Sarah Hartley, MD

The demographic composition of physicians has shifted dramatically in the last five decades. The number of women matriculating into medical school rose from 6% in the 1960s¹ to 52% in 2019²; women accounted for 39% of full-time faculty in 2015.³ Despite this evolution of the physician gender array, many challenges remain.⁴ Women represented only 35% of all associate professors and 22% of full professors in 2015.³ Women experience gender-based discrimination, hostility, and unconscious bias as medical trainees^5-9 and as attending physicians^10-13 with significant deleterious effects including burnout and suicidal thoughts.¹⁴ While types of gender-based challenges are well described in the literature, strategies to navigate and respond to these challenges are less understood.

The approaches and techniques of exemplary teaching attending physicians (hereafter referred to as “attendings”) have previously been reported from groups of predominantly male attendings.^15-18 Because of gender-based challenges female physicians face that lead them to reduce their effort or leave the medical field,¹⁹ there is concern that prior scholarship in effective teaching may not adequately capture the approaches and techniques of female attendings. To our knowledge, no studies have specifically examined female attendings. Therefore, we sought to explore the lived experiences of six female attendings with particular emphasis on how they navigate and respond to gender-based challenges in clinical environments.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. We aimed to examine techniques, approaches, and attitudes of outstanding general medicine teaching attendings among groups previously not well represented (ie, women and self-identified underrepresented minorities [URMs] in medicine). URM was defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.”²⁰ A modified snowball sampling approach²¹ was employed to identify attendings as delineated below.

To maintain quality while guaranteeing diversity in geography and population, potential institutions in which to observe attendings were determined by first creating the following lists: The top 20 hospitals in the U.S. News & World Report’s 2017-2018 Best Hospitals Honor Roll,²² top-rated institutions by Doximity in each geographic region and among rural training sites,²³ and four historically Black colleges and universities (HBCUs) with medical schools. Institutions visited during a previous similar study¹⁶ were excluded. Next, the list was narrowed to 25 by randomly selecting five in each main geographic region and five rural institutions. These were combined with all four HBCUs to create a final list of 29 institutions.

Next, division of hospital medicine chiefs (and/or general medicine chiefs) and internal medicine residency directors at each of these 29 institutions were asked to nominate exemplary attendings, particularly those who identified as women and URMs. Twelve attendings who were themselves observed in a previous study¹⁶ were also asked for nominations. Finally, recommendations were sought from leaders of relevant American Medical Association member groups.²⁴

Using this sampling method, 43 physicians were identified. An internet search was conducted to identify individual characteristics including medical education, training, clinical and research interests, and educational awards. These characteristics were considered and discussed by the research team. Preference was given to those attendings nominated by more than one individual (n = 3), those who had received teaching awards, and those with interests involving women in medicine. Research team members narrowed the list to seven attendings who were contacted via email and invited to participate. One did not respond, while six agreed to participate. The six attendings identified current team members who would be rounding on the visit date. Attendings were asked to recommend 6-10 former learners; we contacted these former learners and invited them to participate. Former learners were included to understand lasting effects from their attendings.

Data Collection

Observations

All 1-day site visits were conducted by two research team members, a physician (NH) and a qualitative research specialist (MQ). In four visits, an additional author accompanied the research team. In order to ensure consistency and diversity in perspectives, all authors attended at least one visit. These occurred between April 16 and August 28, 2018. Each visit began with direct observation of attendings (n = 6) and current learners (n = 24) during inpatient general medicine teaching rounds. Each researcher unobtrusively recorded their observations via handwritten, open field notes, paying particular attention to group interactions, teaching approach, conversations within and peripheral to the team, and patient–team interactions. After each visit, researchers met to compare and combine field notes.

Interviews and Focus Groups

Researchers then conducted individual, semistructured interviews with attendings and focus groups with current (n = 21) and former (n = 17) learners. Focus groups with learners varied in size from two to five participants. Former learners were occasionally not available for on-site focus groups and were interviewed separately by telephone after the visit. The interview guide for attendings (Appendix 1) was adapted from the prior study¹⁶ but expanded with questions related to experiences, challenges, and approaches of female and URM physicians. A separate guide was used to facilitate focus groups with learners (Appendix 1). Three current learners were unable to participate in focus groups due to clinical duties. All interviews and focus groups were audio recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a content analysis approach.²⁵ Inductive coding was used to identify codes derived from the data. Two team members (MQ and MH) independently coded the first transcript to develop a codebook, then met to compare and discuss codes. Codes and definitions were entered into the codebook. These team members continued coding five additional transcripts, meeting to compare codes, discussing any discrepancies until agreement was reached, adding new codes identified, and ensuring consistent code application. They reviewed prior transcripts and recoded if necessary. Once no new codes were identified, one team member coded the remaining transcripts. The same codebook was used to code field note documents using the same iterative process. After all qualitative data were coded and verified, they were entered into NVivo 10. Code reports were generated and reviewed by three team members to identify themes and check for coding consistency.

Role of the Funding Source

This study received no external funding.

We examined six exemplary attendings through direct observation of rounds and individual interviews. We also discussed these attendings with 21 current learners and 17 former learners (Appendix 2). All attendings self-identified as female. The group was diverse in terms of race/ethnicity, with three identifying as Black or African American, two as Asian, and one as White or Caucasian. Levels of experience as an attending ranged from 8 to 20 years (mean, 15.3 years). At the time of observation, two were professors and four were associate professors. The group included all three attendings who had been nominated by more than one individual, and all six had won multiple teaching awards. The observation sites represented several areas of the United States (Table 1).

The coded interview data and field notes were categorized into three broad overlapping themes based on strategies our attendings used to respond to gender-based challenges. The following sections describe types of challenges faced by female attendings along with specific strategies they employed to actively position themselves as physician team leaders, manage gender-based stereotypes and perceptions, and identify and embrace their unique qualities. Illustrative quotations or observations that further elucidate meaning are provided.

Female Attendings Actively Position Themselves as Physician Team Leaders

Our attendings frequently stated that they were assumed to be other healthcare provider types, such as nurses or physical therapists, and that these assumptions originated from patients, faculty, and staff (Table 2). Attending 3 commented, “I think every woman in this role has been mistaken for a different caretaker role, so lots of requests for nursing help. I’m sure I have taken more patients off of bed pans and brought more cups of water than maybe some of my male counterparts.” Some attendings responded to this challenge with the strategy of routinely wearing a white coat during rounds and patient encounters. This external visual cue was seen as a necessary reminder of the female attending role.

We found that patients and healthcare providers often believe teams are led by men, leading to a feeling of invisibility for female attendings. One current learner remarked, “If it was a new patient, more than likely, if we had a female attending, the patient’s eyes would always divert to the male physician.” This was not limited to patients. Attending 6 remembered comments from her consultants including, “‘Who is your attending? Let me talk with them,’ kind of assuming that I’m not the person making the decisions.” Female attendings would respond to this challenge by clearly introducing team members, including themselves, with roles and responsibilities. At times, this would require reintroductions and redirection if individuals still misidentified female team members.

Female attendings’ decision-making and thought processes were frequently second-guessed. This would often lead to power struggles with consultants, nurses, and learners. Attending 5 commented, “Even in residency, I felt this sometimes adversarial relationship with...female nurses where they would treat [female attendings] differently...questioning our decisions.” Female attendings would respond to this challenge by asserting themselves and demonstrating confidence with colleagues and at the bedside. This was an active process for women, as one former learner described: “[Female] attendings have to be a little bit more ‘on’—whatever ‘on’ is—more forceful, more direct....There is more slack given to a male attending.”

Female Attendings Consciously Work to Manage Gender-Based Stereotypes and Perceptions

Our attendings navigated gender-based stereotypes and perceptions, ranging from subtle microaggressions to overt sexual harassment (Table 3). This required balance between extremes of being perceived as “too nice” and “too aggressive,” each of which was associated with negativity. Attending 1 remarked, “I know that other [female] faculty struggle with that a bit, with being...assertive. They are assertive, and it’s interpreted [negatively].” Attending 6 described insidiously sexist comments from patients: “‘You are too young to be a physician, you are too pretty to be a physician.’ ‘Oh, the woman doctor...rather than just ‘doctor.’” During one observation of rounds, a patient remarked to the attending, “You have cold hands. You know, I’m going to have to warm those up.” Our attendings responded to these challenges by proactively avoiding characteristics and behaviors considered to be stereotypically feminine in order to draw attention to their qualities as physicians rather than as women. During interviews, some attendings directed conversation away from themselves and instead placed emphasis on coaching female learners to navigate their own demeanors, behaviors, and responses to gender bias and harassment. This would include intentional planning of how to carry oneself, as well as feedback and debrief sessions after instances of harassment.

Our attendings grappled with how to physically portray themselves to avoid gender-based stereotypes. Attending 6 said, “Sometimes you might be taken less seriously if you pay more attention to your makeup or jewelry.” The same attending recalled “times where people would say inappropriate things based on what I was wearing—and I know that doesn’t happen with my male colleagues.” Our attendings responded to this challenge through purposeful choices of attire, personal appearance, and even external facial expressions that would avoid drawing unwanted or negative personal attention outside of the attending role.

Female Attendings Intentionally Identify and Embrace Their Unique Qualities

Our attendings identified societal gender norms and “traditional” masculine expectations in medicine (Table 4). Attending 4 drew attention to her institution’s healthcare leaders by remarking, “I think that women in medicine have similar challenges as women in other professional fields....Well, I guess it is different in that the pictures on the wall behind me are all White men.” Female attendings responded to this challenge by eschewing stereotypical qualities and intentionally finding and exhibiting their own unique strengths (eg, teaching approaches, areas of expertise, communication styles). By embracing their unique strengths, attendings gained confidence and felt more comfortable as physicians and educators. Advice from Attending 3 for other female physicians encapsulated this strategy: “But if [medicine] is what you love doing, then find a style that works for you, even if it’s different....Embrace being different.”

Several attendings identified patterns of thought in themselves that caused them to doubt their accomplishments and have a persistent fear of being exposed as a fraud, commonly known as impostor syndrome. Attending 2 summarized this with, “I know it’s irrational a little bit, but part of me [asks], ‘Am I getting all these opportunities because I’m female, because I’m a minority?’” Our attendings responded by recognizing impostor syndrome and addressing it through repeated positive self-reinforcing thoughts and language and by “letting go” of the doubt. Attending 4 recalled her feelings after being announced as a teaching award recipient for the fourth year in a row: “It was just like something changed in me....Maybe you are a good attending. Maybe you are doing something that is resonating with a unique class of medical students year after year.”

Our interviews also revealed strategies used by female attendings to support and advance their own careers, as well as those of other female faculty, to address the effects of impostor syndrome. Our participants noted the important role of female mentors and sponsors. One former learner mentioned, “I think some of the administration, there are definitely females that are helping promote [the attending].” During an observation, Attending 1 indicated that she was part of a network of women and junior faculty forged to promote each other’s work since “some people are good at self-promotion and some are not.” This group shares accomplishments by distributing and publicizing their accolades.

This multisite, qualitative study informs the complex ways in which exemplary female teaching attendings must navigate being women in medicine. We identified myriad challenges female attendings face originating from patients, from healthcare workers, and within themselves. Our attendings relied upon the following key strategies to mitigate such challenges: (1) they actively position themselves as physician team leaders, (2) they consciously work to manage gender-based stereotypes and perceptions, and (3) they intentionally identify and embrace their unique qualities.

Prior scholarship surrounding gender-based challenges has focused primarily on strategies to improve healthcare systems for women. Much scrutiny has been placed on elevating institutional culture,^26-29 enacting clear policy surrounding sexual harassment,³⁰ ensuring women are actively recruited and retained,³¹ providing resources to assist in work-life balance,^26,32 and cultivating effective mentorship and social networks.^11,33,34

While our findings support the importance of improving healthcare systems, they are more congruent with recent scholarship on explicit personal tactics to mitigate gender-based challenges. Researchers have suggested physicians use algorithmic responses to patient-initiated sexual harassment,³⁵ advocate for those who experience harassment in real time,³⁶ and engage in dedicated practice responding to harassment.^37,38 Our results build on these studies by outlining strategies intended to navigate complex gender dynamics and role model approaches for learners. Interestingly, it was more common for attendings to discuss how they guide their learners and debrief after difficult situations than to discuss how they personally respond to gender-based harassment. While we are not certain why this occurred, three factors may have contributed. First, attendings mentioned that these conversations are often uncomfortable. Second, attendings appeared to accept a higher level of gender-based challenges than they would have tolerated for their learners. Lastly, although we did not gather demographic data from learners, several attendings voiced a strong desire to advocate for and equip female learners with strategies to address and navigate these challenges for themselves.

Gender stereotypes are ubiquitous and firmly rooted in long-standing belief patterns. Certain characteristics are considered masculine (eg, aggressiveness, confidence) and others feminine (eg, kindness, cooperation).¹⁰ Role congruity theory purports that stereotypes lead women to demonstrate behaviors that reflect socially accepted gender norms³⁹ and that social approval is at risk if they behave in ways discordant with these norms.^10,40 Our study provides perspectives from female physicians who walk the tightrope of forcefully asserting themselves more than their male counterparts while not being overly aggressive, since both approaches may have negative connotations.

This study has several limitations. First, it was conducted with a limited number of site visits, attendings, and learners. Likewise, attendings were internists with relatively advanced academic rank. This may reduce the study’s generalizability since attendings in other fields and at earlier career stages may utilize different strategies. However, we believe that if more senior-level female attendings experienced difficulties being recognized and legitimized in their roles, then one can assume that junior-level female faculty would experience these challenges even more so. Likewise, data saturation was not the goal of this exploratory study. Through intensive qualitative data collection, we sought to obtain an in-depth understanding of challenges and strategies. Second, many exemplary female attendings were overlooked by our selection methodology, particularly since women are often underrepresented in the factors we chose. The multisite design, modified snowball sampling, and purposeful randomized selection methodology were used to ensure quality and diversity. Third, attendings provided lists of their former learners, and thus, selection and recall biases may have been introduced since attendings may have more readily identified learners with whom they formed positive relationships. Finally, we cannot eliminate a potential Hawthorne effect on data collection. Researchers attempted to lessen this by standing apart from teams and remaining unobtrusive.

We identified strategies employed by exemplary female attendings to navigate gender-based challenges in their workplaces. We found that female attendings face unconscious bias, labels, power struggles, and harassment, simply because of their gender. They consciously and constantly navigate these challenges by positioning themselves to be seen and heard as team leaders, balancing aspects of their outward appearance and demeanor, embracing their differences and avoiding assimilation to masculine stereotypes of physician leaders, working to manage self-doubt, and coaching their female learners in these areas.

The authors are indebted to Suzanne Winter, MS, for assisting with coordination of study participants and site visits.

The demographic composition of physicians has shifted dramatically in the last five decades. The number of women matriculating into medical school rose from 6% in the 1960s¹ to 52% in 2019²; women accounted for 39% of full-time faculty in 2015.³ Despite this evolution of the physician gender array, many challenges remain.⁴ Women represented only 35% of all associate professors and 22% of full professors in 2015.³ Women experience gender-based discrimination, hostility, and unconscious bias as medical trainees^5-9 and as attending physicians^10-13 with significant deleterious effects including burnout and suicidal thoughts.¹⁴ While types of gender-based challenges are well described in the literature, strategies to navigate and respond to these challenges are less understood.

The approaches and techniques of exemplary teaching attending physicians (hereafter referred to as “attendings”) have previously been reported from groups of predominantly male attendings.^15-18 Because of gender-based challenges female physicians face that lead them to reduce their effort or leave the medical field,¹⁹ there is concern that prior scholarship in effective teaching may not adequately capture the approaches and techniques of female attendings. To our knowledge, no studies have specifically examined female attendings. Therefore, we sought to explore the lived experiences of six female attendings with particular emphasis on how they navigate and respond to gender-based challenges in clinical environments.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. We aimed to examine techniques, approaches, and attitudes of outstanding general medicine teaching attendings among groups previously not well represented (ie, women and self-identified underrepresented minorities [URMs] in medicine). URM was defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.”²⁰ A modified snowball sampling approach²¹ was employed to identify attendings as delineated below.

To maintain quality while guaranteeing diversity in geography and population, potential institutions in which to observe attendings were determined by first creating the following lists: The top 20 hospitals in the U.S. News & World Report’s 2017-2018 Best Hospitals Honor Roll,²² top-rated institutions by Doximity in each geographic region and among rural training sites,²³ and four historically Black colleges and universities (HBCUs) with medical schools. Institutions visited during a previous similar study¹⁶ were excluded. Next, the list was narrowed to 25 by randomly selecting five in each main geographic region and five rural institutions. These were combined with all four HBCUs to create a final list of 29 institutions.

Next, division of hospital medicine chiefs (and/or general medicine chiefs) and internal medicine residency directors at each of these 29 institutions were asked to nominate exemplary attendings, particularly those who identified as women and URMs. Twelve attendings who were themselves observed in a previous study¹⁶ were also asked for nominations. Finally, recommendations were sought from leaders of relevant American Medical Association member groups.²⁴

Using this sampling method, 43 physicians were identified. An internet search was conducted to identify individual characteristics including medical education, training, clinical and research interests, and educational awards. These characteristics were considered and discussed by the research team. Preference was given to those attendings nominated by more than one individual (n = 3), those who had received teaching awards, and those with interests involving women in medicine. Research team members narrowed the list to seven attendings who were contacted via email and invited to participate. One did not respond, while six agreed to participate. The six attendings identified current team members who would be rounding on the visit date. Attendings were asked to recommend 6-10 former learners; we contacted these former learners and invited them to participate. Former learners were included to understand lasting effects from their attendings.

Data Collection

Observations

All 1-day site visits were conducted by two research team members, a physician (NH) and a qualitative research specialist (MQ). In four visits, an additional author accompanied the research team. In order to ensure consistency and diversity in perspectives, all authors attended at least one visit. These occurred between April 16 and August 28, 2018. Each visit began with direct observation of attendings (n = 6) and current learners (n = 24) during inpatient general medicine teaching rounds. Each researcher unobtrusively recorded their observations via handwritten, open field notes, paying particular attention to group interactions, teaching approach, conversations within and peripheral to the team, and patient–team interactions. After each visit, researchers met to compare and combine field notes.

Interviews and Focus Groups

Researchers then conducted individual, semistructured interviews with attendings and focus groups with current (n = 21) and former (n = 17) learners. Focus groups with learners varied in size from two to five participants. Former learners were occasionally not available for on-site focus groups and were interviewed separately by telephone after the visit. The interview guide for attendings (Appendix 1) was adapted from the prior study¹⁶ but expanded with questions related to experiences, challenges, and approaches of female and URM physicians. A separate guide was used to facilitate focus groups with learners (Appendix 1). Three current learners were unable to participate in focus groups due to clinical duties. All interviews and focus groups were audio recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a content analysis approach.²⁵ Inductive coding was used to identify codes derived from the data. Two team members (MQ and MH) independently coded the first transcript to develop a codebook, then met to compare and discuss codes. Codes and definitions were entered into the codebook. These team members continued coding five additional transcripts, meeting to compare codes, discussing any discrepancies until agreement was reached, adding new codes identified, and ensuring consistent code application. They reviewed prior transcripts and recoded if necessary. Once no new codes were identified, one team member coded the remaining transcripts. The same codebook was used to code field note documents using the same iterative process. After all qualitative data were coded and verified, they were entered into NVivo 10. Code reports were generated and reviewed by three team members to identify themes and check for coding consistency.

Role of the Funding Source

This study received no external funding.

We examined six exemplary attendings through direct observation of rounds and individual interviews. We also discussed these attendings with 21 current learners and 17 former learners (Appendix 2). All attendings self-identified as female. The group was diverse in terms of race/ethnicity, with three identifying as Black or African American, two as Asian, and one as White or Caucasian. Levels of experience as an attending ranged from 8 to 20 years (mean, 15.3 years). At the time of observation, two were professors and four were associate professors. The group included all three attendings who had been nominated by more than one individual, and all six had won multiple teaching awards. The observation sites represented several areas of the United States (Table 1).

The coded interview data and field notes were categorized into three broad overlapping themes based on strategies our attendings used to respond to gender-based challenges. The following sections describe types of challenges faced by female attendings along with specific strategies they employed to actively position themselves as physician team leaders, manage gender-based stereotypes and perceptions, and identify and embrace their unique qualities. Illustrative quotations or observations that further elucidate meaning are provided.

Female Attendings Actively Position Themselves as Physician Team Leaders

Our attendings frequently stated that they were assumed to be other healthcare provider types, such as nurses or physical therapists, and that these assumptions originated from patients, faculty, and staff (Table 2). Attending 3 commented, “I think every woman in this role has been mistaken for a different caretaker role, so lots of requests for nursing help. I’m sure I have taken more patients off of bed pans and brought more cups of water than maybe some of my male counterparts.” Some attendings responded to this challenge with the strategy of routinely wearing a white coat during rounds and patient encounters. This external visual cue was seen as a necessary reminder of the female attending role.

We found that patients and healthcare providers often believe teams are led by men, leading to a feeling of invisibility for female attendings. One current learner remarked, “If it was a new patient, more than likely, if we had a female attending, the patient’s eyes would always divert to the male physician.” This was not limited to patients. Attending 6 remembered comments from her consultants including, “‘Who is your attending? Let me talk with them,’ kind of assuming that I’m not the person making the decisions.” Female attendings would respond to this challenge by clearly introducing team members, including themselves, with roles and responsibilities. At times, this would require reintroductions and redirection if individuals still misidentified female team members.

Female attendings’ decision-making and thought processes were frequently second-guessed. This would often lead to power struggles with consultants, nurses, and learners. Attending 5 commented, “Even in residency, I felt this sometimes adversarial relationship with...female nurses where they would treat [female attendings] differently...questioning our decisions.” Female attendings would respond to this challenge by asserting themselves and demonstrating confidence with colleagues and at the bedside. This was an active process for women, as one former learner described: “[Female] attendings have to be a little bit more ‘on’—whatever ‘on’ is—more forceful, more direct....There is more slack given to a male attending.”

Female Attendings Consciously Work to Manage Gender-Based Stereotypes and Perceptions

Our attendings navigated gender-based stereotypes and perceptions, ranging from subtle microaggressions to overt sexual harassment (Table 3). This required balance between extremes of being perceived as “too nice” and “too aggressive,” each of which was associated with negativity. Attending 1 remarked, “I know that other [female] faculty struggle with that a bit, with being...assertive. They are assertive, and it’s interpreted [negatively].” Attending 6 described insidiously sexist comments from patients: “‘You are too young to be a physician, you are too pretty to be a physician.’ ‘Oh, the woman doctor...rather than just ‘doctor.’” During one observation of rounds, a patient remarked to the attending, “You have cold hands. You know, I’m going to have to warm those up.” Our attendings responded to these challenges by proactively avoiding characteristics and behaviors considered to be stereotypically feminine in order to draw attention to their qualities as physicians rather than as women. During interviews, some attendings directed conversation away from themselves and instead placed emphasis on coaching female learners to navigate their own demeanors, behaviors, and responses to gender bias and harassment. This would include intentional planning of how to carry oneself, as well as feedback and debrief sessions after instances of harassment.

Our attendings grappled with how to physically portray themselves to avoid gender-based stereotypes. Attending 6 said, “Sometimes you might be taken less seriously if you pay more attention to your makeup or jewelry.” The same attending recalled “times where people would say inappropriate things based on what I was wearing—and I know that doesn’t happen with my male colleagues.” Our attendings responded to this challenge through purposeful choices of attire, personal appearance, and even external facial expressions that would avoid drawing unwanted or negative personal attention outside of the attending role.

Female Attendings Intentionally Identify and Embrace Their Unique Qualities

Our attendings identified societal gender norms and “traditional” masculine expectations in medicine (Table 4). Attending 4 drew attention to her institution’s healthcare leaders by remarking, “I think that women in medicine have similar challenges as women in other professional fields....Well, I guess it is different in that the pictures on the wall behind me are all White men.” Female attendings responded to this challenge by eschewing stereotypical qualities and intentionally finding and exhibiting their own unique strengths (eg, teaching approaches, areas of expertise, communication styles). By embracing their unique strengths, attendings gained confidence and felt more comfortable as physicians and educators. Advice from Attending 3 for other female physicians encapsulated this strategy: “But if [medicine] is what you love doing, then find a style that works for you, even if it’s different....Embrace being different.”

Several attendings identified patterns of thought in themselves that caused them to doubt their accomplishments and have a persistent fear of being exposed as a fraud, commonly known as impostor syndrome. Attending 2 summarized this with, “I know it’s irrational a little bit, but part of me [asks], ‘Am I getting all these opportunities because I’m female, because I’m a minority?’” Our attendings responded by recognizing impostor syndrome and addressing it through repeated positive self-reinforcing thoughts and language and by “letting go” of the doubt. Attending 4 recalled her feelings after being announced as a teaching award recipient for the fourth year in a row: “It was just like something changed in me....Maybe you are a good attending. Maybe you are doing something that is resonating with a unique class of medical students year after year.”

Our interviews also revealed strategies used by female attendings to support and advance their own careers, as well as those of other female faculty, to address the effects of impostor syndrome. Our participants noted the important role of female mentors and sponsors. One former learner mentioned, “I think some of the administration, there are definitely females that are helping promote [the attending].” During an observation, Attending 1 indicated that she was part of a network of women and junior faculty forged to promote each other’s work since “some people are good at self-promotion and some are not.” This group shares accomplishments by distributing and publicizing their accolades.

This multisite, qualitative study informs the complex ways in which exemplary female teaching attendings must navigate being women in medicine. We identified myriad challenges female attendings face originating from patients, from healthcare workers, and within themselves. Our attendings relied upon the following key strategies to mitigate such challenges: (1) they actively position themselves as physician team leaders, (2) they consciously work to manage gender-based stereotypes and perceptions, and (3) they intentionally identify and embrace their unique qualities.

Prior scholarship surrounding gender-based challenges has focused primarily on strategies to improve healthcare systems for women. Much scrutiny has been placed on elevating institutional culture,^26-29 enacting clear policy surrounding sexual harassment,³⁰ ensuring women are actively recruited and retained,³¹ providing resources to assist in work-life balance,^26,32 and cultivating effective mentorship and social networks.^11,33,34

While our findings support the importance of improving healthcare systems, they are more congruent with recent scholarship on explicit personal tactics to mitigate gender-based challenges. Researchers have suggested physicians use algorithmic responses to patient-initiated sexual harassment,³⁵ advocate for those who experience harassment in real time,³⁶ and engage in dedicated practice responding to harassment.^37,38 Our results build on these studies by outlining strategies intended to navigate complex gender dynamics and role model approaches for learners. Interestingly, it was more common for attendings to discuss how they guide their learners and debrief after difficult situations than to discuss how they personally respond to gender-based harassment. While we are not certain why this occurred, three factors may have contributed. First, attendings mentioned that these conversations are often uncomfortable. Second, attendings appeared to accept a higher level of gender-based challenges than they would have tolerated for their learners. Lastly, although we did not gather demographic data from learners, several attendings voiced a strong desire to advocate for and equip female learners with strategies to address and navigate these challenges for themselves.

Gender stereotypes are ubiquitous and firmly rooted in long-standing belief patterns. Certain characteristics are considered masculine (eg, aggressiveness, confidence) and others feminine (eg, kindness, cooperation).¹⁰ Role congruity theory purports that stereotypes lead women to demonstrate behaviors that reflect socially accepted gender norms³⁹ and that social approval is at risk if they behave in ways discordant with these norms.^10,40 Our study provides perspectives from female physicians who walk the tightrope of forcefully asserting themselves more than their male counterparts while not being overly aggressive, since both approaches may have negative connotations.

This study has several limitations. First, it was conducted with a limited number of site visits, attendings, and learners. Likewise, attendings were internists with relatively advanced academic rank. This may reduce the study’s generalizability since attendings in other fields and at earlier career stages may utilize different strategies. However, we believe that if more senior-level female attendings experienced difficulties being recognized and legitimized in their roles, then one can assume that junior-level female faculty would experience these challenges even more so. Likewise, data saturation was not the goal of this exploratory study. Through intensive qualitative data collection, we sought to obtain an in-depth understanding of challenges and strategies. Second, many exemplary female attendings were overlooked by our selection methodology, particularly since women are often underrepresented in the factors we chose. The multisite design, modified snowball sampling, and purposeful randomized selection methodology were used to ensure quality and diversity. Third, attendings provided lists of their former learners, and thus, selection and recall biases may have been introduced since attendings may have more readily identified learners with whom they formed positive relationships. Finally, we cannot eliminate a potential Hawthorne effect on data collection. Researchers attempted to lessen this by standing apart from teams and remaining unobtrusive.

We identified strategies employed by exemplary female attendings to navigate gender-based challenges in their workplaces. We found that female attendings face unconscious bias, labels, power struggles, and harassment, simply because of their gender. They consciously and constantly navigate these challenges by positioning themselves to be seen and heard as team leaders, balancing aspects of their outward appearance and demeanor, embracing their differences and avoiding assimilation to masculine stereotypes of physician leaders, working to manage self-doubt, and coaching their female learners in these areas.

The authors are indebted to Suzanne Winter, MS, for assisting with coordination of study participants and site visits.

The demographic composition of physicians has shifted dramatically in the last five decades. The number of women matriculating into medical school rose from 6% in the 1960s¹ to 52% in 2019²; women accounted for 39% of full-time faculty in 2015.³ Despite this evolution of the physician gender array, many challenges remain.⁴ Women represented only 35% of all associate professors and 22% of full professors in 2015.³ Women experience gender-based discrimination, hostility, and unconscious bias as medical trainees^5-9 and as attending physicians^10-13 with significant deleterious effects including burnout and suicidal thoughts.¹⁴ While types of gender-based challenges are well described in the literature, strategies to navigate and respond to these challenges are less understood.

The approaches and techniques of exemplary teaching attending physicians (hereafter referred to as “attendings”) have previously been reported from groups of predominantly male attendings.^15-18 Because of gender-based challenges female physicians face that lead them to reduce their effort or leave the medical field,¹⁹ there is concern that prior scholarship in effective teaching may not adequately capture the approaches and techniques of female attendings. To our knowledge, no studies have specifically examined female attendings. Therefore, we sought to explore the lived experiences of six female attendings with particular emphasis on how they navigate and respond to gender-based challenges in clinical environments.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. We aimed to examine techniques, approaches, and attitudes of outstanding general medicine teaching attendings among groups previously not well represented (ie, women and self-identified underrepresented minorities [URMs] in medicine). URM was defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.”²⁰ A modified snowball sampling approach²¹ was employed to identify attendings as delineated below.

To maintain quality while guaranteeing diversity in geography and population, potential institutions in which to observe attendings were determined by first creating the following lists: The top 20 hospitals in the U.S. News & World Report’s 2017-2018 Best Hospitals Honor Roll,²² top-rated institutions by Doximity in each geographic region and among rural training sites,²³ and four historically Black colleges and universities (HBCUs) with medical schools. Institutions visited during a previous similar study¹⁶ were excluded. Next, the list was narrowed to 25 by randomly selecting five in each main geographic region and five rural institutions. These were combined with all four HBCUs to create a final list of 29 institutions.

Next, division of hospital medicine chiefs (and/or general medicine chiefs) and internal medicine residency directors at each of these 29 institutions were asked to nominate exemplary attendings, particularly those who identified as women and URMs. Twelve attendings who were themselves observed in a previous study¹⁶ were also asked for nominations. Finally, recommendations were sought from leaders of relevant American Medical Association member groups.²⁴

Using this sampling method, 43 physicians were identified. An internet search was conducted to identify individual characteristics including medical education, training, clinical and research interests, and educational awards. These characteristics were considered and discussed by the research team. Preference was given to those attendings nominated by more than one individual (n = 3), those who had received teaching awards, and those with interests involving women in medicine. Research team members narrowed the list to seven attendings who were contacted via email and invited to participate. One did not respond, while six agreed to participate. The six attendings identified current team members who would be rounding on the visit date. Attendings were asked to recommend 6-10 former learners; we contacted these former learners and invited them to participate. Former learners were included to understand lasting effects from their attendings.

Data Collection

Observations

All 1-day site visits were conducted by two research team members, a physician (NH) and a qualitative research specialist (MQ). In four visits, an additional author accompanied the research team. In order to ensure consistency and diversity in perspectives, all authors attended at least one visit. These occurred between April 16 and August 28, 2018. Each visit began with direct observation of attendings (n = 6) and current learners (n = 24) during inpatient general medicine teaching rounds. Each researcher unobtrusively recorded their observations via handwritten, open field notes, paying particular attention to group interactions, teaching approach, conversations within and peripheral to the team, and patient–team interactions. After each visit, researchers met to compare and combine field notes.

Interviews and Focus Groups

Researchers then conducted individual, semistructured interviews with attendings and focus groups with current (n = 21) and former (n = 17) learners. Focus groups with learners varied in size from two to five participants. Former learners were occasionally not available for on-site focus groups and were interviewed separately by telephone after the visit. The interview guide for attendings (Appendix 1) was adapted from the prior study¹⁶ but expanded with questions related to experiences, challenges, and approaches of female and URM physicians. A separate guide was used to facilitate focus groups with learners (Appendix 1). Three current learners were unable to participate in focus groups due to clinical duties. All interviews and focus groups were audio recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a content analysis approach.²⁵ Inductive coding was used to identify codes derived from the data. Two team members (MQ and MH) independently coded the first transcript to develop a codebook, then met to compare and discuss codes. Codes and definitions were entered into the codebook. These team members continued coding five additional transcripts, meeting to compare codes, discussing any discrepancies until agreement was reached, adding new codes identified, and ensuring consistent code application. They reviewed prior transcripts and recoded if necessary. Once no new codes were identified, one team member coded the remaining transcripts. The same codebook was used to code field note documents using the same iterative process. After all qualitative data were coded and verified, they were entered into NVivo 10. Code reports were generated and reviewed by three team members to identify themes and check for coding consistency.

Role of the Funding Source

This study received no external funding.

We examined six exemplary attendings through direct observation of rounds and individual interviews. We also discussed these attendings with 21 current learners and 17 former learners (Appendix 2). All attendings self-identified as female. The group was diverse in terms of race/ethnicity, with three identifying as Black or African American, two as Asian, and one as White or Caucasian. Levels of experience as an attending ranged from 8 to 20 years (mean, 15.3 years). At the time of observation, two were professors and four were associate professors. The group included all three attendings who had been nominated by more than one individual, and all six had won multiple teaching awards. The observation sites represented several areas of the United States (Table 1).

The coded interview data and field notes were categorized into three broad overlapping themes based on strategies our attendings used to respond to gender-based challenges. The following sections describe types of challenges faced by female attendings along with specific strategies they employed to actively position themselves as physician team leaders, manage gender-based stereotypes and perceptions, and identify and embrace their unique qualities. Illustrative quotations or observations that further elucidate meaning are provided.

Female Attendings Actively Position Themselves as Physician Team Leaders

Our attendings frequently stated that they were assumed to be other healthcare provider types, such as nurses or physical therapists, and that these assumptions originated from patients, faculty, and staff (Table 2). Attending 3 commented, “I think every woman in this role has been mistaken for a different caretaker role, so lots of requests for nursing help. I’m sure I have taken more patients off of bed pans and brought more cups of water than maybe some of my male counterparts.” Some attendings responded to this challenge with the strategy of routinely wearing a white coat during rounds and patient encounters. This external visual cue was seen as a necessary reminder of the female attending role.

We found that patients and healthcare providers often believe teams are led by men, leading to a feeling of invisibility for female attendings. One current learner remarked, “If it was a new patient, more than likely, if we had a female attending, the patient’s eyes would always divert to the male physician.” This was not limited to patients. Attending 6 remembered comments from her consultants including, “‘Who is your attending? Let me talk with them,’ kind of assuming that I’m not the person making the decisions.” Female attendings would respond to this challenge by clearly introducing team members, including themselves, with roles and responsibilities. At times, this would require reintroductions and redirection if individuals still misidentified female team members.

Female attendings’ decision-making and thought processes were frequently second-guessed. This would often lead to power struggles with consultants, nurses, and learners. Attending 5 commented, “Even in residency, I felt this sometimes adversarial relationship with...female nurses where they would treat [female attendings] differently...questioning our decisions.” Female attendings would respond to this challenge by asserting themselves and demonstrating confidence with colleagues and at the bedside. This was an active process for women, as one former learner described: “[Female] attendings have to be a little bit more ‘on’—whatever ‘on’ is—more forceful, more direct....There is more slack given to a male attending.”

Female Attendings Consciously Work to Manage Gender-Based Stereotypes and Perceptions

Our attendings navigated gender-based stereotypes and perceptions, ranging from subtle microaggressions to overt sexual harassment (Table 3). This required balance between extremes of being perceived as “too nice” and “too aggressive,” each of which was associated with negativity. Attending 1 remarked, “I know that other [female] faculty struggle with that a bit, with being...assertive. They are assertive, and it’s interpreted [negatively].” Attending 6 described insidiously sexist comments from patients: “‘You are too young to be a physician, you are too pretty to be a physician.’ ‘Oh, the woman doctor...rather than just ‘doctor.’” During one observation of rounds, a patient remarked to the attending, “You have cold hands. You know, I’m going to have to warm those up.” Our attendings responded to these challenges by proactively avoiding characteristics and behaviors considered to be stereotypically feminine in order to draw attention to their qualities as physicians rather than as women. During interviews, some attendings directed conversation away from themselves and instead placed emphasis on coaching female learners to navigate their own demeanors, behaviors, and responses to gender bias and harassment. This would include intentional planning of how to carry oneself, as well as feedback and debrief sessions after instances of harassment.

Our attendings grappled with how to physically portray themselves to avoid gender-based stereotypes. Attending 6 said, “Sometimes you might be taken less seriously if you pay more attention to your makeup or jewelry.” The same attending recalled “times where people would say inappropriate things based on what I was wearing—and I know that doesn’t happen with my male colleagues.” Our attendings responded to this challenge through purposeful choices of attire, personal appearance, and even external facial expressions that would avoid drawing unwanted or negative personal attention outside of the attending role.

Female Attendings Intentionally Identify and Embrace Their Unique Qualities

Our attendings identified societal gender norms and “traditional” masculine expectations in medicine (Table 4). Attending 4 drew attention to her institution’s healthcare leaders by remarking, “I think that women in medicine have similar challenges as women in other professional fields....Well, I guess it is different in that the pictures on the wall behind me are all White men.” Female attendings responded to this challenge by eschewing stereotypical qualities and intentionally finding and exhibiting their own unique strengths (eg, teaching approaches, areas of expertise, communication styles). By embracing their unique strengths, attendings gained confidence and felt more comfortable as physicians and educators. Advice from Attending 3 for other female physicians encapsulated this strategy: “But if [medicine] is what you love doing, then find a style that works for you, even if it’s different....Embrace being different.”

Several attendings identified patterns of thought in themselves that caused them to doubt their accomplishments and have a persistent fear of being exposed as a fraud, commonly known as impostor syndrome. Attending 2 summarized this with, “I know it’s irrational a little bit, but part of me [asks], ‘Am I getting all these opportunities because I’m female, because I’m a minority?’” Our attendings responded by recognizing impostor syndrome and addressing it through repeated positive self-reinforcing thoughts and language and by “letting go” of the doubt. Attending 4 recalled her feelings after being announced as a teaching award recipient for the fourth year in a row: “It was just like something changed in me....Maybe you are a good attending. Maybe you are doing something that is resonating with a unique class of medical students year after year.”

Our interviews also revealed strategies used by female attendings to support and advance their own careers, as well as those of other female faculty, to address the effects of impostor syndrome. Our participants noted the important role of female mentors and sponsors. One former learner mentioned, “I think some of the administration, there are definitely females that are helping promote [the attending].” During an observation, Attending 1 indicated that she was part of a network of women and junior faculty forged to promote each other’s work since “some people are good at self-promotion and some are not.” This group shares accomplishments by distributing and publicizing their accolades.

This multisite, qualitative study informs the complex ways in which exemplary female teaching attendings must navigate being women in medicine. We identified myriad challenges female attendings face originating from patients, from healthcare workers, and within themselves. Our attendings relied upon the following key strategies to mitigate such challenges: (1) they actively position themselves as physician team leaders, (2) they consciously work to manage gender-based stereotypes and perceptions, and (3) they intentionally identify and embrace their unique qualities.

Prior scholarship surrounding gender-based challenges has focused primarily on strategies to improve healthcare systems for women. Much scrutiny has been placed on elevating institutional culture,^26-29 enacting clear policy surrounding sexual harassment,³⁰ ensuring women are actively recruited and retained,³¹ providing resources to assist in work-life balance,^26,32 and cultivating effective mentorship and social networks.^11,33,34

While our findings support the importance of improving healthcare systems, they are more congruent with recent scholarship on explicit personal tactics to mitigate gender-based challenges. Researchers have suggested physicians use algorithmic responses to patient-initiated sexual harassment,³⁵ advocate for those who experience harassment in real time,³⁶ and engage in dedicated practice responding to harassment.^37,38 Our results build on these studies by outlining strategies intended to navigate complex gender dynamics and role model approaches for learners. Interestingly, it was more common for attendings to discuss how they guide their learners and debrief after difficult situations than to discuss how they personally respond to gender-based harassment. While we are not certain why this occurred, three factors may have contributed. First, attendings mentioned that these conversations are often uncomfortable. Second, attendings appeared to accept a higher level of gender-based challenges than they would have tolerated for their learners. Lastly, although we did not gather demographic data from learners, several attendings voiced a strong desire to advocate for and equip female learners with strategies to address and navigate these challenges for themselves.

Gender stereotypes are ubiquitous and firmly rooted in long-standing belief patterns. Certain characteristics are considered masculine (eg, aggressiveness, confidence) and others feminine (eg, kindness, cooperation).¹⁰ Role congruity theory purports that stereotypes lead women to demonstrate behaviors that reflect socially accepted gender norms³⁹ and that social approval is at risk if they behave in ways discordant with these norms.^10,40 Our study provides perspectives from female physicians who walk the tightrope of forcefully asserting themselves more than their male counterparts while not being overly aggressive, since both approaches may have negative connotations.

This study has several limitations. First, it was conducted with a limited number of site visits, attendings, and learners. Likewise, attendings were internists with relatively advanced academic rank. This may reduce the study’s generalizability since attendings in other fields and at earlier career stages may utilize different strategies. However, we believe that if more senior-level female attendings experienced difficulties being recognized and legitimized in their roles, then one can assume that junior-level female faculty would experience these challenges even more so. Likewise, data saturation was not the goal of this exploratory study. Through intensive qualitative data collection, we sought to obtain an in-depth understanding of challenges and strategies. Second, many exemplary female attendings were overlooked by our selection methodology, particularly since women are often underrepresented in the factors we chose. The multisite design, modified snowball sampling, and purposeful randomized selection methodology were used to ensure quality and diversity. Third, attendings provided lists of their former learners, and thus, selection and recall biases may have been introduced since attendings may have more readily identified learners with whom they formed positive relationships. Finally, we cannot eliminate a potential Hawthorne effect on data collection. Researchers attempted to lessen this by standing apart from teams and remaining unobtrusive.

We identified strategies employed by exemplary female attendings to navigate gender-based challenges in their workplaces. We found that female attendings face unconscious bias, labels, power struggles, and harassment, simply because of their gender. They consciously and constantly navigate these challenges by positioning themselves to be seen and heard as team leaders, balancing aspects of their outward appearance and demeanor, embracing their differences and avoiding assimilation to masculine stereotypes of physician leaders, working to manage self-doubt, and coaching their female learners in these areas.

The authors are indebted to Suzanne Winter, MS, for assisting with coordination of study participants and site visits.

Case

A 63-year-old man with hypertension, diabetes, and recently diagnosed squamous-cell lung cancer presents with diffuse abdominal pain and confusion of two-day duration. He weighs 105 Kg, his blood pressure is 105/65 mm/Hg, heart rate is 105 beats per minute, and temperature is 99.0 degrees Fahrenheit. His respirations are 18 breaths per minute, oxygen saturation is 95% on room air, and his orthostatics are positive. Dry mucus membranes with decreased skin turgor are noted on physical examination. Laboratory evaluation reveals a calcium level of 15.5 mg/dL, creatinine level of 1.2 mg/dL, albumin level of 4.3 g/dL, and a phosphorous level of 2.9 mg/dL.

What is the best treatment of this condition?

Overview

Calcium homeostasis involves complex interactions between the kidney, gastrointestinal (GI) tract, and the skeletal system via hormonal influences. Although 99% of the body’s calcium is stored in the bones, 50% of serum calcium is in the active ionized form, 40% is bound to albumin, and 10% is complexed with anions.¹ It’s important to remember these percentages when evaluating a patient’s serum calcium; elevated serum calcium can be validated by using either a correction formula (corrected calcium=measured total calcium + [0.8 x (4.5-albumin)]) or by direct measurement of the ionized calcium, which is the physiologically active form.

Hypercalcemia of malignancy is the most common cause of hypercalcemia in the hospitalized patient. Twenty to 30% of patients with cancer will develop hypercalcemia at some point in their disease course.² Overall, this portends a poor prognosis with a median survival of three to four months.³

Four general mechanisms are involved in the pathogenesis of malignant hypercalcemia; these mechanisms form the basis for available treatment strategies available:

• Osteolytic tumors, such as multiple myeloma, can directly act on bone, leading to osteoclast activation and release of calcium;
• Humoral mediators elaborated by malignant cells, such as parathyroid hormone-related peptide (PTH-RP), can effect activation of osteoclasts and decrease renal elimination of calcium, causing humoral hypercalcemia of malignancy;
• Some malignancies (most commonly lymphomas) can directly synthesize 1,25 (OH)2 vitamin D, leading to increased luminal absorption of both calcium and phosphorus from the GI tract; and
• Direct production of parathyroid hormone (PTH) by the malignant cells is rare, but has been reported.²

Other factors, including impaired mobility, might lead to further bone resorption and a worsening of the hypercalcemic state.

A patient with hypercalcemia must have a systematic workup, with knowledge of other causes of hypercalcemia that could be present, irrespective of malignancy. Examples include primary hyperparathyroidism, medications effect, and genetic etiologies. Although further discussion is beyond the scope of this article, a broad diagnostic approach is represented in Figure 1 (at right).

Effective management of hypercalcemia demands consideration of both the patient’s immediate, as well as longer-term, clinical situation in light of the patient’s prognosis. The primary aim in the acute management of hypercalcemia is to normalize serum values and decrease symptoms. However, this must be done with appreciation that the metabolic derangement was generated by an underlying malignancy. The main focus of clinical therapeutics should be aimed at this.

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Review of the Data

Intravenous (IV) fluids. IV hydration with isotonic saline represents the most immediate and critical intervention in the acute management of malignant hypercalcemia. This condition has multiple, potentially deleterious effects on the kidney, including vasoconstriction, inhibition of salt absorption distally, and antagonism of anti-diuretic hormone (ADH), leading to both salt and water loss. The decrease in intravascular volume then potentiates increased sodium re-absorption proximally in the kidney.

Isotonic saline restores the volume depletion that invariably occurs in the setting of hypercalcemia-provoked urinary salt wasting. The restoration of intravascular volume results in an increase in the glomerular filtration rate and, thus, an increase in calcium filtration. Furthermore, proximal tubular sodium and calcium re-absorption decrease as the glomerular filtration rate increases. Additionally, an increase in sodium and water presentation to the distal renal tubular sites provokes a further calciuresis.

It is estimated that with saline hydration, the calcium concentration should decline, at least by the degree to which dehydration raised it, typically in the range of 1.6 mg to 2.4 mg per deciliter.⁴ Hydration alone, however, rarely leads to normalization of the serum calcium concentration in patients with severe hypercalcemia.

The rate of infusion is based on the severity of hypercalcemia, and the patient’s age and comorbidities, with particular attention to cardiac or renal disease. A standard approach for most patients without edema and without heart or renal failure is to begin a saline infusion at an initial rate between 200 mL/h to 300 mL/h. The goal is to maintain urine output at 100 mL/h to 150 mL/h.

Furosemide. Following the administration of intravenous fluids to re-establish a euvolemic state, furosemide historically has been used because it has a calcinuric effect with forced diuresis. It also is useful for managing and preventing the fluid overload that occurs with saline hydration. However, data does not support its routine use to lower calcium levels in hypercalcemic patients.

The majority of articles studying the use of furosemide were published in the 1970s and ’80s, and they involve a variety of doses and administration schedules ranging from 40 mg orally daily to 100 mg IV hourly with variable improvement in serum calcium levels and effects that were short-lived. Although some studies have shown that these high doses (2,400 mg/24 hours) of furosemide can decrease calcium levels, resultant severe metabolic derangements in other electrolytes were encountered. This approach required frequent and invasive monitoring to prevent such derangements.⁵ The clinical application of these studies have led to published recommendations that are as variable as the doses used in the initial studies more than 30 years ago.

This includes the consideration that, in light of the availability and efficacy of bisphosphonates, furosemide might no longer be clinically helpful in this endeavor.⁶ The current role of furosemide in the management in hypercalcemic patients remains on an as-needed basis for management of fluid overload states brought about after aggressive IV fluid resuscitation.

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Bisphosphonates. Bisphosph-onates first became available for the management of hypercalcemia in the early 1990s and have dramatically changed the acute intervention and improved the long-term clinical course of patients with malignant hypercalcemia. Though first developed in the 19th century with industrial applications, it wasn’t until the 1960s that their role in bone metabolism was appreciated.

While their complex mechanism of action remains an issue of ongoing investigations, it is known that bisphosphonates are directed to the bones, where they inhibit an enzyme in the HMG-CoA reductase pathway and promote apoptotic cell death of osteoclasts.⁷ By blocking osteoclast-mediated bone resorption, the bisphosphonates are effective in treating the hypercalcemia that occurs with a variety of bone-resorbing disease processes, malignant hypercalcemia included. As relatively nontoxic compounds capable of conferring a profound and sustained diminution in serum calcium, these agents have become preferred in the management of acute and chronic hypercalcemia of malignancy.

There are five parenteral bisphosphonates available for the treatment of malignant hypercalcemia: pamidronate, zoledronic acid, ibandronate, etidronate, and clodronate. Etidronate and clodronate are first-generation agents, which are less potent and have more side effects than other agents and are not as commonly used. Ibandronate is a useful agent with a long half-life shown to be as effective as pamidronate, though it has not been as extensively studied as the other agents.

Pamidronate has been studied thoroughly in multiple observational and randomized trials, and has been shown to be highly efficacious and minimally toxic in the treatment of hypercalcemia due to multiple causes, including malignant hypercalcemia.^8,9 A maximum calcium-lowering effect occurs at a dose of 90 mg, and the dose is often titrated based on the measured serum calcium. It is infused over two to four hours, effects a lowering of serum calcium within one to two days, and has a sustained effect lasting for up to two weeks or more.

As the most potent and most easily administered bisphosphonate, zoledronic acid is considered by many the agent of choice in the treatment of malignant hypercalcemia. It can be administered as a 4 mg-8 mg dose intravenously over 15 minutes (compared with two hours for pamidronate). Two Phase III trials comprising 275 patients have demonstrated zoledronic acid’s superior efficacy compared with pamidronate, with 88% of patients accomplishing a normalized serum calcium (compared with 70% of patients receiving a 90-mg dose of pamidronate).¹⁰

Even though these agents are relatively nontoxic, each can provoke a mild, transient flulike illness in recipients. Renal dysfunction has been noted rarely. These agents should be renally dosed and used with caution in patients with advanced renal insufficiency (serum creatinine >2.5). Osteonecrosis of the jaw has been observed in less than 2% of patients receiving IV bisphosphonates. Accordingly, it is recommended that patients undergo dental evaluation prior to receiving the agent (if feasible) and avoid invasive dental procedures around the time that they receive the agent.¹¹

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Other therapeutic interventions. The bisphosphonates represent the best studied and most efficacious pharmaceutical agents available to treat hypercalcemia. Straying from these agents should be considered only when they are contraindicated, in severe circumstances, or after the patient has failed to respond.

Calcitonin has long had FDA approval for treatment of hypercalcemia in adults. It has been shown in small, nonrandomized studies from the 1970s and ’80s to rapidly (within two hours) decrease calcium levels in hypercalcemic patients.^12,13,14 However, these reductions are small (<10%) and transient (usually persisting up to 72 to 96 hours) due to the tachyphylaxsis noted with this medication. Nonetheless, calcitonin can be used as an adjuvant bridge to lower calcium levels in severely hypercalcemic patients for the first few days before other agents start taking effect.

Glucocorticoids have been used to treat hypercalcemia since the 1950s. Prednisone, dexamethasone, and methylprednisolone all carry FDA indications for hypercalcemia, but data are lacking and contradictory. A small (n=28) randomized controlled trial (RCT) conducted in 1984 showed no additional efficacy of glucocorticoids with IV fluids when compared with IV fluids alone.¹⁵ Another small (n=30) RCT done in 1992 on women with metastatic breast cancer showed a significant improvement in patients treated with prednisolone, IV fluids, and furosemide when compared with IV fluids and furosemide.¹⁶ Other nonrandomized trials have shown response to be unpredictable at best.¹⁷ Despite this, glucocorticoids likely retain a limited role for treatment in specific cases, including hypercalcemia induced by lymphomas elevating levels of 1,25(OH)2 vitamin D (as this interacts with a steroid-regulated receptor), or multiple myelomas where they potentially impact disease progression.

Gallium nitrate, an anhydrous salt of a heavy metal, has been shown in several randomized trials to be an effective therapeutic agent in lowering calcium levels in hypercalcemic patients.^18,19 Furthermore, a double-blinded trial of 64 patients with hypercalcemia of malignancy showed gallium nitrate to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia.²⁰ However, the need for continuous infusion over a five-day period has limited the application of this agent.

Hemodialysis with a calcium-lacking dialysate has been shown in small, nonrandomized studies to be a temporarily effective method of reducing serum calcium levels.^21,22 However, this treatment modality would best be reserved for patients with severe hypercalcemia, in whom aggressive intravascular volume repletion and bisphosphonates are not advisable (e.g. those with significant heart or kidney failure) and have an underlying etiology that is likely to be responsive to other treatment. Furthermore, consideration as to the appropriateness of such invasive temporizing procedures in patients with metastatic cancer should be undertaken.

Back to the Case

This patient had an ionized calcium level of 1.9 mmol/L (normal 1.1-1.4 mmol/L). He was started on aggressive IV hydration with normal saline and zoledronic acid. His home medications were reviewed, and it was confirmed that he was not taking such contraindicated medications as thiazides or calcium/vitamin D supplementation.

Further workup for the etiology of his hypercalcemia revealed an appropriately suppressed, intact PTH and normal 25 (OH) Vitamin D and 1,25 (OH)2 Vitamin D levels. His intact PTH-RP was elevated at 10pmol/L, and consistent with hypercalcemia of malignancy.

Oncology and palliative-care consults were requested to assist with coordination of the treatment of the patient’s underlying lung cancer; plans were made for systemic chemotherapy. His symptoms slowly improved, and 72 hours after admission, his serum calcium had normalized. He was discharged with a plan to initiate chemotherapy and continued follow-up with oncology.

Bottom Line

Acute management of hypercalcemia of malignancy focuses on lowering the serum calcium through a variety of pharmacologic agents. However, such long-term issues as treatment of the underlying malignancy and discussions about goals of care in this high-mortality patient population is paramount. TH

Dr. Hartley and Dr. Repaskey are clinical instructors in internal medicine at the University of Michigan Health System. Dr. Rohde is a clinical assistant professor of internal medicine at UMHS.

References

1. Assadi F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009;3:(2):71-79.
2. Stewart A. Hypercalcemia associated with cancer. N Engl J Med. 2005;542(4):373-379.
3. Seccareccia D. Cancer-related hypercalcemia. Can Fam Physician. 2010;56:(3):244-246.
4. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326(18):1196-1203.
5. Suki WN, Yium JJ, VonMinden M, et al. Acute treatment of hypercalcemia with furosemide. N Engl J Med. 1970;283:836-840.
6. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149:259-263.
7. Drake MT, Bart LC, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clinic Proc. 2008;83(9):1032-1045.
8. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med. 1993; 95(3):297-304.
9. Gucalp R, Ritch P, Riernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. 1992;10(1):134-142.
10. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2): 558-567.
11. Tanvetyanon T. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17(6):897-907.
12. Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther. 1978; 24:219-222.
13. Binstock ML, Mundy GR. Effect of calcitonin and glucocorticoids in combination on the hypercalcemia of malignancy. Ann Intern Med. 1980;93(2):269-272.
14. Nilsson O, Almqvist S, Karlberg BE. Salmon calcitonin in the acute treatment of moderate and severe hypercalcemia in man. Acta Med Scand. 1978;204(4): 249-252.
15. Percival RC, Yates AJ, Gray RE, et al. Role of glucocorticoids in management of malignant hypercalcemia. Br Med J. 1984;289(6440):287.
16. Kristensen B, Ejlertsen B, Holmegaard SN, et al. Prednisolone in the treatment of severe malignant hypercalcemia in metastatic breast cancer: a randomized study. J Intern Med. 1992;232(3):237-245.
17. Thalassinos NC, Joplin GF. Failure of corticosteroid therapy to correct the hypercalcemia of malignant disease. Lancet. 1970;2(7672):537-538.
18. Warrell RP Jr, Murphy WK, Schulman P, et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol. 1991;9(8):1467-1475.
19. Warrell RP Jr, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blinded comparison to calcitonin. Ann Intern Med. 1988;108:669-674.
20. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J. 2006;12 (1):47-53.
21. Cardella CJ, Birkin BL, Rapoport A. Role of dialysis in the treatment of severe hypercalcemia: report of two cases successfully treated with hemodialysis and review of the literature. Clin Nephrol. 1979; 12(6):285-290.
22. Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the management of hypercalcemia. Nephron. 1996;72(3):424-428.

Case

A 63-year-old man with hypertension, diabetes, and recently diagnosed squamous-cell lung cancer presents with diffuse abdominal pain and confusion of two-day duration. He weighs 105 Kg, his blood pressure is 105/65 mm/Hg, heart rate is 105 beats per minute, and temperature is 99.0 degrees Fahrenheit. His respirations are 18 breaths per minute, oxygen saturation is 95% on room air, and his orthostatics are positive. Dry mucus membranes with decreased skin turgor are noted on physical examination. Laboratory evaluation reveals a calcium level of 15.5 mg/dL, creatinine level of 1.2 mg/dL, albumin level of 4.3 g/dL, and a phosphorous level of 2.9 mg/dL.

What is the best treatment of this condition?

Overview

Calcium homeostasis involves complex interactions between the kidney, gastrointestinal (GI) tract, and the skeletal system via hormonal influences. Although 99% of the body’s calcium is stored in the bones, 50% of serum calcium is in the active ionized form, 40% is bound to albumin, and 10% is complexed with anions.¹ It’s important to remember these percentages when evaluating a patient’s serum calcium; elevated serum calcium can be validated by using either a correction formula (corrected calcium=measured total calcium + [0.8 x (4.5-albumin)]) or by direct measurement of the ionized calcium, which is the physiologically active form.

Hypercalcemia of malignancy is the most common cause of hypercalcemia in the hospitalized patient. Twenty to 30% of patients with cancer will develop hypercalcemia at some point in their disease course.² Overall, this portends a poor prognosis with a median survival of three to four months.³

Four general mechanisms are involved in the pathogenesis of malignant hypercalcemia; these mechanisms form the basis for available treatment strategies available:

• Osteolytic tumors, such as multiple myeloma, can directly act on bone, leading to osteoclast activation and release of calcium;
• Humoral mediators elaborated by malignant cells, such as parathyroid hormone-related peptide (PTH-RP), can effect activation of osteoclasts and decrease renal elimination of calcium, causing humoral hypercalcemia of malignancy;
• Some malignancies (most commonly lymphomas) can directly synthesize 1,25 (OH)2 vitamin D, leading to increased luminal absorption of both calcium and phosphorus from the GI tract; and
• Direct production of parathyroid hormone (PTH) by the malignant cells is rare, but has been reported.²

Other factors, including impaired mobility, might lead to further bone resorption and a worsening of the hypercalcemic state.

A patient with hypercalcemia must have a systematic workup, with knowledge of other causes of hypercalcemia that could be present, irrespective of malignancy. Examples include primary hyperparathyroidism, medications effect, and genetic etiologies. Although further discussion is beyond the scope of this article, a broad diagnostic approach is represented in Figure 1 (at right).

Effective management of hypercalcemia demands consideration of both the patient’s immediate, as well as longer-term, clinical situation in light of the patient’s prognosis. The primary aim in the acute management of hypercalcemia is to normalize serum values and decrease symptoms. However, this must be done with appreciation that the metabolic derangement was generated by an underlying malignancy. The main focus of clinical therapeutics should be aimed at this.

click for large version

Review of the Data

Intravenous (IV) fluids. IV hydration with isotonic saline represents the most immediate and critical intervention in the acute management of malignant hypercalcemia. This condition has multiple, potentially deleterious effects on the kidney, including vasoconstriction, inhibition of salt absorption distally, and antagonism of anti-diuretic hormone (ADH), leading to both salt and water loss. The decrease in intravascular volume then potentiates increased sodium re-absorption proximally in the kidney.

Isotonic saline restores the volume depletion that invariably occurs in the setting of hypercalcemia-provoked urinary salt wasting. The restoration of intravascular volume results in an increase in the glomerular filtration rate and, thus, an increase in calcium filtration. Furthermore, proximal tubular sodium and calcium re-absorption decrease as the glomerular filtration rate increases. Additionally, an increase in sodium and water presentation to the distal renal tubular sites provokes a further calciuresis.

It is estimated that with saline hydration, the calcium concentration should decline, at least by the degree to which dehydration raised it, typically in the range of 1.6 mg to 2.4 mg per deciliter.⁴ Hydration alone, however, rarely leads to normalization of the serum calcium concentration in patients with severe hypercalcemia.

The rate of infusion is based on the severity of hypercalcemia, and the patient’s age and comorbidities, with particular attention to cardiac or renal disease. A standard approach for most patients without edema and without heart or renal failure is to begin a saline infusion at an initial rate between 200 mL/h to 300 mL/h. The goal is to maintain urine output at 100 mL/h to 150 mL/h.

Furosemide. Following the administration of intravenous fluids to re-establish a euvolemic state, furosemide historically has been used because it has a calcinuric effect with forced diuresis. It also is useful for managing and preventing the fluid overload that occurs with saline hydration. However, data does not support its routine use to lower calcium levels in hypercalcemic patients.

The majority of articles studying the use of furosemide were published in the 1970s and ’80s, and they involve a variety of doses and administration schedules ranging from 40 mg orally daily to 100 mg IV hourly with variable improvement in serum calcium levels and effects that were short-lived. Although some studies have shown that these high doses (2,400 mg/24 hours) of furosemide can decrease calcium levels, resultant severe metabolic derangements in other electrolytes were encountered. This approach required frequent and invasive monitoring to prevent such derangements.⁵ The clinical application of these studies have led to published recommendations that are as variable as the doses used in the initial studies more than 30 years ago.

This includes the consideration that, in light of the availability and efficacy of bisphosphonates, furosemide might no longer be clinically helpful in this endeavor.⁶ The current role of furosemide in the management in hypercalcemic patients remains on an as-needed basis for management of fluid overload states brought about after aggressive IV fluid resuscitation.

click for large version

Bisphosphonates. Bisphosph-onates first became available for the management of hypercalcemia in the early 1990s and have dramatically changed the acute intervention and improved the long-term clinical course of patients with malignant hypercalcemia. Though first developed in the 19th century with industrial applications, it wasn’t until the 1960s that their role in bone metabolism was appreciated.

While their complex mechanism of action remains an issue of ongoing investigations, it is known that bisphosphonates are directed to the bones, where they inhibit an enzyme in the HMG-CoA reductase pathway and promote apoptotic cell death of osteoclasts.⁷ By blocking osteoclast-mediated bone resorption, the bisphosphonates are effective in treating the hypercalcemia that occurs with a variety of bone-resorbing disease processes, malignant hypercalcemia included. As relatively nontoxic compounds capable of conferring a profound and sustained diminution in serum calcium, these agents have become preferred in the management of acute and chronic hypercalcemia of malignancy.

There are five parenteral bisphosphonates available for the treatment of malignant hypercalcemia: pamidronate, zoledronic acid, ibandronate, etidronate, and clodronate. Etidronate and clodronate are first-generation agents, which are less potent and have more side effects than other agents and are not as commonly used. Ibandronate is a useful agent with a long half-life shown to be as effective as pamidronate, though it has not been as extensively studied as the other agents.

Pamidronate has been studied thoroughly in multiple observational and randomized trials, and has been shown to be highly efficacious and minimally toxic in the treatment of hypercalcemia due to multiple causes, including malignant hypercalcemia.^8,9 A maximum calcium-lowering effect occurs at a dose of 90 mg, and the dose is often titrated based on the measured serum calcium. It is infused over two to four hours, effects a lowering of serum calcium within one to two days, and has a sustained effect lasting for up to two weeks or more.

As the most potent and most easily administered bisphosphonate, zoledronic acid is considered by many the agent of choice in the treatment of malignant hypercalcemia. It can be administered as a 4 mg-8 mg dose intravenously over 15 minutes (compared with two hours for pamidronate). Two Phase III trials comprising 275 patients have demonstrated zoledronic acid’s superior efficacy compared with pamidronate, with 88% of patients accomplishing a normalized serum calcium (compared with 70% of patients receiving a 90-mg dose of pamidronate).¹⁰

Even though these agents are relatively nontoxic, each can provoke a mild, transient flulike illness in recipients. Renal dysfunction has been noted rarely. These agents should be renally dosed and used with caution in patients with advanced renal insufficiency (serum creatinine >2.5). Osteonecrosis of the jaw has been observed in less than 2% of patients receiving IV bisphosphonates. Accordingly, it is recommended that patients undergo dental evaluation prior to receiving the agent (if feasible) and avoid invasive dental procedures around the time that they receive the agent.¹¹

click for large version

Other therapeutic interventions. The bisphosphonates represent the best studied and most efficacious pharmaceutical agents available to treat hypercalcemia. Straying from these agents should be considered only when they are contraindicated, in severe circumstances, or after the patient has failed to respond.

Calcitonin has long had FDA approval for treatment of hypercalcemia in adults. It has been shown in small, nonrandomized studies from the 1970s and ’80s to rapidly (within two hours) decrease calcium levels in hypercalcemic patients.^12,13,14 However, these reductions are small (<10%) and transient (usually persisting up to 72 to 96 hours) due to the tachyphylaxsis noted with this medication. Nonetheless, calcitonin can be used as an adjuvant bridge to lower calcium levels in severely hypercalcemic patients for the first few days before other agents start taking effect.

Glucocorticoids have been used to treat hypercalcemia since the 1950s. Prednisone, dexamethasone, and methylprednisolone all carry FDA indications for hypercalcemia, but data are lacking and contradictory. A small (n=28) randomized controlled trial (RCT) conducted in 1984 showed no additional efficacy of glucocorticoids with IV fluids when compared with IV fluids alone.¹⁵ Another small (n=30) RCT done in 1992 on women with metastatic breast cancer showed a significant improvement in patients treated with prednisolone, IV fluids, and furosemide when compared with IV fluids and furosemide.¹⁶ Other nonrandomized trials have shown response to be unpredictable at best.¹⁷ Despite this, glucocorticoids likely retain a limited role for treatment in specific cases, including hypercalcemia induced by lymphomas elevating levels of 1,25(OH)2 vitamin D (as this interacts with a steroid-regulated receptor), or multiple myelomas where they potentially impact disease progression.

Gallium nitrate, an anhydrous salt of a heavy metal, has been shown in several randomized trials to be an effective therapeutic agent in lowering calcium levels in hypercalcemic patients.^18,19 Furthermore, a double-blinded trial of 64 patients with hypercalcemia of malignancy showed gallium nitrate to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia.²⁰ However, the need for continuous infusion over a five-day period has limited the application of this agent.

Hemodialysis with a calcium-lacking dialysate has been shown in small, nonrandomized studies to be a temporarily effective method of reducing serum calcium levels.^21,22 However, this treatment modality would best be reserved for patients with severe hypercalcemia, in whom aggressive intravascular volume repletion and bisphosphonates are not advisable (e.g. those with significant heart or kidney failure) and have an underlying etiology that is likely to be responsive to other treatment. Furthermore, consideration as to the appropriateness of such invasive temporizing procedures in patients with metastatic cancer should be undertaken.

Back to the Case

This patient had an ionized calcium level of 1.9 mmol/L (normal 1.1-1.4 mmol/L). He was started on aggressive IV hydration with normal saline and zoledronic acid. His home medications were reviewed, and it was confirmed that he was not taking such contraindicated medications as thiazides or calcium/vitamin D supplementation.

Further workup for the etiology of his hypercalcemia revealed an appropriately suppressed, intact PTH and normal 25 (OH) Vitamin D and 1,25 (OH)2 Vitamin D levels. His intact PTH-RP was elevated at 10pmol/L, and consistent with hypercalcemia of malignancy.

Oncology and palliative-care consults were requested to assist with coordination of the treatment of the patient’s underlying lung cancer; plans were made for systemic chemotherapy. His symptoms slowly improved, and 72 hours after admission, his serum calcium had normalized. He was discharged with a plan to initiate chemotherapy and continued follow-up with oncology.

Bottom Line

Acute management of hypercalcemia of malignancy focuses on lowering the serum calcium through a variety of pharmacologic agents. However, such long-term issues as treatment of the underlying malignancy and discussions about goals of care in this high-mortality patient population is paramount. TH

Dr. Hartley and Dr. Repaskey are clinical instructors in internal medicine at the University of Michigan Health System. Dr. Rohde is a clinical assistant professor of internal medicine at UMHS.

References

1. Assadi F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009;3:(2):71-79.
2. Stewart A. Hypercalcemia associated with cancer. N Engl J Med. 2005;542(4):373-379.
3. Seccareccia D. Cancer-related hypercalcemia. Can Fam Physician. 2010;56:(3):244-246.
4. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326(18):1196-1203.
5. Suki WN, Yium JJ, VonMinden M, et al. Acute treatment of hypercalcemia with furosemide. N Engl J Med. 1970;283:836-840.
6. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149:259-263.
7. Drake MT, Bart LC, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clinic Proc. 2008;83(9):1032-1045.
8. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med. 1993; 95(3):297-304.
9. Gucalp R, Ritch P, Riernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. 1992;10(1):134-142.
10. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2): 558-567.
11. Tanvetyanon T. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17(6):897-907.
12. Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther. 1978; 24:219-222.
13. Binstock ML, Mundy GR. Effect of calcitonin and glucocorticoids in combination on the hypercalcemia of malignancy. Ann Intern Med. 1980;93(2):269-272.
14. Nilsson O, Almqvist S, Karlberg BE. Salmon calcitonin in the acute treatment of moderate and severe hypercalcemia in man. Acta Med Scand. 1978;204(4): 249-252.
15. Percival RC, Yates AJ, Gray RE, et al. Role of glucocorticoids in management of malignant hypercalcemia. Br Med J. 1984;289(6440):287.
16. Kristensen B, Ejlertsen B, Holmegaard SN, et al. Prednisolone in the treatment of severe malignant hypercalcemia in metastatic breast cancer: a randomized study. J Intern Med. 1992;232(3):237-245.
17. Thalassinos NC, Joplin GF. Failure of corticosteroid therapy to correct the hypercalcemia of malignant disease. Lancet. 1970;2(7672):537-538.
18. Warrell RP Jr, Murphy WK, Schulman P, et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol. 1991;9(8):1467-1475.
19. Warrell RP Jr, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blinded comparison to calcitonin. Ann Intern Med. 1988;108:669-674.
20. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J. 2006;12 (1):47-53.
21. Cardella CJ, Birkin BL, Rapoport A. Role of dialysis in the treatment of severe hypercalcemia: report of two cases successfully treated with hemodialysis and review of the literature. Clin Nephrol. 1979; 12(6):285-290.
22. Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the management of hypercalcemia. Nephron. 1996;72(3):424-428.

Case

A 63-year-old man with hypertension, diabetes, and recently diagnosed squamous-cell lung cancer presents with diffuse abdominal pain and confusion of two-day duration. He weighs 105 Kg, his blood pressure is 105/65 mm/Hg, heart rate is 105 beats per minute, and temperature is 99.0 degrees Fahrenheit. His respirations are 18 breaths per minute, oxygen saturation is 95% on room air, and his orthostatics are positive. Dry mucus membranes with decreased skin turgor are noted on physical examination. Laboratory evaluation reveals a calcium level of 15.5 mg/dL, creatinine level of 1.2 mg/dL, albumin level of 4.3 g/dL, and a phosphorous level of 2.9 mg/dL.

What is the best treatment of this condition?

Overview

Calcium homeostasis involves complex interactions between the kidney, gastrointestinal (GI) tract, and the skeletal system via hormonal influences. Although 99% of the body’s calcium is stored in the bones, 50% of serum calcium is in the active ionized form, 40% is bound to albumin, and 10% is complexed with anions.¹ It’s important to remember these percentages when evaluating a patient’s serum calcium; elevated serum calcium can be validated by using either a correction formula (corrected calcium=measured total calcium + [0.8 x (4.5-albumin)]) or by direct measurement of the ionized calcium, which is the physiologically active form.

Hypercalcemia of malignancy is the most common cause of hypercalcemia in the hospitalized patient. Twenty to 30% of patients with cancer will develop hypercalcemia at some point in their disease course.² Overall, this portends a poor prognosis with a median survival of three to four months.³

Four general mechanisms are involved in the pathogenesis of malignant hypercalcemia; these mechanisms form the basis for available treatment strategies available:

• Osteolytic tumors, such as multiple myeloma, can directly act on bone, leading to osteoclast activation and release of calcium;
• Humoral mediators elaborated by malignant cells, such as parathyroid hormone-related peptide (PTH-RP), can effect activation of osteoclasts and decrease renal elimination of calcium, causing humoral hypercalcemia of malignancy;
• Some malignancies (most commonly lymphomas) can directly synthesize 1,25 (OH)2 vitamin D, leading to increased luminal absorption of both calcium and phosphorus from the GI tract; and
• Direct production of parathyroid hormone (PTH) by the malignant cells is rare, but has been reported.²

Other factors, including impaired mobility, might lead to further bone resorption and a worsening of the hypercalcemic state.

A patient with hypercalcemia must have a systematic workup, with knowledge of other causes of hypercalcemia that could be present, irrespective of malignancy. Examples include primary hyperparathyroidism, medications effect, and genetic etiologies. Although further discussion is beyond the scope of this article, a broad diagnostic approach is represented in Figure 1 (at right).

Effective management of hypercalcemia demands consideration of both the patient’s immediate, as well as longer-term, clinical situation in light of the patient’s prognosis. The primary aim in the acute management of hypercalcemia is to normalize serum values and decrease symptoms. However, this must be done with appreciation that the metabolic derangement was generated by an underlying malignancy. The main focus of clinical therapeutics should be aimed at this.

click for large version

Review of the Data

Intravenous (IV) fluids. IV hydration with isotonic saline represents the most immediate and critical intervention in the acute management of malignant hypercalcemia. This condition has multiple, potentially deleterious effects on the kidney, including vasoconstriction, inhibition of salt absorption distally, and antagonism of anti-diuretic hormone (ADH), leading to both salt and water loss. The decrease in intravascular volume then potentiates increased sodium re-absorption proximally in the kidney.

Isotonic saline restores the volume depletion that invariably occurs in the setting of hypercalcemia-provoked urinary salt wasting. The restoration of intravascular volume results in an increase in the glomerular filtration rate and, thus, an increase in calcium filtration. Furthermore, proximal tubular sodium and calcium re-absorption decrease as the glomerular filtration rate increases. Additionally, an increase in sodium and water presentation to the distal renal tubular sites provokes a further calciuresis.

It is estimated that with saline hydration, the calcium concentration should decline, at least by the degree to which dehydration raised it, typically in the range of 1.6 mg to 2.4 mg per deciliter.⁴ Hydration alone, however, rarely leads to normalization of the serum calcium concentration in patients with severe hypercalcemia.

The rate of infusion is based on the severity of hypercalcemia, and the patient’s age and comorbidities, with particular attention to cardiac or renal disease. A standard approach for most patients without edema and without heart or renal failure is to begin a saline infusion at an initial rate between 200 mL/h to 300 mL/h. The goal is to maintain urine output at 100 mL/h to 150 mL/h.

Furosemide. Following the administration of intravenous fluids to re-establish a euvolemic state, furosemide historically has been used because it has a calcinuric effect with forced diuresis. It also is useful for managing and preventing the fluid overload that occurs with saline hydration. However, data does not support its routine use to lower calcium levels in hypercalcemic patients.

The majority of articles studying the use of furosemide were published in the 1970s and ’80s, and they involve a variety of doses and administration schedules ranging from 40 mg orally daily to 100 mg IV hourly with variable improvement in serum calcium levels and effects that were short-lived. Although some studies have shown that these high doses (2,400 mg/24 hours) of furosemide can decrease calcium levels, resultant severe metabolic derangements in other electrolytes were encountered. This approach required frequent and invasive monitoring to prevent such derangements.⁵ The clinical application of these studies have led to published recommendations that are as variable as the doses used in the initial studies more than 30 years ago.

This includes the consideration that, in light of the availability and efficacy of bisphosphonates, furosemide might no longer be clinically helpful in this endeavor.⁶ The current role of furosemide in the management in hypercalcemic patients remains on an as-needed basis for management of fluid overload states brought about after aggressive IV fluid resuscitation.

click for large version

Bisphosphonates. Bisphosph-onates first became available for the management of hypercalcemia in the early 1990s and have dramatically changed the acute intervention and improved the long-term clinical course of patients with malignant hypercalcemia. Though first developed in the 19th century with industrial applications, it wasn’t until the 1960s that their role in bone metabolism was appreciated.

While their complex mechanism of action remains an issue of ongoing investigations, it is known that bisphosphonates are directed to the bones, where they inhibit an enzyme in the HMG-CoA reductase pathway and promote apoptotic cell death of osteoclasts.⁷ By blocking osteoclast-mediated bone resorption, the bisphosphonates are effective in treating the hypercalcemia that occurs with a variety of bone-resorbing disease processes, malignant hypercalcemia included. As relatively nontoxic compounds capable of conferring a profound and sustained diminution in serum calcium, these agents have become preferred in the management of acute and chronic hypercalcemia of malignancy.

There are five parenteral bisphosphonates available for the treatment of malignant hypercalcemia: pamidronate, zoledronic acid, ibandronate, etidronate, and clodronate. Etidronate and clodronate are first-generation agents, which are less potent and have more side effects than other agents and are not as commonly used. Ibandronate is a useful agent with a long half-life shown to be as effective as pamidronate, though it has not been as extensively studied as the other agents.

Pamidronate has been studied thoroughly in multiple observational and randomized trials, and has been shown to be highly efficacious and minimally toxic in the treatment of hypercalcemia due to multiple causes, including malignant hypercalcemia.^8,9 A maximum calcium-lowering effect occurs at a dose of 90 mg, and the dose is often titrated based on the measured serum calcium. It is infused over two to four hours, effects a lowering of serum calcium within one to two days, and has a sustained effect lasting for up to two weeks or more.

As the most potent and most easily administered bisphosphonate, zoledronic acid is considered by many the agent of choice in the treatment of malignant hypercalcemia. It can be administered as a 4 mg-8 mg dose intravenously over 15 minutes (compared with two hours for pamidronate). Two Phase III trials comprising 275 patients have demonstrated zoledronic acid’s superior efficacy compared with pamidronate, with 88% of patients accomplishing a normalized serum calcium (compared with 70% of patients receiving a 90-mg dose of pamidronate).¹⁰

Even though these agents are relatively nontoxic, each can provoke a mild, transient flulike illness in recipients. Renal dysfunction has been noted rarely. These agents should be renally dosed and used with caution in patients with advanced renal insufficiency (serum creatinine >2.5). Osteonecrosis of the jaw has been observed in less than 2% of patients receiving IV bisphosphonates. Accordingly, it is recommended that patients undergo dental evaluation prior to receiving the agent (if feasible) and avoid invasive dental procedures around the time that they receive the agent.¹¹

click for large version

Other therapeutic interventions. The bisphosphonates represent the best studied and most efficacious pharmaceutical agents available to treat hypercalcemia. Straying from these agents should be considered only when they are contraindicated, in severe circumstances, or after the patient has failed to respond.

Calcitonin has long had FDA approval for treatment of hypercalcemia in adults. It has been shown in small, nonrandomized studies from the 1970s and ’80s to rapidly (within two hours) decrease calcium levels in hypercalcemic patients.^12,13,14 However, these reductions are small (<10%) and transient (usually persisting up to 72 to 96 hours) due to the tachyphylaxsis noted with this medication. Nonetheless, calcitonin can be used as an adjuvant bridge to lower calcium levels in severely hypercalcemic patients for the first few days before other agents start taking effect.

Glucocorticoids have been used to treat hypercalcemia since the 1950s. Prednisone, dexamethasone, and methylprednisolone all carry FDA indications for hypercalcemia, but data are lacking and contradictory. A small (n=28) randomized controlled trial (RCT) conducted in 1984 showed no additional efficacy of glucocorticoids with IV fluids when compared with IV fluids alone.¹⁵ Another small (n=30) RCT done in 1992 on women with metastatic breast cancer showed a significant improvement in patients treated with prednisolone, IV fluids, and furosemide when compared with IV fluids and furosemide.¹⁶ Other nonrandomized trials have shown response to be unpredictable at best.¹⁷ Despite this, glucocorticoids likely retain a limited role for treatment in specific cases, including hypercalcemia induced by lymphomas elevating levels of 1,25(OH)2 vitamin D (as this interacts with a steroid-regulated receptor), or multiple myelomas where they potentially impact disease progression.

Gallium nitrate, an anhydrous salt of a heavy metal, has been shown in several randomized trials to be an effective therapeutic agent in lowering calcium levels in hypercalcemic patients.^18,19 Furthermore, a double-blinded trial of 64 patients with hypercalcemia of malignancy showed gallium nitrate to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia.²⁰ However, the need for continuous infusion over a five-day period has limited the application of this agent.

Hemodialysis with a calcium-lacking dialysate has been shown in small, nonrandomized studies to be a temporarily effective method of reducing serum calcium levels.^21,22 However, this treatment modality would best be reserved for patients with severe hypercalcemia, in whom aggressive intravascular volume repletion and bisphosphonates are not advisable (e.g. those with significant heart or kidney failure) and have an underlying etiology that is likely to be responsive to other treatment. Furthermore, consideration as to the appropriateness of such invasive temporizing procedures in patients with metastatic cancer should be undertaken.

Back to the Case

This patient had an ionized calcium level of 1.9 mmol/L (normal 1.1-1.4 mmol/L). He was started on aggressive IV hydration with normal saline and zoledronic acid. His home medications were reviewed, and it was confirmed that he was not taking such contraindicated medications as thiazides or calcium/vitamin D supplementation.

Further workup for the etiology of his hypercalcemia revealed an appropriately suppressed, intact PTH and normal 25 (OH) Vitamin D and 1,25 (OH)2 Vitamin D levels. His intact PTH-RP was elevated at 10pmol/L, and consistent with hypercalcemia of malignancy.

Oncology and palliative-care consults were requested to assist with coordination of the treatment of the patient’s underlying lung cancer; plans were made for systemic chemotherapy. His symptoms slowly improved, and 72 hours after admission, his serum calcium had normalized. He was discharged with a plan to initiate chemotherapy and continued follow-up with oncology.

Bottom Line

Acute management of hypercalcemia of malignancy focuses on lowering the serum calcium through a variety of pharmacologic agents. However, such long-term issues as treatment of the underlying malignancy and discussions about goals of care in this high-mortality patient population is paramount. TH

Dr. Hartley and Dr. Repaskey are clinical instructors in internal medicine at the University of Michigan Health System. Dr. Rohde is a clinical assistant professor of internal medicine at UMHS.

References

1. Assadi F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009;3:(2):71-79.
2. Stewart A. Hypercalcemia associated with cancer. N Engl J Med. 2005;542(4):373-379.
3. Seccareccia D. Cancer-related hypercalcemia. Can Fam Physician. 2010;56:(3):244-246.
4. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326(18):1196-1203.
5. Suki WN, Yium JJ, VonMinden M, et al. Acute treatment of hypercalcemia with furosemide. N Engl J Med. 1970;283:836-840.
6. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149:259-263.
7. Drake MT, Bart LC, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clinic Proc. 2008;83(9):1032-1045.
8. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med. 1993; 95(3):297-304.
9. Gucalp R, Ritch P, Riernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. 1992;10(1):134-142.
10. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2): 558-567.
11. Tanvetyanon T. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17(6):897-907.
12. Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther. 1978; 24:219-222.
13. Binstock ML, Mundy GR. Effect of calcitonin and glucocorticoids in combination on the hypercalcemia of malignancy. Ann Intern Med. 1980;93(2):269-272.
14. Nilsson O, Almqvist S, Karlberg BE. Salmon calcitonin in the acute treatment of moderate and severe hypercalcemia in man. Acta Med Scand. 1978;204(4): 249-252.
15. Percival RC, Yates AJ, Gray RE, et al. Role of glucocorticoids in management of malignant hypercalcemia. Br Med J. 1984;289(6440):287.
16. Kristensen B, Ejlertsen B, Holmegaard SN, et al. Prednisolone in the treatment of severe malignant hypercalcemia in metastatic breast cancer: a randomized study. J Intern Med. 1992;232(3):237-245.
17. Thalassinos NC, Joplin GF. Failure of corticosteroid therapy to correct the hypercalcemia of malignant disease. Lancet. 1970;2(7672):537-538.
18. Warrell RP Jr, Murphy WK, Schulman P, et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol. 1991;9(8):1467-1475.
19. Warrell RP Jr, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blinded comparison to calcitonin. Ann Intern Med. 1988;108:669-674.
20. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J. 2006;12 (1):47-53.
21. Cardella CJ, Birkin BL, Rapoport A. Role of dialysis in the treatment of severe hypercalcemia: report of two cases successfully treated with hemodialysis and review of the literature. Clin Nephrol. 1979; 12(6):285-290.
22. Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the management of hypercalcemia. Nephron. 1996;72(3):424-428.