost meaning may choose dehydration as a means to hasten their departure.^4-6 Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients. It can be difficult for caregivers, but it is medically indicated to comply with a patient’s desire for comfort when death is imminent.

Providing palliation as a priority over treatment is sometimes challenging, but comfort care takes preference and is always coordinated with the person’s own wishes. Facilitating dehydration removes assisted-suicide issues or requests and thus affords everyone involved more emotional comfort. An advantage of this method is that a decisional patient maintains full control over the direction of their choices and helps preserve dignity during the end of life.

CORRESPONDENCE
Steven Lippmann, MD, Department of Psychiatry, University of Louisville School of Medicine, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; sblipp01@louisville.edu

CASE 1

A 94-year-old white woman, who had been in excellent health (other than pernicious anemia, treated with monthly cyanocobalamin injections), suddenly developed gastrointestinal distress 2 weeks earlier. A work-up performed by her physician revealed advanced pancreatic cancer.

Over the next 2 weeks, she experienced pain and nausea. A left-sided fistula developed externally at her flank that drained feces and induced considerable discomfort. An indwelling drain was placed, which provided some relief, but the patient’s dyspepsia, pain, and nausea escalated.

One month into her disease course, an oncologist reported on her potential treatment options and prognosis. Her life expectancy was about 3 months without treatment. This could be extended by 1 to 2 months with extensive surgical and chemotherapeutic interventions, but would further diminish her quality of life. The patient declined further treatment.

Her clinical status declined, and her quality of life significantly deteriorated. At 3 months, she felt life had lost meaning and was not worth living. She began asking for a morphine overdose, stating a desire to end her life.

After several discussions with the oncologist, one of the patient’s adult children suggested that her mother stop eating and drinking in order to diminish discomfort and hasten her demise. This plan was adopted, and the patient declined food and drank only enough to swish for oral comfort. At 4 months, she reported less physical discomfort and an improved mood. She died otherwise uneventfully 2 weeks later.

CASE 2

An 83-year-old woman with advanced Parkinson’s disease had become increasingly disabled. Her gait and motor skills were dramatically and progressively compromised. Pharmacotherapy yielded only transient improvement and considerable adverse effects of choreiform hyperkinesia and hallucinations, which were troublesome and embarrassing. Her social, physical, and personal well-being declined to the point that she was placed in a nursing home.

Despite this help, worsening parkinsonism progressively diminished her physical capacity. She became largely bedridden and developed decubitus ulcerations, especially at the coccyx, which produced severe pain and distress.

Continue to: The confluence of pain...

The confluence of pain, bedfastness, constipation, and social isolation yielded a loss of interest and joy in life. The patient required assistance with almost every aspect of daily life, including eating. As the illness progressed, she prayed at night that God would “take her.” Each morning, she spoke of disappointment upon reawakening. She overtly expressed her lack of desire to live to her family. Medical interventions were increasingly ineffective.

After repeated family and physician discussions had focused on her death wishes, one adult daughter recommended her mother stop eating and drinking; her food intake was already minimal. Although she did not endorse this plan verbally, the patient’s oral intake significantly diminished. Within 2 weeks, her physical state had declined, and she died one night during sleep.

Adequate hydration is stressed in physician education and practice. A conventional expectation to normalize fluid balance is important to restore health and improve well-being. In addition to being good medical practice, it can also show patients (and their families) that we care about their well-being.^1-3

Do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.

Treating dehydration in individuals with terminal illness is controversial from both medical and ethical standpoints. While the natural tendency of physicians is to restore full hydration to their patients, in select cases of imminent death, being fully hydrated may prolong discomfort.^1,2 Emphasis in this population should be consistently placed on improving comfort care and quality of life, rather than prolonging life or delaying death.^3-5

Continue to: A multifactorial, patient-based decision

Years ago, before the advent of hospitalizing people with terminal illnesses, dying at home amongst loved ones was believed to be peaceful. Nevertheless, questions arise about the practical vs ethical approach to caring for patients with terminal illness.² Sometimes it is difficult to find a balance between potential health care benefits and the burdens induced by medical, legal, moral, and/or social pressures. Our medical communities and the general population uphold preserving dignity at the end of life, which is supported by organizations such as Compassion & Choices (a nonprofit group that seeks to improve and expand options for end of life care; https://www.compassionandchoices.org).

Allowing for voluntary, patient-determined dehydration in those with terminal illness can offer greater comfort than maintaining the physiologic degrees of fluid balance. There are 3 key considerations to bear in mind:

• Hydration is usually a standard part of quality medical care.¹
• Selectively allowing dehydration in patients who are dying can facilitate comfort.^1-5
• Dehydration may be a deliberate strategy to hasten death.⁶

When is dehydration appropriate?

Hydration is not favored whenever doing so may increase discomfort and prolong pain without meaningful life.³ In people with terminal illness, hydration may reduce quality of life.⁷

The data support dehydration in certain patients. A randomized controlled trial involving 129 patients receiving hospice care compared parenteral hydration with placebo, documenting that rehydration did not improve symptoms or quality of life; there was no significant difference between patients who were hydrated and those who were dehydrated.⁷ In fact, dehydration may even yield greater patient comfort.⁸

Case reports, retrospective chart reviews, and testimonials from health care professionals have reported that being less hydrated can diminish nausea, vomiting, diarrhea, ascites, edema, and urinary or bowel incontinence, with less skin breakdown.⁸ Hydration, on the other hand, may exacerbate dyspnea, coughing, and choking, increasing the need for suctioning.

Continue to: A component of palliative care

A component of palliative care. When death is imminent, palliation becomes key. Pain may be more manageable with less fluids, an important goal for this population.^6,8 Dehydration is associated with an accumulation of opioids throughout body fluid volumes, which may decrease pain, consciousness, and/or agony.² Pharmacotherapies might also have greater efficacy in a dehydrated patient.⁹ In addition, tissue shrinkage might mitigate pain from tumors, especially those in confined spaces.⁸

Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients.

Hospice care and palliative medicine confirm that routine hydration is not always advisable; allowing for dehydration is a conventional practice, especially in older adults with terminal illness.⁷ However, do not deny access to liquids if a patient wants them, and never force unwanted fluids by any route.⁸ Facilitate oral care in the form of swishing fluids, elective drinking, or providing mouth lubrication for any patients selectively allowed to become dehydrated.^3,8

The role of the physician in decision-making

Patients with terminal illness sometimes do not want fluids and may actively decline food and drink.¹⁰ This can be emotionally distressing for family members and/or caregivers to witness. Physicians can address this concern by compassionately explaining: “I know you are concerned that your relative is not eating or drinking, but there is no indication that hydration or parenteral feeding will improve function or quality of life.”¹⁰ This can generate a discussion between physicians and families by acknowledging concerns, relieving distress, and leading to what is ultimately best for the patient.

Implications for practice: Individualized autonomy

Physicians must identify patients who wish to die by purposely becoming dehydrated and uphold the important physician obligation to hydrate those with a recoverable illness. Allowing for a moderate degree of dehydration might provide greater comfort in select people with terminal illness. Some individuals for whom life has lost meaning may choose dehydration as a means to hasten their departure.^4-6 Allowing individualized autonomy over life and death choices is part of a physician’s obligation to their patients. It can be difficult for caregivers, but it is medically indicated to comply with a patient’s desire for comfort when death is imminent.

Providing palliation as a priority over treatment is sometimes challenging, but comfort care takes preference and is always coordinated with the person’s own wishes. Facilitating dehydration removes assisted-suicide issues or requests and thus affords everyone involved more emotional comfort. An advantage of this method is that a decisional patient maintains full control over the direction of their choices and helps preserve dignity during the end of life.

CORRESPONDENCE
Steven Lippmann, MD, Department of Psychiatry, University of Louisville School of Medicine, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; sblipp01@louisville.edu

Diabetes mellitus (DM) is a metabolic disorder affecting about 5% to 13% of the population in the US.¹ Since 1552, the earliest record of a person with DM, many treatment advances have been made.²Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newest antidiabetic pharmaceuticals on the market. The SGLT2 inhibitor drugs include canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin; however, only canagliflozin, dapagliflozin, and empagliflozin have been approved by the US Food and Drug Administration (FDA). These pharmaceuticals promote glycosuria via the kidneys and enhance sugar excretion from the body. Along with lifestyle changes and self-care measures, such as healthful eating and increased physical activity, SGLT2 inhibitor pharmaceuticals provide antidiabetic efficacy by facilitating normoglycemia and minimizing vascular pathology.

Although SGLT2 inhibitor pharmaceuticals are newly introduced into the market, their discovery dates to 1835.³ Phlorizin, a nonselective SGLT inhibitor, was first isolated by French chemists from the bark of an apple tree.⁴ Phlorizin inhibits SGLT1 mostly in small intestinal cells, and SGLT2 similarly affects the kidney.⁴ Renal SGLT2 is the primary therapeutic target. Canagliflozin was the first pharmaceutical SGLT2 inhibitor approved by the FDA in 2013. Dapagliflozin’s FDA approval followed in 2013 and empagliflozin in 2014.⁵

Mechanism Of Action

In healthy individuals, tubular glucose is absorbed, resulting in no urinary glucose excretion. Sodium-glucose cotransporters 1 and 2 contribute to the renal absorption of glucose. A SGLT2 is responsible for 90% of the glucose reuptake in the segment 1 of the proximal tubule, while SGLT 1 is accountable for the remaining 10%.³ Unlike other antidiabetic medications, which act by increasing insulin secretion or improving insulin sensitivity for the receptors, SGLT2 inhibitor drugs prevent the reuptake of glucose into the bloodstream. This selective action spares the inhibition of SGLT1 present in other tissues, avoiding gastrointestinal effects.⁶

Benefits

The SGLT2 inhibitor action is focused on renal excretion of glucose and is independent of insulin action. 

Hemoglobin A_1c Levels

Canagliflozin, dapagliflozin, and empagliflozin reduce hemoglobin A_1c (HbA_1c) levels.⁵ Inagaki and colleagues found significant reductions in HbA_1c and weight gain with > 100 mg canagliflozin compared with that of placebo when used for 12 weeks.⁷ In a study where 2.5-mg, 5-mg, and 10-mg dapagliflozin was compared with placebo, the mean HbA_1c change from the baseline was -0.23% with placebo; -0.58% at 2.5 mg; -0.77% at 5 mg; and -0.89% at 10 mg.⁸ Empagliflozin was more effective in reducing HbA_1c levels than was sitagliptin.⁹ When patients were treated with 10-mg empagliflozin, 25-mg empagliflozin, and sitagliptin, HbA_1c levels dropped -1.44%, -1.43%, and -1.04%, respectively.⁹

Cholesterol

Sodium-glucose cotransporter 2 inhibitors have the beneficial effect of reducing vascular disease risk factors.^10,11 A study by Hayashi and colleagues found that dapagliflozin decreases harmful atherogenic small, low-density lipoprotein-cholesterol (LDL-C), increases less atherogenic large, buoyant LDL-C, and increases high-density, lipoprotein-2 cholesterol (HDL-2C).¹⁰ Empagliflozin, however, can cause a small dose-dependent increase in HDL-C and LDL-C.¹¹ Although there is an increase in serum LDL-C concentrations, empagliflozin can induce a decrease in intestinal absorption of cholesterol, thus promoting fecal excretion of LDL-C and macrophage-derived cholesterol.¹¹

Weight Loss

A study by Weber and colleagues found that the SGLT2 inhibitor dapagloflozin lead to a reduction in body weight from -1.0 kg to -0.3 kg compared with placebo.¹² Cefalu and colleagues found that daily prescribing of 100 mg and/or 300 mg of canagliflozin evidenced dose-dependent loss of weight.¹³ Neeland and colleagues found that empagliflozin utilization resulted in less adiposity indices in 3,300 subjects.¹⁴

Albuminuria

Sodium-glucose cotransporter 2 inhibitors have a reno-protective role in patients with type 2 DM (T2DM). In those receiving renin-angiotensin blockers with T2DM and hypertension, dapagliflozin decreased their albuminuria.¹⁵ Canagliflozin has a similar potential.¹⁶ Empagliflozin reduced the urine albumin-creatinine ratio in patients with macro- or micro-albuminuria, supporting a direct renal effect by SGLT2 inhibitors.¹⁷

Systolic Blood Pressure

Sodium-glucose cotransporter 2 inhibitors can have beneficial effects on physiologic vascular outcomes. In patients with T2DM and hypertension, dapagliflozin reduced mean systolic blood pressure (SBP) compared with placebo: -7.3 mm Hg vs -10.4 mm Hg, respectively.¹² Prescribing canagliflozin treatment at 100 mg or 300 mg reduced SBP (-4.3 mm Hg and -5.0 mm Hg, respectively, vs placebo at -0.3 mm Hg).¹⁸ Subjects taking empagliflozin 10 mg or 25 mg exhibited an adjusted mean BP change from baseline of -4.60 mm Hg and -5.47mm Hg, respectively, whereas placebo induced a -0.67 mm Hg decline.¹⁹

Risks

Nausea, fatigue, polyuria, polydipsia, and xerostomia are common SGLT2 AEs. Use of SGLT2 inhibitors can induce certain other more serious AEs as well.

Increased Risk for Amputations

The Canagliflozin Cardiovascular Assessment Study (CANVAS) and the Canagliflozin Cardiovascular Assessment Study-Renal (CANVAS-R) documented that canagliflozin doubled the incidence of leg and foot amputations in research participants compared with placebo (6.3 vs 3.4 per 1,000 patient-years).¹⁶ Therefore, canagliflozin should be prescribed with caution in persons with a prior history of foot ulceration, neuropathy, and/or vascular diseases.²⁰

Acute Renal Injury

The mechanism of kidney damage by SGLT2 inhibitor drugs is not completely understood. About 100 patients experienced renal failure after the intake of SGLT2 inhibitor drugs.²¹ Among them, more than half reported symptom onset within a month of starting the medication, and their symptoms improved after discontinuing the SGLT2 medication. As a result, the FDA issued a warning to monitor renal function before initiating and during such pharmacotherapy.²¹

Ketoacidosis

Sodium-glucose cotransporter 2 inhibitors might lead to elevated ketone body levels²² and euglycemic ketoacidosis;²³ however, this risk reportedly is negligible.²⁴ Use of SGLT2 inhibitors is not recommended for patients evidencing the presence of precipitating factors like acute gastroenteritis or insulin pump failure.²⁵

Genitourinary Infections

About 10% to 15% of women taking SGLT2 inhibitor medications developed urinary tract infections and vulvovaginitis.²⁶ This could be because of a glycosuria effect caused by SGLT2 inhibitors.²⁷

Hypotension

Sodium-glucose cotransporter 2 inhibitors cause contraction of intravascular volume. Therefore, patients taking SGLT2 inhibitors are at risk for hypotension, leading to dizziness and potentially dangerous falls. Patients already taking volume-depleting medications, such as diuretics, should be advised to use this group of medications with caution and report these AEs.²⁸

Bone Fractures

A clinical trial revealed that SGLT2 inhibitors, such as canagliflozin, decrease bone mineral density possibly leading to bone fractures.²⁹ Bone fractures occurred in about 1.5% of cases of patients taking 100 mg and 300 mg of canagliflozin compared with a 1.1% fracture rate among the placebo group.²⁹

Conclusion

Since the FDA approval of SGLT2 inhibitor medications, their usage has increased. The American Diabetes Association first recommends nonpharmacologic approaches, such as diet modification, exercise, and weight loss for patients diagnosed with DM, followed by a medicinal intervention with metformin if required. Sodium-glucose cotransporter 2 inhibitors are suggested as an additional medication in dual or triple pharmacotherapies when metformin alone fails to achieve normoglycemia.

Prior to starting a patient on SGLT2 inhibitor medication, clinicians should monitor hydration adequacy, check bone density, review the patient’s cardiac profile, and assess hepatic and renal function. Prescribing SGLT2 inhibitors should be restricted if the patient has a history of type 1 DM, ketosisprone T2DM, and in those with a glomerular filtration rate of < 60 mL/min. Considering the preexisting medical conditions of the patient and monitoring the blood glucose levels, renal function, and volume status at every visit should minimize risks and enhance the benefits of prescribing this new medication class.

Diabetes mellitus (DM) is a metabolic disorder affecting about 5% to 13% of the population in the US.¹ Since 1552, the earliest record of a person with DM, many treatment advances have been made.²Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newest antidiabetic pharmaceuticals on the market. The SGLT2 inhibitor drugs include canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin; however, only canagliflozin, dapagliflozin, and empagliflozin have been approved by the US Food and Drug Administration (FDA). These pharmaceuticals promote glycosuria via the kidneys and enhance sugar excretion from the body. Along with lifestyle changes and self-care measures, such as healthful eating and increased physical activity, SGLT2 inhibitor pharmaceuticals provide antidiabetic efficacy by facilitating normoglycemia and minimizing vascular pathology.

Although SGLT2 inhibitor pharmaceuticals are newly introduced into the market, their discovery dates to 1835.³ Phlorizin, a nonselective SGLT inhibitor, was first isolated by French chemists from the bark of an apple tree.⁴ Phlorizin inhibits SGLT1 mostly in small intestinal cells, and SGLT2 similarly affects the kidney.⁴ Renal SGLT2 is the primary therapeutic target. Canagliflozin was the first pharmaceutical SGLT2 inhibitor approved by the FDA in 2013. Dapagliflozin’s FDA approval followed in 2013 and empagliflozin in 2014.⁵

Mechanism Of Action

In healthy individuals, tubular glucose is absorbed, resulting in no urinary glucose excretion. Sodium-glucose cotransporters 1 and 2 contribute to the renal absorption of glucose. A SGLT2 is responsible for 90% of the glucose reuptake in the segment 1 of the proximal tubule, while SGLT 1 is accountable for the remaining 10%.³ Unlike other antidiabetic medications, which act by increasing insulin secretion or improving insulin sensitivity for the receptors, SGLT2 inhibitor drugs prevent the reuptake of glucose into the bloodstream. This selective action spares the inhibition of SGLT1 present in other tissues, avoiding gastrointestinal effects.⁶

Benefits

The SGLT2 inhibitor action is focused on renal excretion of glucose and is independent of insulin action. 

Hemoglobin A_1c Levels

Canagliflozin, dapagliflozin, and empagliflozin reduce hemoglobin A_1c (HbA_1c) levels.⁵ Inagaki and colleagues found significant reductions in HbA_1c and weight gain with > 100 mg canagliflozin compared with that of placebo when used for 12 weeks.⁷ In a study where 2.5-mg, 5-mg, and 10-mg dapagliflozin was compared with placebo, the mean HbA_1c change from the baseline was -0.23% with placebo; -0.58% at 2.5 mg; -0.77% at 5 mg; and -0.89% at 10 mg.⁸ Empagliflozin was more effective in reducing HbA_1c levels than was sitagliptin.⁹ When patients were treated with 10-mg empagliflozin, 25-mg empagliflozin, and sitagliptin, HbA_1c levels dropped -1.44%, -1.43%, and -1.04%, respectively.⁹

Cholesterol

Sodium-glucose cotransporter 2 inhibitors have the beneficial effect of reducing vascular disease risk factors.^10,11 A study by Hayashi and colleagues found that dapagliflozin decreases harmful atherogenic small, low-density lipoprotein-cholesterol (LDL-C), increases less atherogenic large, buoyant LDL-C, and increases high-density, lipoprotein-2 cholesterol (HDL-2C).¹⁰ Empagliflozin, however, can cause a small dose-dependent increase in HDL-C and LDL-C.¹¹ Although there is an increase in serum LDL-C concentrations, empagliflozin can induce a decrease in intestinal absorption of cholesterol, thus promoting fecal excretion of LDL-C and macrophage-derived cholesterol.¹¹

Weight Loss

A study by Weber and colleagues found that the SGLT2 inhibitor dapagloflozin lead to a reduction in body weight from -1.0 kg to -0.3 kg compared with placebo.¹² Cefalu and colleagues found that daily prescribing of 100 mg and/or 300 mg of canagliflozin evidenced dose-dependent loss of weight.¹³ Neeland and colleagues found that empagliflozin utilization resulted in less adiposity indices in 3,300 subjects.¹⁴

Albuminuria

Sodium-glucose cotransporter 2 inhibitors have a reno-protective role in patients with type 2 DM (T2DM). In those receiving renin-angiotensin blockers with T2DM and hypertension, dapagliflozin decreased their albuminuria.¹⁵ Canagliflozin has a similar potential.¹⁶ Empagliflozin reduced the urine albumin-creatinine ratio in patients with macro- or micro-albuminuria, supporting a direct renal effect by SGLT2 inhibitors.¹⁷

Systolic Blood Pressure

Sodium-glucose cotransporter 2 inhibitors can have beneficial effects on physiologic vascular outcomes. In patients with T2DM and hypertension, dapagliflozin reduced mean systolic blood pressure (SBP) compared with placebo: -7.3 mm Hg vs -10.4 mm Hg, respectively.¹² Prescribing canagliflozin treatment at 100 mg or 300 mg reduced SBP (-4.3 mm Hg and -5.0 mm Hg, respectively, vs placebo at -0.3 mm Hg).¹⁸ Subjects taking empagliflozin 10 mg or 25 mg exhibited an adjusted mean BP change from baseline of -4.60 mm Hg and -5.47mm Hg, respectively, whereas placebo induced a -0.67 mm Hg decline.¹⁹

Risks

Nausea, fatigue, polyuria, polydipsia, and xerostomia are common SGLT2 AEs. Use of SGLT2 inhibitors can induce certain other more serious AEs as well.

Increased Risk for Amputations

The Canagliflozin Cardiovascular Assessment Study (CANVAS) and the Canagliflozin Cardiovascular Assessment Study-Renal (CANVAS-R) documented that canagliflozin doubled the incidence of leg and foot amputations in research participants compared with placebo (6.3 vs 3.4 per 1,000 patient-years).¹⁶ Therefore, canagliflozin should be prescribed with caution in persons with a prior history of foot ulceration, neuropathy, and/or vascular diseases.²⁰

Acute Renal Injury

The mechanism of kidney damage by SGLT2 inhibitor drugs is not completely understood. About 100 patients experienced renal failure after the intake of SGLT2 inhibitor drugs.²¹ Among them, more than half reported symptom onset within a month of starting the medication, and their symptoms improved after discontinuing the SGLT2 medication. As a result, the FDA issued a warning to monitor renal function before initiating and during such pharmacotherapy.²¹

Ketoacidosis

Sodium-glucose cotransporter 2 inhibitors might lead to elevated ketone body levels²² and euglycemic ketoacidosis;²³ however, this risk reportedly is negligible.²⁴ Use of SGLT2 inhibitors is not recommended for patients evidencing the presence of precipitating factors like acute gastroenteritis or insulin pump failure.²⁵

Genitourinary Infections

About 10% to 15% of women taking SGLT2 inhibitor medications developed urinary tract infections and vulvovaginitis.²⁶ This could be because of a glycosuria effect caused by SGLT2 inhibitors.²⁷

Hypotension

Sodium-glucose cotransporter 2 inhibitors cause contraction of intravascular volume. Therefore, patients taking SGLT2 inhibitors are at risk for hypotension, leading to dizziness and potentially dangerous falls. Patients already taking volume-depleting medications, such as diuretics, should be advised to use this group of medications with caution and report these AEs.²⁸

Bone Fractures

A clinical trial revealed that SGLT2 inhibitors, such as canagliflozin, decrease bone mineral density possibly leading to bone fractures.²⁹ Bone fractures occurred in about 1.5% of cases of patients taking 100 mg and 300 mg of canagliflozin compared with a 1.1% fracture rate among the placebo group.²⁹

Conclusion

Since the FDA approval of SGLT2 inhibitor medications, their usage has increased. The American Diabetes Association first recommends nonpharmacologic approaches, such as diet modification, exercise, and weight loss for patients diagnosed with DM, followed by a medicinal intervention with metformin if required. Sodium-glucose cotransporter 2 inhibitors are suggested as an additional medication in dual or triple pharmacotherapies when metformin alone fails to achieve normoglycemia.

Prior to starting a patient on SGLT2 inhibitor medication, clinicians should monitor hydration adequacy, check bone density, review the patient’s cardiac profile, and assess hepatic and renal function. Prescribing SGLT2 inhibitors should be restricted if the patient has a history of type 1 DM, ketosisprone T2DM, and in those with a glomerular filtration rate of < 60 mL/min. Considering the preexisting medical conditions of the patient and monitoring the blood glucose levels, renal function, and volume status at every visit should minimize risks and enhance the benefits of prescribing this new medication class.

Diabetes mellitus (DM) is a metabolic disorder affecting about 5% to 13% of the population in the US.¹ Since 1552, the earliest record of a person with DM, many treatment advances have been made.²Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newest antidiabetic pharmaceuticals on the market. The SGLT2 inhibitor drugs include canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin; however, only canagliflozin, dapagliflozin, and empagliflozin have been approved by the US Food and Drug Administration (FDA). These pharmaceuticals promote glycosuria via the kidneys and enhance sugar excretion from the body. Along with lifestyle changes and self-care measures, such as healthful eating and increased physical activity, SGLT2 inhibitor pharmaceuticals provide antidiabetic efficacy by facilitating normoglycemia and minimizing vascular pathology.

Although SGLT2 inhibitor pharmaceuticals are newly introduced into the market, their discovery dates to 1835.³ Phlorizin, a nonselective SGLT inhibitor, was first isolated by French chemists from the bark of an apple tree.⁴ Phlorizin inhibits SGLT1 mostly in small intestinal cells, and SGLT2 similarly affects the kidney.⁴ Renal SGLT2 is the primary therapeutic target. Canagliflozin was the first pharmaceutical SGLT2 inhibitor approved by the FDA in 2013. Dapagliflozin’s FDA approval followed in 2013 and empagliflozin in 2014.⁵

Mechanism Of Action

In healthy individuals, tubular glucose is absorbed, resulting in no urinary glucose excretion. Sodium-glucose cotransporters 1 and 2 contribute to the renal absorption of glucose. A SGLT2 is responsible for 90% of the glucose reuptake in the segment 1 of the proximal tubule, while SGLT 1 is accountable for the remaining 10%.³ Unlike other antidiabetic medications, which act by increasing insulin secretion or improving insulin sensitivity for the receptors, SGLT2 inhibitor drugs prevent the reuptake of glucose into the bloodstream. This selective action spares the inhibition of SGLT1 present in other tissues, avoiding gastrointestinal effects.⁶

Benefits

The SGLT2 inhibitor action is focused on renal excretion of glucose and is independent of insulin action. 

Hemoglobin A_1c Levels

Canagliflozin, dapagliflozin, and empagliflozin reduce hemoglobin A_1c (HbA_1c) levels.⁵ Inagaki and colleagues found significant reductions in HbA_1c and weight gain with > 100 mg canagliflozin compared with that of placebo when used for 12 weeks.⁷ In a study where 2.5-mg, 5-mg, and 10-mg dapagliflozin was compared with placebo, the mean HbA_1c change from the baseline was -0.23% with placebo; -0.58% at 2.5 mg; -0.77% at 5 mg; and -0.89% at 10 mg.⁸ Empagliflozin was more effective in reducing HbA_1c levels than was sitagliptin.⁹ When patients were treated with 10-mg empagliflozin, 25-mg empagliflozin, and sitagliptin, HbA_1c levels dropped -1.44%, -1.43%, and -1.04%, respectively.⁹

Cholesterol

Sodium-glucose cotransporter 2 inhibitors have the beneficial effect of reducing vascular disease risk factors.^10,11 A study by Hayashi and colleagues found that dapagliflozin decreases harmful atherogenic small, low-density lipoprotein-cholesterol (LDL-C), increases less atherogenic large, buoyant LDL-C, and increases high-density, lipoprotein-2 cholesterol (HDL-2C).¹⁰ Empagliflozin, however, can cause a small dose-dependent increase in HDL-C and LDL-C.¹¹ Although there is an increase in serum LDL-C concentrations, empagliflozin can induce a decrease in intestinal absorption of cholesterol, thus promoting fecal excretion of LDL-C and macrophage-derived cholesterol.¹¹

Weight Loss

A study by Weber and colleagues found that the SGLT2 inhibitor dapagloflozin lead to a reduction in body weight from -1.0 kg to -0.3 kg compared with placebo.¹² Cefalu and colleagues found that daily prescribing of 100 mg and/or 300 mg of canagliflozin evidenced dose-dependent loss of weight.¹³ Neeland and colleagues found that empagliflozin utilization resulted in less adiposity indices in 3,300 subjects.¹⁴

Albuminuria

Sodium-glucose cotransporter 2 inhibitors have a reno-protective role in patients with type 2 DM (T2DM). In those receiving renin-angiotensin blockers with T2DM and hypertension, dapagliflozin decreased their albuminuria.¹⁵ Canagliflozin has a similar potential.¹⁶ Empagliflozin reduced the urine albumin-creatinine ratio in patients with macro- or micro-albuminuria, supporting a direct renal effect by SGLT2 inhibitors.¹⁷

Systolic Blood Pressure

Sodium-glucose cotransporter 2 inhibitors can have beneficial effects on physiologic vascular outcomes. In patients with T2DM and hypertension, dapagliflozin reduced mean systolic blood pressure (SBP) compared with placebo: -7.3 mm Hg vs -10.4 mm Hg, respectively.¹² Prescribing canagliflozin treatment at 100 mg or 300 mg reduced SBP (-4.3 mm Hg and -5.0 mm Hg, respectively, vs placebo at -0.3 mm Hg).¹⁸ Subjects taking empagliflozin 10 mg or 25 mg exhibited an adjusted mean BP change from baseline of -4.60 mm Hg and -5.47mm Hg, respectively, whereas placebo induced a -0.67 mm Hg decline.¹⁹

Risks

Nausea, fatigue, polyuria, polydipsia, and xerostomia are common SGLT2 AEs. Use of SGLT2 inhibitors can induce certain other more serious AEs as well.

Increased Risk for Amputations

The Canagliflozin Cardiovascular Assessment Study (CANVAS) and the Canagliflozin Cardiovascular Assessment Study-Renal (CANVAS-R) documented that canagliflozin doubled the incidence of leg and foot amputations in research participants compared with placebo (6.3 vs 3.4 per 1,000 patient-years).¹⁶ Therefore, canagliflozin should be prescribed with caution in persons with a prior history of foot ulceration, neuropathy, and/or vascular diseases.²⁰

Acute Renal Injury

The mechanism of kidney damage by SGLT2 inhibitor drugs is not completely understood. About 100 patients experienced renal failure after the intake of SGLT2 inhibitor drugs.²¹ Among them, more than half reported symptom onset within a month of starting the medication, and their symptoms improved after discontinuing the SGLT2 medication. As a result, the FDA issued a warning to monitor renal function before initiating and during such pharmacotherapy.²¹

Ketoacidosis

Sodium-glucose cotransporter 2 inhibitors might lead to elevated ketone body levels²² and euglycemic ketoacidosis;²³ however, this risk reportedly is negligible.²⁴ Use of SGLT2 inhibitors is not recommended for patients evidencing the presence of precipitating factors like acute gastroenteritis or insulin pump failure.²⁵

Genitourinary Infections

About 10% to 15% of women taking SGLT2 inhibitor medications developed urinary tract infections and vulvovaginitis.²⁶ This could be because of a glycosuria effect caused by SGLT2 inhibitors.²⁷

Hypotension

Sodium-glucose cotransporter 2 inhibitors cause contraction of intravascular volume. Therefore, patients taking SGLT2 inhibitors are at risk for hypotension, leading to dizziness and potentially dangerous falls. Patients already taking volume-depleting medications, such as diuretics, should be advised to use this group of medications with caution and report these AEs.²⁸

Bone Fractures

A clinical trial revealed that SGLT2 inhibitors, such as canagliflozin, decrease bone mineral density possibly leading to bone fractures.²⁹ Bone fractures occurred in about 1.5% of cases of patients taking 100 mg and 300 mg of canagliflozin compared with a 1.1% fracture rate among the placebo group.²⁹

Conclusion

Since the FDA approval of SGLT2 inhibitor medications, their usage has increased. The American Diabetes Association first recommends nonpharmacologic approaches, such as diet modification, exercise, and weight loss for patients diagnosed with DM, followed by a medicinal intervention with metformin if required. Sodium-glucose cotransporter 2 inhibitors are suggested as an additional medication in dual or triple pharmacotherapies when metformin alone fails to achieve normoglycemia.

Prior to starting a patient on SGLT2 inhibitor medication, clinicians should monitor hydration adequacy, check bone density, review the patient’s cardiac profile, and assess hepatic and renal function. Prescribing SGLT2 inhibitors should be restricted if the patient has a history of type 1 DM, ketosisprone T2DM, and in those with a glomerular filtration rate of < 60 mL/min. Considering the preexisting medical conditions of the patient and monitoring the blood glucose levels, renal function, and volume status at every visit should minimize risks and enhance the benefits of prescribing this new medication class.

More than 64,000 people in the United States died of drug overdoses in 2016.¹ Of those overdose deaths, more than 34,000 were related to the use of natural (eg, codeine, morphine); synthetic (eg, fentanyl); and semisynthetic (eg, oxycodone, hydrocodone) opioids.¹ The number of drug-overdose fatalities (driven largely by opioids) has increased so dramatically in recent years that drug overdose is now the leading cause of intentional and unintentional injury-related death in the United States.² Furthermore, opioid use is increasing among college students, with many injecting these agents.³ Those injecting (as opposed to other routes of delivery) have the highest death rate.⁴

The Department of Health and Human Services has identified 3 important issues to address with regard to the opioid epidemic: prescriber education, community naloxone access, and better interventions (such as naloxone overdose-reversal take-home kits) for people with opioid use disorders and/or a history of overdoses.⁵ (For more on overdose reversal kits, see “What FPs need to know about naloxone kits,” a 3-in-3 video.) With these goals in mind, we provide the following review of naloxone dosing and postoverdose treatment.

Steps FPs can take to reverse the overdose

Opioids act on delta, kappa, and mu receptors in the brain to produce analgesic effects,⁶ but, in large quantities, their mu receptor activity can cause fatal respiratory depression.⁷ Some of the most commonly abused opioids are heroin and the prescription opioids fentanyl, oxycodone, and hydrocodone.⁸

People who have overdosed on opioids generally present with evidence of obtundation, miosis, and difficulty breathing. Respiratory failure is the most common cause of death.⁹ Hypothermia, compartment syndrome, rhabdomyolysis, renal failure, and acute pulmonary edema are less common complications. Overdoses and these medical issues can potentially be reversed and/or mitigated by naloxone administration.^10,11

Naloxone and its routes of administration. Naloxone is the agent of choice in overdose situations.¹² It works as an antagonist of the delta, kappa, and mu receptors,^6,13 has a rapid onset of action, and is associated with minimal adverse effects.¹⁴

Naloxone can be administered via the intravenous (IV), intranasal, intramuscular, subcutaneous, intraosseous, or endotracheal routes.⁶ Although IV administration has been the most common and is still generally preferred in the hospital setting, the intranasal route has gained favor, partly because it can be difficult to establish an IV in IV drug users and partly because it is easier for nonmedical people to administer.⁶

In addition, the nasal mucosa has an abundant blood supply resulting in rapid absorption. The drug reaches the systemic circulation quickly and avoids first-pass hepatic metabolism.⁶ Intranasal route absorption is enhanced by deep inhalation and patient cooperation, but it can still be effective in an unconscious patient. Response time is nearly the same as that with IV administration (both act within 1-2 mins).⁶

Naloxone has a short duration of action (shorter than that of some opiates), and its duration of action is influenced by the pharmacology and toxicity of the overdose drug.¹⁵ The serum half-life in adults ranges from 30 to 81 mins, and clinical impact varies from minutes to an hour.¹⁵ Thus, even if a patient initially improves after administration, close observation is mandatory due to the frequent need for repeat naloxone dosing.

Adverse effects. Naloxone is considered safe, with relatively few adverse effects and doesn’t have any effects on someone who isn’t experiencing an opioid overdose or currently on opioids.¹⁵ The only downside is that naloxone administration to an opioid-dependent person often precipitates an acute withdrawal event, characterized by global pain, agitation, generalized distress, and gastrointestinal complaints, including vomiting and diarrhea. Although withdrawal is not life-threatening, it can cause great discomfort.

Getting a handle on naloxone dosing

The starting dose of naloxone used to be 0.04 mg, but this was later increased to 0.4 mg. The advent and high overdose lethality of more potent drugs like fentanyl and carfentanil has made low-dose naloxone less effective.¹² 

Currently, 1 mg is often the initial recommendation, but doses of 2 to 4 mg are not uncommon, and multiple administrations or continuous IV administration are frequently needed to reverse severe toxicities, such as those involving fentanyl or longer-action opioids like methadone. Anyone exhibiting difficulty breathing mandates a starting naloxone dose of at least 1 to 2 mg.^12,16 In addition to breathing, additional doses are indicated clinically by medical parameters such as vital signs, ocular pupil diameter, and/or alertness.⁶

Intranasal administration often utilizes up to 4 mg of naloxone in one nostril, followed by a titrated additional administration in the other nostril. In life-threatening circumstances, especially those in which a patient is exhibiting respiratory depression, a much larger quantity of naloxone—up to 10 mg—may be administered by trained medical personnel.^12,16 In the end, all dosing varies and must be individualized to the patient’s signs and symptoms. Those who have overdosed require prolonged monitoring to treat potential complications.

Emergency assistance and transport. Because of the dangers that can result from opioid toxicities, any hint or evidence of physiologic compromise merits a 911 call for emergency medical assistance and transport to a hospital emergency department (ED). Hospitalization is at the physician’s discretion. 

Expanding the availability of naloxone in the community

The availability of naloxone overdose-reversal kits is growing among hospitals, other types of health care facilities, first responders, medical offices, and the general public. Distributing the kits to opioid users and their families has wide support but remains controversial (more on this in a bit).

Opioids are responsible for 61% of drug-overdose deaths.

Support even includes that from the current US Surgeon General, Jerome Adams, MD, MPH, who noted in a statement on April 5, 2018, the lifesaving success of opioid-overdose reversal naloxone kits by medical personnel, first responders, and other people. As a result, he formally recommended that more Americans keep such kits available in order to be able to quickly diminish opioid toxicities.^17,18 His advice was especially directed toward people at risk for an opioid overdose or anyone associated with opioid drug users.

Prehospital management of overdoses is ideally managed by emergency medical service (EMS) personnel,¹⁰ but even nonmedical people can safely administer naloxone. About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.¹⁰ Many states have laws limiting the civil and criminal liability for naloxone administrators. New Mexico was the first state to legally allow naloxone administration by individuals without a prescription.⁷ Pharmacists often participate in efforts to counter opioid drug overdose deaths by offering naloxone administration kits, along with training about techniques of use, to people filling opioid prescriptions and to household members and/or other individuals in the social support network of an opioid user.⁶ Some physicians co-prescribe naloxone to patients along with opioid therapies during long-term pain management. Such dual prescribing is encouraged by many clinics.¹⁹ This method has decreased opioid overdose deaths in North Carolina,²⁰ in its army base at Fort Bragg,¹⁹ and in California.²¹

The issue of “risk compensation”

About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.

To those who say that having naloxone available to users of opioids or those in their social network promotes even riskier behavior resulting in increased overdoses, research points to just the opposite. A nonrandomized study that examined co-prescribing naloxone to patients on chronic opioid therapy for non-cancer-related pain, documented fewer opioid-related ED visits following use by prescribers and patients at community health centers.²² Other research has demonstrated a reduced number of community-level opioid overdose deaths once opioid overdose education and community naloxone distribution were implemented.^23,24

After the overdose: Getting patients into treatment

After reversing initial toxicities, a protracted period of assessment is required to assure patient safety. Beyond prolonged observation after an overdose, it is critical to recommend and provide long-term substance abuse therapies. Simply reversing the overdose is not medically sufficient, even if postoverdose patients refuse such treatment referrals. The fact that many of these people subsequently die is evidence of the importance of adhering to a formal, long-term chemical dependence intervention program.

Persistent diligence is usually needed to convince a patient who has recovered from an acute drug overdose event to accept a treatment referral. Some EDs institute special teams to facilitate such referrals, using a multidisciplinary approach, including substance abuse counselors and social workers. Referral agencies are also sometimes included to aid patient acceptance and retention in drug abuse treatment interventions. (See "Resources" below for more information.)

CORRESPONDENCE
Steven Lippmann, MD, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; Steven.lippmann@louisville.edu.

More than 64,000 people in the United States died of drug overdoses in 2016.¹ Of those overdose deaths, more than 34,000 were related to the use of natural (eg, codeine, morphine); synthetic (eg, fentanyl); and semisynthetic (eg, oxycodone, hydrocodone) opioids.¹ The number of drug-overdose fatalities (driven largely by opioids) has increased so dramatically in recent years that drug overdose is now the leading cause of intentional and unintentional injury-related death in the United States.² Furthermore, opioid use is increasing among college students, with many injecting these agents.³ Those injecting (as opposed to other routes of delivery) have the highest death rate.⁴

The Department of Health and Human Services has identified 3 important issues to address with regard to the opioid epidemic: prescriber education, community naloxone access, and better interventions (such as naloxone overdose-reversal take-home kits) for people with opioid use disorders and/or a history of overdoses.⁵ (For more on overdose reversal kits, see “What FPs need to know about naloxone kits,” a 3-in-3 video.) With these goals in mind, we provide the following review of naloxone dosing and postoverdose treatment.

Steps FPs can take to reverse the overdose

Opioids act on delta, kappa, and mu receptors in the brain to produce analgesic effects,⁶ but, in large quantities, their mu receptor activity can cause fatal respiratory depression.⁷ Some of the most commonly abused opioids are heroin and the prescription opioids fentanyl, oxycodone, and hydrocodone.⁸

People who have overdosed on opioids generally present with evidence of obtundation, miosis, and difficulty breathing. Respiratory failure is the most common cause of death.⁹ Hypothermia, compartment syndrome, rhabdomyolysis, renal failure, and acute pulmonary edema are less common complications. Overdoses and these medical issues can potentially be reversed and/or mitigated by naloxone administration.^10,11

Naloxone and its routes of administration. Naloxone is the agent of choice in overdose situations.¹² It works as an antagonist of the delta, kappa, and mu receptors,^6,13 has a rapid onset of action, and is associated with minimal adverse effects.¹⁴

Naloxone can be administered via the intravenous (IV), intranasal, intramuscular, subcutaneous, intraosseous, or endotracheal routes.⁶ Although IV administration has been the most common and is still generally preferred in the hospital setting, the intranasal route has gained favor, partly because it can be difficult to establish an IV in IV drug users and partly because it is easier for nonmedical people to administer.⁶

In addition, the nasal mucosa has an abundant blood supply resulting in rapid absorption. The drug reaches the systemic circulation quickly and avoids first-pass hepatic metabolism.⁶ Intranasal route absorption is enhanced by deep inhalation and patient cooperation, but it can still be effective in an unconscious patient. Response time is nearly the same as that with IV administration (both act within 1-2 mins).⁶

Naloxone has a short duration of action (shorter than that of some opiates), and its duration of action is influenced by the pharmacology and toxicity of the overdose drug.¹⁵ The serum half-life in adults ranges from 30 to 81 mins, and clinical impact varies from minutes to an hour.¹⁵ Thus, even if a patient initially improves after administration, close observation is mandatory due to the frequent need for repeat naloxone dosing.

Adverse effects. Naloxone is considered safe, with relatively few adverse effects and doesn’t have any effects on someone who isn’t experiencing an opioid overdose or currently on opioids.¹⁵ The only downside is that naloxone administration to an opioid-dependent person often precipitates an acute withdrawal event, characterized by global pain, agitation, generalized distress, and gastrointestinal complaints, including vomiting and diarrhea. Although withdrawal is not life-threatening, it can cause great discomfort.

Getting a handle on naloxone dosing

The starting dose of naloxone used to be 0.04 mg, but this was later increased to 0.4 mg. The advent and high overdose lethality of more potent drugs like fentanyl and carfentanil has made low-dose naloxone less effective.¹² 

Currently, 1 mg is often the initial recommendation, but doses of 2 to 4 mg are not uncommon, and multiple administrations or continuous IV administration are frequently needed to reverse severe toxicities, such as those involving fentanyl or longer-action opioids like methadone. Anyone exhibiting difficulty breathing mandates a starting naloxone dose of at least 1 to 2 mg.^12,16 In addition to breathing, additional doses are indicated clinically by medical parameters such as vital signs, ocular pupil diameter, and/or alertness.⁶

Intranasal administration often utilizes up to 4 mg of naloxone in one nostril, followed by a titrated additional administration in the other nostril. In life-threatening circumstances, especially those in which a patient is exhibiting respiratory depression, a much larger quantity of naloxone—up to 10 mg—may be administered by trained medical personnel.^12,16 In the end, all dosing varies and must be individualized to the patient’s signs and symptoms. Those who have overdosed require prolonged monitoring to treat potential complications.

Emergency assistance and transport. Because of the dangers that can result from opioid toxicities, any hint or evidence of physiologic compromise merits a 911 call for emergency medical assistance and transport to a hospital emergency department (ED). Hospitalization is at the physician’s discretion. 

Expanding the availability of naloxone in the community

The availability of naloxone overdose-reversal kits is growing among hospitals, other types of health care facilities, first responders, medical offices, and the general public. Distributing the kits to opioid users and their families has wide support but remains controversial (more on this in a bit).

Opioids are responsible for 61% of drug-overdose deaths.

Support even includes that from the current US Surgeon General, Jerome Adams, MD, MPH, who noted in a statement on April 5, 2018, the lifesaving success of opioid-overdose reversal naloxone kits by medical personnel, first responders, and other people. As a result, he formally recommended that more Americans keep such kits available in order to be able to quickly diminish opioid toxicities.^17,18 His advice was especially directed toward people at risk for an opioid overdose or anyone associated with opioid drug users.

Prehospital management of overdoses is ideally managed by emergency medical service (EMS) personnel,¹⁰ but even nonmedical people can safely administer naloxone. About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.¹⁰ Many states have laws limiting the civil and criminal liability for naloxone administrators. New Mexico was the first state to legally allow naloxone administration by individuals without a prescription.⁷ Pharmacists often participate in efforts to counter opioid drug overdose deaths by offering naloxone administration kits, along with training about techniques of use, to people filling opioid prescriptions and to household members and/or other individuals in the social support network of an opioid user.⁶ Some physicians co-prescribe naloxone to patients along with opioid therapies during long-term pain management. Such dual prescribing is encouraged by many clinics.¹⁹ This method has decreased opioid overdose deaths in North Carolina,²⁰ in its army base at Fort Bragg,¹⁹ and in California.²¹

The issue of “risk compensation”

About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.

To those who say that having naloxone available to users of opioids or those in their social network promotes even riskier behavior resulting in increased overdoses, research points to just the opposite. A nonrandomized study that examined co-prescribing naloxone to patients on chronic opioid therapy for non-cancer-related pain, documented fewer opioid-related ED visits following use by prescribers and patients at community health centers.²² Other research has demonstrated a reduced number of community-level opioid overdose deaths once opioid overdose education and community naloxone distribution were implemented.^23,24

After the overdose: Getting patients into treatment

After reversing initial toxicities, a protracted period of assessment is required to assure patient safety. Beyond prolonged observation after an overdose, it is critical to recommend and provide long-term substance abuse therapies. Simply reversing the overdose is not medically sufficient, even if postoverdose patients refuse such treatment referrals. The fact that many of these people subsequently die is evidence of the importance of adhering to a formal, long-term chemical dependence intervention program.

Persistent diligence is usually needed to convince a patient who has recovered from an acute drug overdose event to accept a treatment referral. Some EDs institute special teams to facilitate such referrals, using a multidisciplinary approach, including substance abuse counselors and social workers. Referral agencies are also sometimes included to aid patient acceptance and retention in drug abuse treatment interventions. (See "Resources" below for more information.)

CORRESPONDENCE
Steven Lippmann, MD, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; Steven.lippmann@louisville.edu.

More than 64,000 people in the United States died of drug overdoses in 2016.¹ Of those overdose deaths, more than 34,000 were related to the use of natural (eg, codeine, morphine); synthetic (eg, fentanyl); and semisynthetic (eg, oxycodone, hydrocodone) opioids.¹ The number of drug-overdose fatalities (driven largely by opioids) has increased so dramatically in recent years that drug overdose is now the leading cause of intentional and unintentional injury-related death in the United States.² Furthermore, opioid use is increasing among college students, with many injecting these agents.³ Those injecting (as opposed to other routes of delivery) have the highest death rate.⁴

The Department of Health and Human Services has identified 3 important issues to address with regard to the opioid epidemic: prescriber education, community naloxone access, and better interventions (such as naloxone overdose-reversal take-home kits) for people with opioid use disorders and/or a history of overdoses.⁵ (For more on overdose reversal kits, see “What FPs need to know about naloxone kits,” a 3-in-3 video.) With these goals in mind, we provide the following review of naloxone dosing and postoverdose treatment.

Steps FPs can take to reverse the overdose

Opioids act on delta, kappa, and mu receptors in the brain to produce analgesic effects,⁶ but, in large quantities, their mu receptor activity can cause fatal respiratory depression.⁷ Some of the most commonly abused opioids are heroin and the prescription opioids fentanyl, oxycodone, and hydrocodone.⁸

People who have overdosed on opioids generally present with evidence of obtundation, miosis, and difficulty breathing. Respiratory failure is the most common cause of death.⁹ Hypothermia, compartment syndrome, rhabdomyolysis, renal failure, and acute pulmonary edema are less common complications. Overdoses and these medical issues can potentially be reversed and/or mitigated by naloxone administration.^10,11

Naloxone and its routes of administration. Naloxone is the agent of choice in overdose situations.¹² It works as an antagonist of the delta, kappa, and mu receptors,^6,13 has a rapid onset of action, and is associated with minimal adverse effects.¹⁴

Naloxone can be administered via the intravenous (IV), intranasal, intramuscular, subcutaneous, intraosseous, or endotracheal routes.⁶ Although IV administration has been the most common and is still generally preferred in the hospital setting, the intranasal route has gained favor, partly because it can be difficult to establish an IV in IV drug users and partly because it is easier for nonmedical people to administer.⁶

In addition, the nasal mucosa has an abundant blood supply resulting in rapid absorption. The drug reaches the systemic circulation quickly and avoids first-pass hepatic metabolism.⁶ Intranasal route absorption is enhanced by deep inhalation and patient cooperation, but it can still be effective in an unconscious patient. Response time is nearly the same as that with IV administration (both act within 1-2 mins).⁶

Naloxone has a short duration of action (shorter than that of some opiates), and its duration of action is influenced by the pharmacology and toxicity of the overdose drug.¹⁵ The serum half-life in adults ranges from 30 to 81 mins, and clinical impact varies from minutes to an hour.¹⁵ Thus, even if a patient initially improves after administration, close observation is mandatory due to the frequent need for repeat naloxone dosing.

Adverse effects. Naloxone is considered safe, with relatively few adverse effects and doesn’t have any effects on someone who isn’t experiencing an opioid overdose or currently on opioids.¹⁵ The only downside is that naloxone administration to an opioid-dependent person often precipitates an acute withdrawal event, characterized by global pain, agitation, generalized distress, and gastrointestinal complaints, including vomiting and diarrhea. Although withdrawal is not life-threatening, it can cause great discomfort.

Getting a handle on naloxone dosing

The starting dose of naloxone used to be 0.04 mg, but this was later increased to 0.4 mg. The advent and high overdose lethality of more potent drugs like fentanyl and carfentanil has made low-dose naloxone less effective.¹² 

Currently, 1 mg is often the initial recommendation, but doses of 2 to 4 mg are not uncommon, and multiple administrations or continuous IV administration are frequently needed to reverse severe toxicities, such as those involving fentanyl or longer-action opioids like methadone. Anyone exhibiting difficulty breathing mandates a starting naloxone dose of at least 1 to 2 mg.^12,16 In addition to breathing, additional doses are indicated clinically by medical parameters such as vital signs, ocular pupil diameter, and/or alertness.⁶

Intranasal administration often utilizes up to 4 mg of naloxone in one nostril, followed by a titrated additional administration in the other nostril. In life-threatening circumstances, especially those in which a patient is exhibiting respiratory depression, a much larger quantity of naloxone—up to 10 mg—may be administered by trained medical personnel.^12,16 In the end, all dosing varies and must be individualized to the patient’s signs and symptoms. Those who have overdosed require prolonged monitoring to treat potential complications.

Emergency assistance and transport. Because of the dangers that can result from opioid toxicities, any hint or evidence of physiologic compromise merits a 911 call for emergency medical assistance and transport to a hospital emergency department (ED). Hospitalization is at the physician’s discretion. 

Expanding the availability of naloxone in the community

The availability of naloxone overdose-reversal kits is growing among hospitals, other types of health care facilities, first responders, medical offices, and the general public. Distributing the kits to opioid users and their families has wide support but remains controversial (more on this in a bit).

Opioids are responsible for 61% of drug-overdose deaths.

Support even includes that from the current US Surgeon General, Jerome Adams, MD, MPH, who noted in a statement on April 5, 2018, the lifesaving success of opioid-overdose reversal naloxone kits by medical personnel, first responders, and other people. As a result, he formally recommended that more Americans keep such kits available in order to be able to quickly diminish opioid toxicities.^17,18 His advice was especially directed toward people at risk for an opioid overdose or anyone associated with opioid drug users.

Prehospital management of overdoses is ideally managed by emergency medical service (EMS) personnel,¹⁰ but even nonmedical people can safely administer naloxone. About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.¹⁰ Many states have laws limiting the civil and criminal liability for naloxone administrators. New Mexico was the first state to legally allow naloxone administration by individuals without a prescription.⁷ Pharmacists often participate in efforts to counter opioid drug overdose deaths by offering naloxone administration kits, along with training about techniques of use, to people filling opioid prescriptions and to household members and/or other individuals in the social support network of an opioid user.⁶ Some physicians co-prescribe naloxone to patients along with opioid therapies during long-term pain management. Such dual prescribing is encouraged by many clinics.¹⁹ This method has decreased opioid overdose deaths in North Carolina,²⁰ in its army base at Fort Bragg,¹⁹ and in California.²¹

The issue of “risk compensation”

About 10,000 overdose cases were documented to have been reversed by nonmedical providers between 1996 and 2010.

To those who say that having naloxone available to users of opioids or those in their social network promotes even riskier behavior resulting in increased overdoses, research points to just the opposite. A nonrandomized study that examined co-prescribing naloxone to patients on chronic opioid therapy for non-cancer-related pain, documented fewer opioid-related ED visits following use by prescribers and patients at community health centers.²² Other research has demonstrated a reduced number of community-level opioid overdose deaths once opioid overdose education and community naloxone distribution were implemented.^23,24

After the overdose: Getting patients into treatment

After reversing initial toxicities, a protracted period of assessment is required to assure patient safety. Beyond prolonged observation after an overdose, it is critical to recommend and provide long-term substance abuse therapies. Simply reversing the overdose is not medically sufficient, even if postoverdose patients refuse such treatment referrals. The fact that many of these people subsequently die is evidence of the importance of adhering to a formal, long-term chemical dependence intervention program.

Persistent diligence is usually needed to convince a patient who has recovered from an acute drug overdose event to accept a treatment referral. Some EDs institute special teams to facilitate such referrals, using a multidisciplinary approach, including substance abuse counselors and social workers. Referral agencies are also sometimes included to aid patient acceptance and retention in drug abuse treatment interventions. (See "Resources" below for more information.)

CORRESPONDENCE
Steven Lippmann, MD, 401 East Chestnut Street, Suite 610, Louisville, KY 40202; Steven.lippmann@louisville.edu.

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

[polldaddy:9903171]

The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

[polldaddy:9903172]

Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

[polldaddy:9903171]

The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

[polldaddy:9903172]

Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

CASE Depressed, avoidant

Mr. R, age 95, has a history of recurrent major depressive disorder. He presents to the emergency department with depressive symptoms that began 6 weeks ago. His symptoms include depressed mood, hopelessness, anhedonia, anxiety, and insomnia. Co-occurring anorexia nervosa has resulted in a 20-lb weight loss. He denies suicidal ideation.

A mental status examination reveals profound psychomotor agitation, dysphoric mood, tearfulness, and mood-congruent delusions. Mr. R’s Mini-Mental State Examination (MMSE) score is 14/30; his Hamilton Depression Rating Scale (HAM-D) score is 21, indicating severe depression (19 to 22). However, the examiner feels that these scores may not reflect an accurate assessment because Mr. R gave flippant responses and did not cooperate during the interview. Physical examination is unremarkable. Previous medication trials included buspirone, escitalopram, and risperidone; none of these medications successfully alleviated his depressive symptoms.

On admission, Mr. R is given oral mirtazapine, 15 mg/d, and quetiapine, 25 mg/d, to target depressive mood, insomnia, and weight loss. Urgent intervention is indicated because his depressive symptoms are profoundly causing failure to thrive and are compromising his physical health. Mr. R’s deterioration concerns the physician team. Because of a history of failed pharma­cotherapy trials, the team reassesses Mr. R’s treatment options.

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The authors’ observations

The physician team recommends that Mr. R undergo ECT to obtain rapid relief from his depressive symptoms. After discussion of the potential risks and benefits, Mr. R agrees to this treatment. Quetiapine is discontinued prior to initiating ECT to avoid unnecessary medications; mirtazapine is continued.

Mr. R’s lack of response to previous antidepressants and significant deterioration were concerning. The physicians wanted to avoid higher-dose medications because of the risk of falls or somnolence. Their clinical experience and the literature supporting ECT for patients of Mr. R’s age lead them to select ECT as the most appropriate therapeutic option.

ECT has no absolute contraindications.¹ The rate of ECT use in the United States has fluctuated over time because of factors unrelated to the efficacy and availability of ECT or alternative treatments.² This form of intervention is also somewhat stigmatized.

Some psychiatrists are reluctant to prescribe ECT for geriatric patients because of concerns of potential neurocognitive or medical complications and risks during anesthesia. However, in the United States, older patients with depression are more likely to be treated with ECT than their younger counterparts.³ ECT usually induces greater immediate efficacy than antidepressants.⁴

Evidence supports using ECT in older patients

Multiple studies have found that ECT is a rapid, safe, and efficacious intervention for treating older persons with depression. Patients age >60 who receive ECT plus pharma­cotherapy have lower HAM-D scores than those receiving pharmacotherapy alone.⁵ Overall, the rates of remission for depression range from 50% to 70%; yet geriatric patients who receive only ECT have response rates around 90%.⁶ Older age, presence of psychotic symptoms, and shorter duration of illness can predict a rapidly positive ECT response.⁷

When treated with ECT, older patients, including those age >85, have fewer subsequent episodes of depression compared with those who receive pharmacotherapy alone.¹ Older individuals with physical illness or cognitive impairment respond to and tolerate ECT much like younger patients.⁶ Older patients receiving ECT may experience less cognitive decline than younger ones.⁷ Those in their ninth decade of life with treatment-resistant depression, psychotic features, and post-stroke depression often respond robustly with improvement following ECT.⁸

Remission rates also depend on the technique of administration. Interactions between electrode placement and stimulus parameter dosage affect efficacy and adverse effects.⁹ Right-sided, unilateral ECT induces less cognitive dysfunction compared with bilateral electrode placement,⁹ but bilateral ECT is more clinically effective.¹⁰ However, the efficacy of right-sided ECT is more dose-sensitive, and some data suggest that suboptimal response is due to insufficient stimulus dosages.¹¹ One double-blind randomized controlled trial documented that when using a high-dose stimulus parameter, unilateral ECT is as effective as bilateral ECT.¹² When there is a suboptimal response to unilateral ECT, bilateral ECT might be beneficial.^12,13 For preventing relapse in older patients, increasing the interval between ECT treatments is more effective than stopping ECT abruptly.¹³

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Indications of ECT

ECT is indicated for patients with severe depression, mania, and other conditions (Table).¹⁴ The most common indication for ECT in older persons is a history of treatment-resistant depression, with melancholia, psychosis, or suicidal ideations.^1-6,12 There are also age-related and clinical factors to consider with ECT. This treatment provides a safe, rapid remission for patients age >65, even after adjusting for somatic conditions, duration of illness, medication resistance, or case severity.¹⁵ Compared with younger patients, older adults may not tolerate antidepressants as well because of age-related pharmacokinetic alterations, including increased sensitivity to anticholinergic and/or hypotensive effects.¹

Factors that favor ECT include a previous good response to it; patient preference; and an indication for rapid intervention, such as suicidality, catatonia, dehydration, malnutrition, or a suboptimal result from pharmacotherapy.³ Mortality among individuals age >85 who receive ECT reportedly is lower than that among their counterparts who receive alternative treatments.¹⁶ ECT has been administered safely and effectively in patients with comorbid medical illnesses such as stroke, cerebral aneurysm, cardiovascular disease with ischemia or arrhythmia, dementia, and osteoporosis.¹⁷

Neurocognitive effects

Reports on the effects of ECT on neurocognitive functioning have varied. In some studies, performance improved or did not change in severely depressed older patients who received ECT.^18,19 In older people who receive ECT, MMSE scores often return to baseline by the end of treatment.²⁰ There often is only mild transient cognitive impairment in patients with late-life depression who receive ECT. Areas of concern include attention span, orientation, and speed of mental processing.²⁰ Physicians should conduct cognitive tests before, during, and after ECT sessions to monitor their patient’s mental status.²⁰

Cognitive stability can be maintained by administering ECT twice a week; applying right-sided, unilateral electrode placement; and using short, ultra-brief stimulus pulse width parameters.²¹ Cognitive impairment induced by ECT is not associated with age in geriatric patients with depression.²² Older adults who experienced longer postictal reorientation time periods have better outcomes than others who reach orientation faster; their intellectual impairment returned to baseline.²⁰ Falling is another complication associated with ECT. A longitudinal cohort study found the incident of falls among patients receiving ECT was 13%.²² Risk factors for falls during a course of ECT include the number of treatments and the presence of coexisting Parkinson’s disease.²³

OUTCOME Improvement

Mr. R receives 8 sessions of right-sided, unilateral ECT with an individualized dosage titration method. Treatments are completed with a stimulus intensity at 6 times seizure threshold, with an ultra-brief pulse width at 0.3 milliseconds. Mr. R’s mood and affect begin to improve after 3 ECT sessions. His MMSE score increases to 28/30 (Figure). His clinical improvement is progressively sustained; he develops an increasingly jovial attitude and experiences less anxiety. Mr. R’s confidence, appetite, and sleep also improve. There are no complications with treatment, and Mr. R has no complaints. After 8 ECT sessions, Mr. R has no affective symptoms and does not experience any cognitive impairment.

The authors’ observations

Depression among older people is a growing public health concern. It is a leading cause of disability, and often leads to nursing home placement.²⁴ ECT is a safe, effective treatment for late-life depression, but is underutilized in patients age >75 because of concerns for cognitive impairment.⁶ However, there is evidence that response rates to ECT are higher in patients ages 45 to 85, compared with young individuals ages 18 to 45.²⁵ ECT is a viable intervention for older depressed patients, particularly for those who do not tolerate or fail to respond to pharmacotherapy. Many of these patients are at risk for drug-induced toxicities or interactions or suicide.¹

Cannavaping—the inhalation of a cannabis-containing aerosol, created by a battery-driven, heated atomizer in e-cigarettes or similar devices¹—is touted as a less expensive and safer alternative to smoking marijuana. It’s also gaining in popularity.² One study of Connecticut high school students found that 5.4% had used e-cigarettes to vaporize cannabis.³ But what do we know about this new way to get high?

We know that those who wish to cannavape can easily obtain e-cigarettes from gas stations and tobacco shops. They then have to obtain a cartridge, filled with either hash oil or tetrahydrocannabinol-infused wax, to attach to the e-cigarette. These cartridges are available for purchase in states that have legalized the sale of marijuana. They also find their way into states where the sale of marijuana is not legal, and are purchased illegally for the purpose of cannavaping.

And while cannavaping does appear to reduce the cost of smoking marijuana,⁴ it has not been widely researched, nor determined to be safe.⁵

In fact, although marijuana has several important therapeutic and medicinal purposes, cannavaping the substance can result in medical concerns.⁶ The vaping aerosols of some compounds can induce lung pathology and may be carcinogenic, since they often contain a number of dangerous toxins.⁴

Chronic marijuana use can increase the likelihood of motor vehicles accidents, cognitive impairment, psychoses, and demotivation.⁴ It may predispose certain individuals to use other drugs and tobacco products and could increase the consumption of marijuana.^4,5 Increased consumption could have a detrimental effect on intellect and behavior when used chronically—especially in youngsters, whose nervous systems are not yet fully matured.^7-9

Because cannavaping has potentially deleterious effects, more regulations on the manufacture, distribution, access, and use are indicated—at least until research sheds more light on issues surrounding this practice.

Steven Lippman, MD; Devina Singh, MD
Louisville, KY

Cannavaping—the inhalation of a cannabis-containing aerosol, created by a battery-driven, heated atomizer in e-cigarettes or similar devices¹—is touted as a less expensive and safer alternative to smoking marijuana. It’s also gaining in popularity.² One study of Connecticut high school students found that 5.4% had used e-cigarettes to vaporize cannabis.³ But what do we know about this new way to get high?

We know that those who wish to cannavape can easily obtain e-cigarettes from gas stations and tobacco shops. They then have to obtain a cartridge, filled with either hash oil or tetrahydrocannabinol-infused wax, to attach to the e-cigarette. These cartridges are available for purchase in states that have legalized the sale of marijuana. They also find their way into states where the sale of marijuana is not legal, and are purchased illegally for the purpose of cannavaping.

And while cannavaping does appear to reduce the cost of smoking marijuana,⁴ it has not been widely researched, nor determined to be safe.⁵

In fact, although marijuana has several important therapeutic and medicinal purposes, cannavaping the substance can result in medical concerns.⁶ The vaping aerosols of some compounds can induce lung pathology and may be carcinogenic, since they often contain a number of dangerous toxins.⁴

Chronic marijuana use can increase the likelihood of motor vehicles accidents, cognitive impairment, psychoses, and demotivation.⁴ It may predispose certain individuals to use other drugs and tobacco products and could increase the consumption of marijuana.^4,5 Increased consumption could have a detrimental effect on intellect and behavior when used chronically—especially in youngsters, whose nervous systems are not yet fully matured.^7-9

Because cannavaping has potentially deleterious effects, more regulations on the manufacture, distribution, access, and use are indicated—at least until research sheds more light on issues surrounding this practice.

Steven Lippman, MD; Devina Singh, MD
Louisville, KY

Cannavaping—the inhalation of a cannabis-containing aerosol, created by a battery-driven, heated atomizer in e-cigarettes or similar devices¹—is touted as a less expensive and safer alternative to smoking marijuana. It’s also gaining in popularity.² One study of Connecticut high school students found that 5.4% had used e-cigarettes to vaporize cannabis.³ But what do we know about this new way to get high?

We know that those who wish to cannavape can easily obtain e-cigarettes from gas stations and tobacco shops. They then have to obtain a cartridge, filled with either hash oil or tetrahydrocannabinol-infused wax, to attach to the e-cigarette. These cartridges are available for purchase in states that have legalized the sale of marijuana. They also find their way into states where the sale of marijuana is not legal, and are purchased illegally for the purpose of cannavaping.

And while cannavaping does appear to reduce the cost of smoking marijuana,⁴ it has not been widely researched, nor determined to be safe.⁵

In fact, although marijuana has several important therapeutic and medicinal purposes, cannavaping the substance can result in medical concerns.⁶ The vaping aerosols of some compounds can induce lung pathology and may be carcinogenic, since they often contain a number of dangerous toxins.⁴

Chronic marijuana use can increase the likelihood of motor vehicles accidents, cognitive impairment, psychoses, and demotivation.⁴ It may predispose certain individuals to use other drugs and tobacco products and could increase the consumption of marijuana.^4,5 Increased consumption could have a detrimental effect on intellect and behavior when used chronically—especially in youngsters, whose nervous systems are not yet fully matured.^7-9

Because cannavaping has potentially deleterious effects, more regulations on the manufacture, distribution, access, and use are indicated—at least until research sheds more light on issues surrounding this practice.

Steven Lippman, MD; Devina Singh, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.