For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.

Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.

The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.

ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.

Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.

The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.

“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.

Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”

F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.

SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.

For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.

Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.

The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.

ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.

Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.

The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.

“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.

Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”

F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.

SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.

For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.

Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.

The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.

ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.

Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.

The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.

“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.

Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”

F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.

SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

 

 

Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

 

 

Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

 

 

Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA: No differences

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

Astonished by physician hourly rate calculation 

I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!

My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.

Hamid Banooni, MD
Farmington Hills, Michigan

Dr. Kim responds

I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.¹ To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Astonished by physician hourly rate calculation 

I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!

My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.

Hamid Banooni, MD
Farmington Hills, Michigan

Dr. Kim responds

I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.¹ To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Astonished by physician hourly rate calculation 

I always enjoy the articles and incredible insights presented in OBG Management. Some very sophisticated, well-founded ideas are presented in the article on deciding on purchasing medical equipment. Then, however, you get to the calculations: $50 for 30 minutes of physician time!

My plumber charges me $100 for the first half hour of a visit (okay, there are lots of cliched jokes about this), but on average a physician assistant costs almost that much. It is a sad day in the business of medicine when experts value the time of highly educated physicians at $100 per hour. Maybe someday we can expect to be reasonably compensated for our efforts and training. When I advise my colleagues, I calculate their time, depending on their practice model, between $300 and $400 per hour.

Hamid Banooni, MD
Farmington Hills, Michigan

Dr. Kim responds

I thank Dr. Banooni for his comment. I agree that physicians are highly skilled and educated and that their time deserves to be valued at more than $100 per hour. In the article and the example provided, the values (revenues, costs, and so on) were not meant to be exactly representative of the marketplace, but instead were used merely as an example for understanding the calculation tools for purchasing medical equipment. That being said, I arrived at the $100 per hour cost for physician time (included in the variable cost in the Figure, “Breakeven analysis for hysteroscope purchase for use in tubal sterilization”) for 2 primary reasons. First, to simplify the calculation, and second, to use an equivalent universal hourly salary ($100 per hour) for a physician’s comparative labor cost in the marketplace. Currently, the median hourly compensation for an ObGyn laborist is $110 per hour.¹ To simplify, I rounded down to $100. I wholeheartedly agree with Dr. Banooni, however, that a physician’s time should be valued higher in society.
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EVIDENCE SUMMARY

A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine¹ headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE¹). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.

Lisinopril reduces hours, days with headache and days with migraine

The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.² Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.

Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).

Candesartan also decreases headaches and migraine

The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.³ It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.

Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.

Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).

Continue to: Overall both drugs have a significant effect on number of headaches

 

 

Overall both drugs have a significant effect on number of headaches

Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).¹ (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).¹

RECOMMENDATIONS

In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.⁴ The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”

EVIDENCE SUMMARY

A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine¹ headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE¹). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.

Lisinopril reduces hours, days with headache and days with migraine

The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.² Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.

Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).

Candesartan also decreases headaches and migraine

The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.³ It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.

Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.

Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).

Continue to: Overall both drugs have a significant effect on number of headaches

 

 

Overall both drugs have a significant effect on number of headaches

Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).¹ (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).¹

RECOMMENDATIONS

In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.⁴ The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”

EVIDENCE SUMMARY

A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine¹ headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE¹). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.

Lisinopril reduces hours, days with headache and days with migraine

The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.² Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.

Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).

Candesartan also decreases headaches and migraine

The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.³ It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.

Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.

Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).

Continue to: Overall both drugs have a significant effect on number of headaches

 

 

Overall both drugs have a significant effect on number of headaches

Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).¹ (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).¹

RECOMMENDATIONS

In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.⁴ The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”

Agrees that OC use clearly reduces mortality

Recent evidence from long-term observations of hundreds of thousands of women, in 10 European countries, clearly demonstrated that the use of oral contraceptives (OCs) reduced mortality by roughly 10%.^1,2 Newer OCs increase women’s overall survival. 

In comparison, reducing obesity by 5 body mass index points would reduce mortality by only 5%, from 1.05 to 1.³

Dr. Stavros Saripanidis
Thessaloniki, Greece

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Agrees that OC use clearly reduces mortality

Recent evidence from long-term observations of hundreds of thousands of women, in 10 European countries, clearly demonstrated that the use of oral contraceptives (OCs) reduced mortality by roughly 10%.^1,2 Newer OCs increase women’s overall survival. 

In comparison, reducing obesity by 5 body mass index points would reduce mortality by only 5%, from 1.05 to 1.³

Dr. Stavros Saripanidis
Thessaloniki, Greece

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Agrees that OC use clearly reduces mortality

Recent evidence from long-term observations of hundreds of thousands of women, in 10 European countries, clearly demonstrated that the use of oral contraceptives (OCs) reduced mortality by roughly 10%.^1,2 Newer OCs increase women’s overall survival. 

In comparison, reducing obesity by 5 body mass index points would reduce mortality by only 5%, from 1.05 to 1.³

Dr. Stavros Saripanidis
Thessaloniki, Greece

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

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

 

 

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

 

 

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

 

 

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

Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Use metrics for populations, not individuals

Dr. Kanofsky’s commentary on CD metrics is 100% correct. As an ethical question for physicians and society alike, I would ask, is applying metrics to physicians even moral?

As an ObGyn for most of 4 decades, my approach to obstetrics has not changed. In some years, my CD rate was very low, and in others my rate was average. Women must be treated as individuals. Although the industrial revolution increased quality and decreased costs in manufacturing, I do not believe that we can or should apply those principles to our patients.

Government regulators, insurance companies, and many physician leaders have lost sight of the Oath of Maimonides, which states, “May the love of my art actuate me at all times; may neither avarice nor miserliness…engage my mind,”¹ as well as Hippocrates’ ancient observation, “Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient.”² In addition, in the modern version of the Hippocratic Oath that most schools use today, physicians swear to “apply, for the benefit of the sick, all measures [that] are required...”³—not to the benefit of the government, the federal budget, or an accountable care organization (ACO).

Clearly, the informed consent of a 42-year-old who had in vitro fertilization and has a floating presentation with a low Bishop score and an estimated fetal weight of 4,000 at 40 6/7 weeks must include not only the risks of primary CD but also the risks of a long labor that may result in a CD, the occasional risk of shoulder dystocia, or third- or fourth-degree extension. Not having had a case of shoulder dystocia or a third- or fourth-degree in more than a decade clearly justifies my rationale.

The morbidity of a multiple repeat CD or even a primary CD in an obese woman is significantly more risky than a non-labored elective CD in a woman of normal weight who plans to have only 1 or 2 children. We must individualize our care. Metrics are for populations, not individuals.

Health economists who aggressively advocate lower cesarean rates accept stillbirths and babies with hypoxic ischemic encephalopathy, cerebral palsy, or Erb’s palsy as long as governmental expenditures are lowered. Do the parents of these children get a vote? The majority of practicing physicians like myself feel more aligned with the Hippocratic Oath and the Oath of Maimonides. We believe that we have a moral, ethical, and medical responsibility to the individual patient and not to an ACO or government bean counter.

I would suggest an overarching theme: choice—the freedom to make our own intelligent decisions based on reasonable data and interpretation of the medical literature.

One size does not fit all. So why do those pushing comparative metrics tell us there is only one way to practice obstetrics?

Howard C. Mandel, MD
Los Angeles, California
 

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Because of the high prevalence of obesity and diabetes, bariatric surgery has become very popular. In the United States alone, there were an estimated 228,000 weight loss surgical procedures performed in 2017.¹

But I must confess that for many years, I was skeptical about the value of surgery to treat obesity. Yes, everyone who had a bariatric procedure lost weight, but did the long-term benefits really outweigh the harms? I wondered if most people gradually gained back the weight they lost. And the harms can be significant, including dumping syndrome, hypoglycemia, and malabsorption—in addition to the potential for surgical complications and repeat surgery. And, I must confess that my views were likely affected by the death of a friend from complications of gastric bypass 25 years ago.

My skepticism, however, has changed to cautious optimism for carefully selected patients.

My skepticism, however, has changed to cautious optimism for carefully selected patients. I say this because we now have long-term follow-up studies demonstrating the value of bariatric procedures—especially for people with type 2 diabetes.

Most studies have been cohort studies that compare results to similar patients with obesity who did not have surgery, and the outcomes have been consistently better in patients who underwent surgery. Two recent meta-analyses summarized these results; one for all patients with obesity and the other for patients with type 2 diabetes.

Continue to: The first meta-analysis

The first meta-analysis included 11 randomized trials, 4 nonrandomized controlled trials, and 17 cohort studies and showed probable reductions in all-cause mortality and possible reductions in cancer and cardiovascular events.² The second demonstrated significant improvements in microvascular and macrovascular disease and reduced mortality.³ The data were limited, however, because of the lack of large randomized trials with long-term follow-up.

The Stampede trial is one of a few bariatric surgery randomized trials focusing on patients with diabetes.⁴ The 5-year follow-up results are impressive. Nearly 30% of patients who had gastric bypass and 23% who had sleeve gastrectomy had an A1C ≤6 at 5 years compared to only 5% of those treated medically. Some patients discontinued all medications for diabetes, hypertension, and hyperlipidemia.

There is now adequate research to show that bariatric surgery provides significant benefits to properly selected patients who understand the risks. I no longer hesitate to refer patients for bariatric surgery who have been unsuccessful with weight loss—despite their best efforts.

Where do you stand?

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Laparoscopic suturing is an option 

Dr. Lum presented a nicely produced video demonstrating various strategies aimed at facilitating total laparoscopic hysterectomy (TLH) of the very large uterus. Her patient’s evaluation included magnetic resonance imaging. In the video, she demonstrates a variety of interventions, including the use of a preoperative gonadotropin–releasing hormone (GNRH) agonist and immediate perioperative radial artery–uterine artery embolization. Intraoperative techniques include use of ureteral stents and securing the uterine arteries at their origins.

Clearly, TLH of a huge uterus is a technical challenge. However, I’d like to suggest that a relatively basic and important skill would greatly assist in such procedures and likely obviate the need for a GNRH agonist and/or uterine artery embolization. The vessel-sealing devices shown in the video are generally not capable of sealing such large vessels adequately, and this is what leads to the massive hemorrhaging that often occurs.

Laparoscopic suturing with extracorporeal knot tying can  be used effectively to control the extremely large vessels associated with a huge uterus. The judicious placement of sutures can completely control such vessels and prevent bleeding from both proximal and distal ends when 2 sutures are placed and the vessels are transected between the stitches. Many laparoscopic surgeons have come to rely on bipolar energy or ultrasonic devices to coagulate vessels. But when dealing with huge vessels, a return to basics using laparoscopic suturing will greatly benefit the patient and the surgeon by reducing blood loss and operative time.

David L. Zisow, MD
Baltimore, Maryland

Dr. Lum responds

I thank Dr. Zisow for his thoughtful comments. I agree that laparoscopic suturing is an essential skill that can be utilized to suture ligate vessels. If we consider the basics of an open hysterectomy, the uterine artery is clamped first, then suture ligated. When approaching a very large vessel during TLH, I would be concerned that a simple suture around a large vessel might tear through and cause more bleeding. To mitigate this risk, the vessel can be clamped with a grasper first, similar to the approach in an open hysterectomy. However, once a vessel is compressed, a sealing device can usually work just as well as a suture. It becomes a matter of preference and cost.

During hysterectomy of a very large uterus, a big challenge is managing bleeding of the uterus itself during manipulation from above. Bleeding from the vascular sinuses of the myometrium can be brisk and obscure visualization, potentially leading to laparotomy conversion. A common misconception is that uterine artery embolization is equivalent to suturing the uterine arteries. In actuality, the goal of a uterine artery embolization is to embolize the distal branches of the uterine arteries, which can help with any potential bleeding from the uterus itself during hysterectomy.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Carcinoid tumor

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

 

 

If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; Nguyendn3@gmail.com

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Carcinoid tumor

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

 

 

If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; Nguyendn3@gmail.com

A 64-year-old woman with no significant medical history presented to the emergency department with worsening intermittent abdominal pain and chronic diarrhea, which had increased in frequency over the prior 3 months. She had taken loperamide, which yielded mild symptomatic relief. A complete metabolic panel revealed no significant abnormalities, with a normal inflammatory marker and erythrocyte sedimentation rate (ESR).

Physical examination revealed mild tenderness to palpation over the right hemiabdomen, but no rebound tenderness or guarding. An abdominal radiograph (FIGURE 1), computed tomography (CT) without contrast of the abdomen and pelvis (FIGURE 2), and a whole-body octreotide scan (FIGURE 3) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Carcinoid tumor

Based on the patient’s symptoms and imaging studies, we suspected that she had a carcinoid tumor with mesenteric involvement. The CT showed a 2.6-cm mesenteric mass with a characteristic sunburst pattern and desmoplastic stranding, as well as numerous prominent retroperitoneal lymph nodes, suggestive of nodal involvement. The octreotide scan showed abnormal focal intense radiotracer uptake in the corresponding right lower quadrant mass, which confirmed our suspicion. There was no evidence of hepatic metastasis on the CT or octreotide scan.

Most common locations

Carcinoid tumors are the most common type of neuroendocrine tumors and are derived primarily from serotonin-producing enterochromaffin cells.¹ These slow-growing, well-differentiated tumors usually originate in the gastrointestinal and bronchopulmonary tracts (67.5% and 25.3%, respectively), with uncommon primary sites involving the mesentery, ovaries, and kidneys.² Generally, carcinoid tumors that arise in the mesentery are metastatic, often from an occult primary site. It has been reported that 40% to 80% of midgut carcinoid tumors spread to the mesentery.³

Carcinoid tumors are derived primarily from serotonin-producing cells in the gastrointestinal tract, which can lead to symptoms such as chronic diarrhea.

Carcinoid tumors are estimated to occur in 1.9 individuals per 100,000 annually.⁴ Traditionally, the appendix was cited as the most common location for these tumors. However, more recently, Modlin et al² conducted a comprehensive analysis of epidemiologic data from the 13,715 carcinoid tumors registered in the National Cancer Institute database. Over the more than 25-year study period (1973-1999), Modlin and colleagues found a significant change in the distribution of gastrointestinal carcinoid tumors, with the incidence rates of small bowel (41.8%) and rectal carcinoids (27.4%) increasing, while appendiceal carcinoids decreased (24.1%).²

Gastrointestinal complications can arise from metastasis

Small bowel carcinoid tumors often manifest with intermittent abdominal pain, which can be caused by fibrosis of the mesentery, intestinal obstruction, or kinking of the bowel. Less common is the constellation of diarrhea, cutaneous flushing, and asthma seen with carcinoid syndrome. The prevalence of this syndrome is mediated by various humoral factors, the most notable of which is serotonin.

Continue to: Patients with carcinoid syndrome...

Patients with carcinoid syndrome often have metastasis to the liver, where serotonin is normally metabolized. This metastasis allows serotonin and other vasoactive substances to bypass hepatic metabolic degradation, resulting in the aforementioned symptoms. Carcinoid syndrome can also occur without hepatic metastasis in the setting of nodal involvement, which enables direct hormone release into the systemic circulation.⁵

Carcinoid syndrome affects fewer than 10% of patients with carcinoid tumors.⁶ Therefore, although carcinoid tumor should be suspected in patients with suggestive symptoms, other diagnoses must be considered.

Other disorders to consider on work-up

Chronic diarrhea and colicky abdominal pain are nonspecific features also associated with conditions such as inflammatory bowel disease and celiac disease, necessitating further work-up to elucidate the diagnosis.

Inflammatory bowel disease often involves elevated inflammatory markers, such as increased ESR and C-reactive protein.

Ulcerative colitis can show thickened and inflamed bowel walls on CT, with cross-sectional target appearance due to transmural involvement.

Continue to: Crohn's disease

Crohn’s disease usually affects the terminal ileum. CT is useful for identifying complications such as strictures/fistulas and abscesses.

Celiac disease involves elevated endomysial antibody and human tissue transglutaminase antibody. On CT, a characteristic jejunoileal fold pattern reversal can be seen.

A 24-hour urine test + imaging studies

The most useful diagnostic test for carcinoid tumor is the 24-hour urinary test for 5-hydroxyindoleacetic acid (5-HIAA), the metabolic end-product of serotonin. The normal rate of 5-HIAA excretion ranges from 3 to 15 mg/d, whereas the rates of patients with carcinoid tumors may have elevated levels.⁷

What you’ll see. On CT scan, a carcinoid tumor affecting the mesentery appears as a soft tissue mass with calcification and desmoplastic stranding, which produces a “sunburst” appearance. Another diagnostic tool is the octreotide scan, which is considered the test of choice due to its high sensitivity for detection of the tumor and metastases.⁸ The increase in somatostatin receptors seen with carcinoid tumors allows not only imaging by octreotide scan but also therapy using octreotide with larger doses of therapeutic radioactive agents.

Continue to: If tumor is operable, surgery is curative

 

 

If tumor is operable, surgery is curative

Surgery is the only curative therapy and is the mainstay of treatment for carcinoid tumors. Local segmental resection is generally adequate for tumors <2 cm without nodal involvement. However, tumors >2 cm with regional mesentery metastasis and nodal involvement require wide excision of the bowel and mesentery with lymph node dissection because of the associated higher incidence of metastasis.⁹ If the tumor has metastasized to the liver and is considered inoperable, radiolabeled octreotide or ¹³¹I-metaiodobenzylguanidine are potential treatment options for arresting tumor growth and improving survival rates.¹⁰

Our patient underwent an uncomplicated surgical resection of the mesenteric carcinoid tumor and adjacent small bowel, as well as lymph node dissection. Intraoperatively, there was no evidence of tumor elsewhere in the abdomen or pelvis, including the liver, ovaries, and other solid organs, suggesting probable metastasis from an occult primary site. The patient had an unremarkable postoperative course and was reported to be asymptomatic on follow-up.

CORRESPONDENCE
Don N. Nguyen, MD, MHA, Dept. of Diagnostic Radiology, 320 E. North Ave., Pittsburgh, PA 15212; Nguyendn3@gmail.com