Franklin Michota, MD

Deferring management of a postop complication to the surgery team resulted in treatment delay with a serious adverse outcome.

History:

RR is a 54 year-old man with a medical history of hypertension, hyperlipidemia, obesity, and chronic left knee pain from osteoarthritis. He was admitted to the hospital and underwent an elective left total knee replacement with monitored anesthesia care, combined with a left femoral nerve block. There were no intraoperative complications. When RR awoke in the recovery unit, he was in excruciating pain. He received another femoral nerve block and was sent to the regular nursing floor around 4 p.m. By early evening, the pain in his left leg remained poorly controlled and was consistently rated as 10/10. In addition, RR’s heart rates were elevated (130-140 bpm). The orthopedic surgeon was notified of the uncontrolled pain and elevated heart rates and he requested a hospitalist consult.

©Alliance/Fotolia.com

Dr. Hospitalist saw RR sometime before 9 p.m. that evening. RR was somewhat sedated by opiate analgesics, and his wife was at the bedside. During the interview, she related that her husband had been taking nightly benzodiazepines for sleep for several months leading up to the surgery. Dr. Hospitalist did not examine RR’s left foot and leg, and he documented in his consult that he was deferring left leg issues such as bleeding and swelling to the orthopedic surgery team. Dr. Hospitalist’s impression was that RR had sinus tachycardia, possibly because of the benzodiazepine withdrawal. Fluids were ordered along with low-dose benzodiazepines.

Throughout the night, RR awakened and complained of severe pain. The evening nurse charted that RR was having difficulty moving the toes on his left foot and that the pulses in his foot were barely palpable. By the early morning, RR’s pulses were no longer palpable but could still be detected by Doppler. Examination by the surgical team the following morning documented that RR had decreased sensation in his left lower extremity as well. An ultrasound of the left leg was ordered and revealed a large left popliteal pseudoaneurysm with complete occlusion of the left popliteal, tibial, and peroneal arteries below the knee. The patient went to the operating room three times over the next 4 days in an attempt to revascularize the leg. Unfortunately, RR ultimately had an above-the-knee amputation (AKA) performed 9 days after his elective total knee replacement.

Complaint:

RR sought a “quality of life”–enhancing procedure for his chronic left knee pain. What he ended up with was an AKA and a significant decrease in his overall quality of life. RR was angry that his postoperative pain, which was out of proportion to what should have been expected for this type of surgery, was essentially ignored until it was too late. He blamed the surgeon and the hospitalist for failing to diagnose his condition while his leg was still salvageable.

Scientific principles:

Complications during and after total knee replacement are generally uncommon and can often be prevented with meticulous surgical technique and with attentive postoperative management. Vascular injuries in total knee arthroplasty are exceedingly rare, but careful examination of the limbs is necessary to detect signs of acute limb ischemia. The six P’s of acute ischemia include paresthesia, pain, pallor, pulselessness, poikilothermia, and paralysis. A diagnosis of acute lower extremity ischemia can generally be made based upon the history and physical examination. Once the diagnosis of acute arterial occlusion has been made, anticoagulation should be initiated. Subsequent treatment varies depending upon the classification of acute ischemia. The initial options include catheter-directed thrombolytic therapy with or without percutaneous intervention or surgery.

Complaint rebuttal and discussion:

Dr. Hospitalist defended himself by limiting his scope of responsibility. He essentially said this was a surgical complication, and it was therefore the surgical team’s responsibility to make the diagnosis. Defense experts were quick to affirm that Dr. Hospitalist was consulted for a specific issue – postoperative tachycardia – and that he performed a focused history and physical examination to address that issue. Plaintiff experts cited the Society of Hospital Medicine Hospitalist Orthopedic Co-Management Implementation Guide, which outlines that co-management is the “shared responsibility, authority, and accountability for the care of a hospitalized patient.” The Guide further states: “Inevitably, there will be circumstances where either of the co-managing services could manage a specific problem, or where it is unclear which service would be best equipped to manage a specific problem. These situations can be best managed by following two basic principles: 1) Do what is best for the patient in a timely fashion and do not assume that a problem is being handled by the other service; and 2) communicate frequently and directly with the other service.” Plaintiff experts argued that Dr. Hospitalist failed to follow both of these principles.

 

Conclusion:

Hospitalists are frequently co-managers of surgical patients, and thus they are in part responsible for evaluating diagnosing, and treating both medical and surgical complications. Once again, it is vital that hospitalists delineate responsibilities explicitly through direct communication and then memorialize such discussions in the medical record. In this case, the chart consultation deferred examination of the operative leg to a surgical team that claimed they were “unaware” of any issues. This case was settled on behalf of the patient for an undisclosed amount.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Deferring management of a postop complication to the surgery team resulted in treatment delay with a serious adverse outcome.

History:

RR is a 54 year-old man with a medical history of hypertension, hyperlipidemia, obesity, and chronic left knee pain from osteoarthritis. He was admitted to the hospital and underwent an elective left total knee replacement with monitored anesthesia care, combined with a left femoral nerve block. There were no intraoperative complications. When RR awoke in the recovery unit, he was in excruciating pain. He received another femoral nerve block and was sent to the regular nursing floor around 4 p.m. By early evening, the pain in his left leg remained poorly controlled and was consistently rated as 10/10. In addition, RR’s heart rates were elevated (130-140 bpm). The orthopedic surgeon was notified of the uncontrolled pain and elevated heart rates and he requested a hospitalist consult.

©Alliance/Fotolia.com

Dr. Hospitalist saw RR sometime before 9 p.m. that evening. RR was somewhat sedated by opiate analgesics, and his wife was at the bedside. During the interview, she related that her husband had been taking nightly benzodiazepines for sleep for several months leading up to the surgery. Dr. Hospitalist did not examine RR’s left foot and leg, and he documented in his consult that he was deferring left leg issues such as bleeding and swelling to the orthopedic surgery team. Dr. Hospitalist’s impression was that RR had sinus tachycardia, possibly because of the benzodiazepine withdrawal. Fluids were ordered along with low-dose benzodiazepines.

Throughout the night, RR awakened and complained of severe pain. The evening nurse charted that RR was having difficulty moving the toes on his left foot and that the pulses in his foot were barely palpable. By the early morning, RR’s pulses were no longer palpable but could still be detected by Doppler. Examination by the surgical team the following morning documented that RR had decreased sensation in his left lower extremity as well. An ultrasound of the left leg was ordered and revealed a large left popliteal pseudoaneurysm with complete occlusion of the left popliteal, tibial, and peroneal arteries below the knee. The patient went to the operating room three times over the next 4 days in an attempt to revascularize the leg. Unfortunately, RR ultimately had an above-the-knee amputation (AKA) performed 9 days after his elective total knee replacement.

Complaint:

RR sought a “quality of life”–enhancing procedure for his chronic left knee pain. What he ended up with was an AKA and a significant decrease in his overall quality of life. RR was angry that his postoperative pain, which was out of proportion to what should have been expected for this type of surgery, was essentially ignored until it was too late. He blamed the surgeon and the hospitalist for failing to diagnose his condition while his leg was still salvageable.

Scientific principles:

Complications during and after total knee replacement are generally uncommon and can often be prevented with meticulous surgical technique and with attentive postoperative management. Vascular injuries in total knee arthroplasty are exceedingly rare, but careful examination of the limbs is necessary to detect signs of acute limb ischemia. The six P’s of acute ischemia include paresthesia, pain, pallor, pulselessness, poikilothermia, and paralysis. A diagnosis of acute lower extremity ischemia can generally be made based upon the history and physical examination. Once the diagnosis of acute arterial occlusion has been made, anticoagulation should be initiated. Subsequent treatment varies depending upon the classification of acute ischemia. The initial options include catheter-directed thrombolytic therapy with or without percutaneous intervention or surgery.

Complaint rebuttal and discussion:

Dr. Hospitalist defended himself by limiting his scope of responsibility. He essentially said this was a surgical complication, and it was therefore the surgical team’s responsibility to make the diagnosis. Defense experts were quick to affirm that Dr. Hospitalist was consulted for a specific issue – postoperative tachycardia – and that he performed a focused history and physical examination to address that issue. Plaintiff experts cited the Society of Hospital Medicine Hospitalist Orthopedic Co-Management Implementation Guide, which outlines that co-management is the “shared responsibility, authority, and accountability for the care of a hospitalized patient.” The Guide further states: “Inevitably, there will be circumstances where either of the co-managing services could manage a specific problem, or where it is unclear which service would be best equipped to manage a specific problem. These situations can be best managed by following two basic principles: 1) Do what is best for the patient in a timely fashion and do not assume that a problem is being handled by the other service; and 2) communicate frequently and directly with the other service.” Plaintiff experts argued that Dr. Hospitalist failed to follow both of these principles.

 

Conclusion:

Hospitalists are frequently co-managers of surgical patients, and thus they are in part responsible for evaluating diagnosing, and treating both medical and surgical complications. Once again, it is vital that hospitalists delineate responsibilities explicitly through direct communication and then memorialize such discussions in the medical record. In this case, the chart consultation deferred examination of the operative leg to a surgical team that claimed they were “unaware” of any issues. This case was settled on behalf of the patient for an undisclosed amount.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Deferring management of a postop complication to the surgery team resulted in treatment delay with a serious adverse outcome.

History:

RR is a 54 year-old man with a medical history of hypertension, hyperlipidemia, obesity, and chronic left knee pain from osteoarthritis. He was admitted to the hospital and underwent an elective left total knee replacement with monitored anesthesia care, combined with a left femoral nerve block. There were no intraoperative complications. When RR awoke in the recovery unit, he was in excruciating pain. He received another femoral nerve block and was sent to the regular nursing floor around 4 p.m. By early evening, the pain in his left leg remained poorly controlled and was consistently rated as 10/10. In addition, RR’s heart rates were elevated (130-140 bpm). The orthopedic surgeon was notified of the uncontrolled pain and elevated heart rates and he requested a hospitalist consult.

©Alliance/Fotolia.com

Dr. Hospitalist saw RR sometime before 9 p.m. that evening. RR was somewhat sedated by opiate analgesics, and his wife was at the bedside. During the interview, she related that her husband had been taking nightly benzodiazepines for sleep for several months leading up to the surgery. Dr. Hospitalist did not examine RR’s left foot and leg, and he documented in his consult that he was deferring left leg issues such as bleeding and swelling to the orthopedic surgery team. Dr. Hospitalist’s impression was that RR had sinus tachycardia, possibly because of the benzodiazepine withdrawal. Fluids were ordered along with low-dose benzodiazepines.

Throughout the night, RR awakened and complained of severe pain. The evening nurse charted that RR was having difficulty moving the toes on his left foot and that the pulses in his foot were barely palpable. By the early morning, RR’s pulses were no longer palpable but could still be detected by Doppler. Examination by the surgical team the following morning documented that RR had decreased sensation in his left lower extremity as well. An ultrasound of the left leg was ordered and revealed a large left popliteal pseudoaneurysm with complete occlusion of the left popliteal, tibial, and peroneal arteries below the knee. The patient went to the operating room three times over the next 4 days in an attempt to revascularize the leg. Unfortunately, RR ultimately had an above-the-knee amputation (AKA) performed 9 days after his elective total knee replacement.

Complaint:

RR sought a “quality of life”–enhancing procedure for his chronic left knee pain. What he ended up with was an AKA and a significant decrease in his overall quality of life. RR was angry that his postoperative pain, which was out of proportion to what should have been expected for this type of surgery, was essentially ignored until it was too late. He blamed the surgeon and the hospitalist for failing to diagnose his condition while his leg was still salvageable.

Scientific principles:

Complications during and after total knee replacement are generally uncommon and can often be prevented with meticulous surgical technique and with attentive postoperative management. Vascular injuries in total knee arthroplasty are exceedingly rare, but careful examination of the limbs is necessary to detect signs of acute limb ischemia. The six P’s of acute ischemia include paresthesia, pain, pallor, pulselessness, poikilothermia, and paralysis. A diagnosis of acute lower extremity ischemia can generally be made based upon the history and physical examination. Once the diagnosis of acute arterial occlusion has been made, anticoagulation should be initiated. Subsequent treatment varies depending upon the classification of acute ischemia. The initial options include catheter-directed thrombolytic therapy with or without percutaneous intervention or surgery.

Complaint rebuttal and discussion:

Dr. Hospitalist defended himself by limiting his scope of responsibility. He essentially said this was a surgical complication, and it was therefore the surgical team’s responsibility to make the diagnosis. Defense experts were quick to affirm that Dr. Hospitalist was consulted for a specific issue – postoperative tachycardia – and that he performed a focused history and physical examination to address that issue. Plaintiff experts cited the Society of Hospital Medicine Hospitalist Orthopedic Co-Management Implementation Guide, which outlines that co-management is the “shared responsibility, authority, and accountability for the care of a hospitalized patient.” The Guide further states: “Inevitably, there will be circumstances where either of the co-managing services could manage a specific problem, or where it is unclear which service would be best equipped to manage a specific problem. These situations can be best managed by following two basic principles: 1) Do what is best for the patient in a timely fashion and do not assume that a problem is being handled by the other service; and 2) communicate frequently and directly with the other service.” Plaintiff experts argued that Dr. Hospitalist failed to follow both of these principles.

 

Conclusion:

Hospitalists are frequently co-managers of surgical patients, and thus they are in part responsible for evaluating diagnosing, and treating both medical and surgical complications. Once again, it is vital that hospitalists delineate responsibilities explicitly through direct communication and then memorialize such discussions in the medical record. In this case, the chart consultation deferred examination of the operative leg to a surgical team that claimed they were “unaware” of any issues. This case was settled on behalf of the patient for an undisclosed amount.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Medicolegal review has the opportunity to become the morbidity and mortality conference of the modern era. The more we share in our collective failures, the less likely we are to repeat those same mistakes.

CR was a 69-year-old man who presented to the hospital for an elective total knee revision. He had a past medical history of obesity, hypertension, and chronic obstructive pulmonary disease (COPD).

Two weeks prior to the surgery, he received preoperative clearance from his primary care physician. CR had a morning surgery that went well and was without complication. He was transferred to the postanesthesia care unit in good condition with normal oxygen saturations on 2L of oxygen by nasal cannula. His postoperative orders included a routine hospitalist consultation for “medical management,” along with orders for daily low-molecular weight heparin for deep vein thrombosis (DVT) prophylaxis. CR arrived to the orthopedic floor later that afternoon. He did well overnight, and the next morning, he began working with physical therapy. After doing some exercises in the bed, CR had his oxygen removed so that he could ambulate. While up with the physical therapist, CR reported feeling “dizzy.” A chair was brought up behind him so that he could sit down. His oxygen saturation was 88%. CR was placed back on 2L of oxygen, but as he transferred from the chair to the bed his oxygen saturation fell further to 81%. CR had his oxygen increased to 3L and over the next half-hour, his oxygen saturation came up and stayed above 92%.

Dr. Hospitalist met CR about an hour after he worked with physical therapy. CR was without complaints at the time of the evaluation and had good oxygen saturations on 3L of oxygen. Dr. Hospitalist documented that CR denied chest pain, cough, or sputum production. On auscultation, CR had a scattered wheeze. Dr. Hospitalist dictated that his differential diagnosis included pulmonary embolism (PE). He ordered bronchodilator aerosols, a chest radiograph, a troponin and a brain natriuretic peptide (BNP) level. The chest radiograph was performed that afternoon and interpreted as “no acute process,” with no evidence for atelectasis.

Overnight, CR remained on oxygen via nasal cannula. The following morning his nurse noted that CR had bilateral edema in his legs. The labs ordered by Dr. Hospitalist the previous day were now in the chart – the troponin was 0.07 ng/mL (normal < 0.04 ng/ml) and the BNP was 205 pg/mL.

At 11 a.m., CR was again seen by physical therapy. While ambulating in his room, CR began to feel “dizzy” despite the use of oxygen, and he passed out falling to his knees. The therapist and several nurses got him back to a chair and increased his oxygen. He spontaneously regained consciousness, but within a few minutes CR passed out a second time and lost his pulse. Dr. Hospitalist and the surgeon responded to the code. He was unable to be resuscitated and was pronounced dead. An autopsy was performed and determined the cause of death to be massive saddle pulmonary embolism (PE).

Complaint:

A complaint was filed against the hospital, the surgeon, and Dr. Hospitalist for failure to prevent DVT, failure to diagnose PE, and failure to treat PE. The complaint alleged that had the standard of care been followed, CR would not have died postoperatively and would otherwise have had a normal life expectancy.

Scientific principles:

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi and Tiziano Gherli/Creative Commons License

Orthopedic surgery patients are known to be at high risk for venous thromboembolism. In the absence of prophylaxis, postoperative PE is common and often a fatal disease. Nonetheless, even without prophylaxis, mortality from PE can be reduced by prompt diagnosis and therapy. Unfortunately, the clinical presentation of PE is variable and nonspecific; thus, diagnostic testing is necessary before confirming or excluding the diagnosis of PE. The diagnostic approach includes algorithms designed to efficiently diagnose PE while simultaneously avoiding unnecessary testing and minimizing the risk of missing clinically important cases. While there is consensus regarding the need for algorithms, there is no agreed-upon best approach.

Complaint rebuttal and discussion:

The defense responded that the first item in the complaint was baseless as the surgeon ordered both mechanical and low-molecular weight heparin prophylaxis for DVT. The plaintiff experts agreed and the surgeon was dismissed from the case prior to trial. The focus of the case was now on Dr. Hospitalist and his failure to diagnose and treat PE.

 

Dr. Hospitalist defended himself by arguing that CR suffered a sudden fatal PE on the day of his death despite appropriate prophylaxis and that the “dizziness” the prior day was unrelated. The defense explained that the day prior to his death, CR was simply orthostatic from his postanesthesia state, combined with opiate analgesics, and any hypoxia was from CR’s preexisting COPD.

Plaintiff experts replied that CR had virtually no symptoms for a COPD exacerbation (i.e., no cough, no sputum production), and there was no explanation for the elevated troponin other than PE. Plaintiff experts further alleged that Dr. Hospitalist failed to incorporate an algorithm, such as the modified Wells’ Criteria, into his diagnostic approach for PE. Had he done so, Dr. Hospitalist would have recognized that CR had a high enough clinical probability for PE to warrant empiric treatment and confirmatory testing. The defense responded that the use of the modified Wells’ Criteria was nothing but an arcane “academic” exercise that did not match real clinical practice.

Conclusion:

Acute pulmonary embolism is a well-known postoperative pulmonary complication. The diagnosis must be considered in any surgical patient that has postoperative shortness of breath or unexplained hypoxia. The importance of using an algorithm to determine the need for testing and treatment cannot be understated. In this case, the PE diagnosis was considered but no algorithm was used. The jury in this case deliberated for more than a day, but ultimately returned a full defense verdict.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Medicolegal review has the opportunity to become the morbidity and mortality conference of the modern era. The more we share in our collective failures, the less likely we are to repeat those same mistakes.

CR was a 69-year-old man who presented to the hospital for an elective total knee revision. He had a past medical history of obesity, hypertension, and chronic obstructive pulmonary disease (COPD).

Two weeks prior to the surgery, he received preoperative clearance from his primary care physician. CR had a morning surgery that went well and was without complication. He was transferred to the postanesthesia care unit in good condition with normal oxygen saturations on 2L of oxygen by nasal cannula. His postoperative orders included a routine hospitalist consultation for “medical management,” along with orders for daily low-molecular weight heparin for deep vein thrombosis (DVT) prophylaxis. CR arrived to the orthopedic floor later that afternoon. He did well overnight, and the next morning, he began working with physical therapy. After doing some exercises in the bed, CR had his oxygen removed so that he could ambulate. While up with the physical therapist, CR reported feeling “dizzy.” A chair was brought up behind him so that he could sit down. His oxygen saturation was 88%. CR was placed back on 2L of oxygen, but as he transferred from the chair to the bed his oxygen saturation fell further to 81%. CR had his oxygen increased to 3L and over the next half-hour, his oxygen saturation came up and stayed above 92%.

Dr. Hospitalist met CR about an hour after he worked with physical therapy. CR was without complaints at the time of the evaluation and had good oxygen saturations on 3L of oxygen. Dr. Hospitalist documented that CR denied chest pain, cough, or sputum production. On auscultation, CR had a scattered wheeze. Dr. Hospitalist dictated that his differential diagnosis included pulmonary embolism (PE). He ordered bronchodilator aerosols, a chest radiograph, a troponin and a brain natriuretic peptide (BNP) level. The chest radiograph was performed that afternoon and interpreted as “no acute process,” with no evidence for atelectasis.

Overnight, CR remained on oxygen via nasal cannula. The following morning his nurse noted that CR had bilateral edema in his legs. The labs ordered by Dr. Hospitalist the previous day were now in the chart – the troponin was 0.07 ng/mL (normal < 0.04 ng/ml) and the BNP was 205 pg/mL.

At 11 a.m., CR was again seen by physical therapy. While ambulating in his room, CR began to feel “dizzy” despite the use of oxygen, and he passed out falling to his knees. The therapist and several nurses got him back to a chair and increased his oxygen. He spontaneously regained consciousness, but within a few minutes CR passed out a second time and lost his pulse. Dr. Hospitalist and the surgeon responded to the code. He was unable to be resuscitated and was pronounced dead. An autopsy was performed and determined the cause of death to be massive saddle pulmonary embolism (PE).

Complaint:

A complaint was filed against the hospital, the surgeon, and Dr. Hospitalist for failure to prevent DVT, failure to diagnose PE, and failure to treat PE. The complaint alleged that had the standard of care been followed, CR would not have died postoperatively and would otherwise have had a normal life expectancy.

Scientific principles:

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi and Tiziano Gherli/Creative Commons License

Orthopedic surgery patients are known to be at high risk for venous thromboembolism. In the absence of prophylaxis, postoperative PE is common and often a fatal disease. Nonetheless, even without prophylaxis, mortality from PE can be reduced by prompt diagnosis and therapy. Unfortunately, the clinical presentation of PE is variable and nonspecific; thus, diagnostic testing is necessary before confirming or excluding the diagnosis of PE. The diagnostic approach includes algorithms designed to efficiently diagnose PE while simultaneously avoiding unnecessary testing and minimizing the risk of missing clinically important cases. While there is consensus regarding the need for algorithms, there is no agreed-upon best approach.

Complaint rebuttal and discussion:

The defense responded that the first item in the complaint was baseless as the surgeon ordered both mechanical and low-molecular weight heparin prophylaxis for DVT. The plaintiff experts agreed and the surgeon was dismissed from the case prior to trial. The focus of the case was now on Dr. Hospitalist and his failure to diagnose and treat PE.

 

Dr. Hospitalist defended himself by arguing that CR suffered a sudden fatal PE on the day of his death despite appropriate prophylaxis and that the “dizziness” the prior day was unrelated. The defense explained that the day prior to his death, CR was simply orthostatic from his postanesthesia state, combined with opiate analgesics, and any hypoxia was from CR’s preexisting COPD.

Plaintiff experts replied that CR had virtually no symptoms for a COPD exacerbation (i.e., no cough, no sputum production), and there was no explanation for the elevated troponin other than PE. Plaintiff experts further alleged that Dr. Hospitalist failed to incorporate an algorithm, such as the modified Wells’ Criteria, into his diagnostic approach for PE. Had he done so, Dr. Hospitalist would have recognized that CR had a high enough clinical probability for PE to warrant empiric treatment and confirmatory testing. The defense responded that the use of the modified Wells’ Criteria was nothing but an arcane “academic” exercise that did not match real clinical practice.

Conclusion:

Acute pulmonary embolism is a well-known postoperative pulmonary complication. The diagnosis must be considered in any surgical patient that has postoperative shortness of breath or unexplained hypoxia. The importance of using an algorithm to determine the need for testing and treatment cannot be understated. In this case, the PE diagnosis was considered but no algorithm was used. The jury in this case deliberated for more than a day, but ultimately returned a full defense verdict.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Medicolegal review has the opportunity to become the morbidity and mortality conference of the modern era. The more we share in our collective failures, the less likely we are to repeat those same mistakes.

CR was a 69-year-old man who presented to the hospital for an elective total knee revision. He had a past medical history of obesity, hypertension, and chronic obstructive pulmonary disease (COPD).

Two weeks prior to the surgery, he received preoperative clearance from his primary care physician. CR had a morning surgery that went well and was without complication. He was transferred to the postanesthesia care unit in good condition with normal oxygen saturations on 2L of oxygen by nasal cannula. His postoperative orders included a routine hospitalist consultation for “medical management,” along with orders for daily low-molecular weight heparin for deep vein thrombosis (DVT) prophylaxis. CR arrived to the orthopedic floor later that afternoon. He did well overnight, and the next morning, he began working with physical therapy. After doing some exercises in the bed, CR had his oxygen removed so that he could ambulate. While up with the physical therapist, CR reported feeling “dizzy.” A chair was brought up behind him so that he could sit down. His oxygen saturation was 88%. CR was placed back on 2L of oxygen, but as he transferred from the chair to the bed his oxygen saturation fell further to 81%. CR had his oxygen increased to 3L and over the next half-hour, his oxygen saturation came up and stayed above 92%.

Dr. Hospitalist met CR about an hour after he worked with physical therapy. CR was without complaints at the time of the evaluation and had good oxygen saturations on 3L of oxygen. Dr. Hospitalist documented that CR denied chest pain, cough, or sputum production. On auscultation, CR had a scattered wheeze. Dr. Hospitalist dictated that his differential diagnosis included pulmonary embolism (PE). He ordered bronchodilator aerosols, a chest radiograph, a troponin and a brain natriuretic peptide (BNP) level. The chest radiograph was performed that afternoon and interpreted as “no acute process,” with no evidence for atelectasis.

Overnight, CR remained on oxygen via nasal cannula. The following morning his nurse noted that CR had bilateral edema in his legs. The labs ordered by Dr. Hospitalist the previous day were now in the chart – the troponin was 0.07 ng/mL (normal < 0.04 ng/ml) and the BNP was 205 pg/mL.

At 11 a.m., CR was again seen by physical therapy. While ambulating in his room, CR began to feel “dizzy” despite the use of oxygen, and he passed out falling to his knees. The therapist and several nurses got him back to a chair and increased his oxygen. He spontaneously regained consciousness, but within a few minutes CR passed out a second time and lost his pulse. Dr. Hospitalist and the surgeon responded to the code. He was unable to be resuscitated and was pronounced dead. An autopsy was performed and determined the cause of death to be massive saddle pulmonary embolism (PE).

Complaint:

A complaint was filed against the hospital, the surgeon, and Dr. Hospitalist for failure to prevent DVT, failure to diagnose PE, and failure to treat PE. The complaint alleged that had the standard of care been followed, CR would not have died postoperatively and would otherwise have had a normal life expectancy.

Scientific principles:

Courtesy Wikimedia Commons/Walter Serra, Giuseppe De Iaco, Claudio Reverberi and Tiziano Gherli/Creative Commons License

Orthopedic surgery patients are known to be at high risk for venous thromboembolism. In the absence of prophylaxis, postoperative PE is common and often a fatal disease. Nonetheless, even without prophylaxis, mortality from PE can be reduced by prompt diagnosis and therapy. Unfortunately, the clinical presentation of PE is variable and nonspecific; thus, diagnostic testing is necessary before confirming or excluding the diagnosis of PE. The diagnostic approach includes algorithms designed to efficiently diagnose PE while simultaneously avoiding unnecessary testing and minimizing the risk of missing clinically important cases. While there is consensus regarding the need for algorithms, there is no agreed-upon best approach.

Complaint rebuttal and discussion:

The defense responded that the first item in the complaint was baseless as the surgeon ordered both mechanical and low-molecular weight heparin prophylaxis for DVT. The plaintiff experts agreed and the surgeon was dismissed from the case prior to trial. The focus of the case was now on Dr. Hospitalist and his failure to diagnose and treat PE.

 

Dr. Hospitalist defended himself by arguing that CR suffered a sudden fatal PE on the day of his death despite appropriate prophylaxis and that the “dizziness” the prior day was unrelated. The defense explained that the day prior to his death, CR was simply orthostatic from his postanesthesia state, combined with opiate analgesics, and any hypoxia was from CR’s preexisting COPD.

Plaintiff experts replied that CR had virtually no symptoms for a COPD exacerbation (i.e., no cough, no sputum production), and there was no explanation for the elevated troponin other than PE. Plaintiff experts further alleged that Dr. Hospitalist failed to incorporate an algorithm, such as the modified Wells’ Criteria, into his diagnostic approach for PE. Had he done so, Dr. Hospitalist would have recognized that CR had a high enough clinical probability for PE to warrant empiric treatment and confirmatory testing. The defense responded that the use of the modified Wells’ Criteria was nothing but an arcane “academic” exercise that did not match real clinical practice.

Conclusion:

Acute pulmonary embolism is a well-known postoperative pulmonary complication. The diagnosis must be considered in any surgical patient that has postoperative shortness of breath or unexplained hypoxia. The importance of using an algorithm to determine the need for testing and treatment cannot be understated. In this case, the PE diagnosis was considered but no algorithm was used. The jury in this case deliberated for more than a day, but ultimately returned a full defense verdict.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

The story

SJ was a 66-year-old woman with a history of ulcerative colitis (UC) who was recently status post laparoscopic proctocolectomy with ileoanal J pouch and diverting ileostomy 2 weeks ago at Hospital A. At the time of her surgical discharge, she was tolerating an oral diet, but over the next 2 weeks her oral intake declined, she reported feeling light-headed with movement, and she had an increase in abdominal pain despite oral analgesia. SJ was at her surgical follow-up appointment when she passed out in the waiting room. She awoke spontaneously, but she was hypotensive and was taken by ambulance to the emergency room of Hospital B. On examination SJ was very orthostatic. She had blood drawn, and she had an ECG, an abdominal radiograph, and a CT scan of the abdomen and pelvis performed. Her ECG and abdominal imaging were unremarkable. She was found to have an elevated lipase (910 U/dL) and low hemoglobin (9.9 mg/dL), although her anemia was not significantly different from 2 weeks ago. SJ was sent from Hospital B to Hospital C and admitted by Dr. Hospitalist 1 (nighttime, weekend coverage) for dehydration and possible pancreatitis. Dr. Hospitalist 1 initiated intravenous fluids and ordered an ultrasound of the abdomen. Intermittent pneumatic compression devices were ordered for deep vein thrombosis prophylaxis.

The following morning, SJ was seen by Dr. Hospitalist 2 (daytime, weekend coverage). On examination, SJ was noted to have bilateral lower extremity edema. She remained orthostatic despite several liters of saline. Dr. Hospitalist 2 ordered a CT scan of the chest with a PE protocol along with ultrasonography of the legs. SJ’s morning hemoglobin was 8.4 mg/dL and Dr. Hospitalist 2 ordered a blood transfusion. The results of the imaging returned the next day and both the CT and lower extremity ultrasounds were normal. However, the abdominal ultrasound ordered by Dr. Hospitalist 1 incidentally identified an inferior vena cava filter (IVCF) with a small amount of adherent clot.

The next day, SJ was seen by Dr. Hospitalist 3 (daytime, weekday attending). SJ’s hemoglobin was now 10.4 mg/dL and her lipase was normal. Dr. Hospitalist 3 documented that SJ was doing “better,” and that the plan was to wean IV fluids, work with physical therapy, and discharge soon. But SJ continued to complain of abdominal tightness, burning in her legs, and light-headedness with activity. On hospital day 4, Dr. Hospitalist 3 ordered oral antibiotics for possible leg cellulitis. On hospital day 5, SJ passed out briefly during physical therapy and Dr. Hospitalist 3 increased her IV fluids. Over the next 3 days, Dr. Hospitalist 3 stopped and restarted the IV fluids several times.

On hospital day 8, SJ was seen by Dr. Hospitalist 4 (daytime, weekend coverage). SJ remained orthostatic. Dr. Hospitalist 4 ordered a CT of the abdomen to evaluate the IVCF, which identified thrombus material within the IVCF and the entire caudal vena cava, iliac, and femoral vessels. Full-dose anticoagulation was initiated with low-molecular-weight heparin. On hospital day 10, SJ collapsed in physical therapy and lost her pulse. A full code blue response, including systemic TPA administration, failed to revive her and she was pronounced dead. An autopsy was performed and determined pulmonary embolism as the cause of death.

Complaint

SJ’s husband had difficulty reconciling the fact that SJ died so recently after her surgical discharge and that she had been considered “well on her way” to a full recovery. The case was referred to an attorney and subsequent review supported medical negligence and a complaint was filed. The complaint alleged that the Hospitalists (specifically 1, 2, and 3) failed to recognize SJ’s increased risk for thrombosis, failed to diagnose her IVC obstruction, and failed to initiate appropriate treatment in the form of therapeutic anticoagulation. Had the standard of care been followed, the complaint alleged, SJ would not have died.

Scientific principles

Courtesy Wikimedia Commons/BozMo/Creative Commons License

Inferior vena cava obstruction has been reported in 3%-30% of patients following IVC filter placement related to new local thrombus formation, thrombogenicity of the device, trapped embolus, or extension of a more distal DVT cephalad. Patients with inferior vena caval thrombosis (IVCT) may present with a spectrum of signs and symptoms and this variability is a significant part of the challenge of diagnosis. The classic presentation of IVCT includes bilateral lower extremity edema with dilated, visible superficial abdominal veins.

Complaint rebuttal and discussion

The Hospitalists defended themselves by providing reasonable alternatives to the actual diagnosis. SJ had a new ileostomy and orthostasis is common in such patients. Yet SJ did not have documented high stoma outputs and her electrolytes and renal function were inconsistent with hypovolemia.

 

Defense experts also pointed to SJ’s anemia and orthostasis and opined that anticoagulation would be contraindicated until hemorrhage could be ruled out. Yet SJ’s anemia was not significantly different from her surgical discharge and SJ was on anticoagulant DVT prophylaxis her entire surgical hospitalization with even lower levels of hemoglobin.

Plaintiff experts asserted that the Hospitalists should have contacted SJ’s colorectal surgeon if they were reluctant to use anticoagulants to further inform the risks and benefits. Ultimately, the defense had little explanation for the Hospitalists’ collective failure to follow-up on the abdominal ultrasound that demonstrated a small amount of adherent clot.

Conclusion

SJ was at two different hospitals and had four different Hospitalist s in 10 days.

Dr. Hospitalist 1 never saw the radiology films from Hospital B that showed an IVCF. When Dr. Hospitalist 2 began caring for SJ, he was unaware that SJ even had an IVCF or that she had a prior history of PE. Over the weekend, Dr. Hospitalist 2 did not access the labs from Hospital A to see if SJ’s anemia was new or not. Dr. Hospitalist 3 did not know that Dr. Hospitalist 1 ordered an abdominal ultrasound on admission and because the result was not flagged as “abnormal” the small adherent clot on the IVCF was not integrated into SJ’s clinical presentation.

All Hospitalist groups struggle to provide continuity in a system of discontinuity. In this case, important details were missed and it led to a delay in diagnosis and ultimately treatment.

This case was settled for an undisclosed amount on behalf of the plaintiff.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

The story

SJ was a 66-year-old woman with a history of ulcerative colitis (UC) who was recently status post laparoscopic proctocolectomy with ileoanal J pouch and diverting ileostomy 2 weeks ago at Hospital A. At the time of her surgical discharge, she was tolerating an oral diet, but over the next 2 weeks her oral intake declined, she reported feeling light-headed with movement, and she had an increase in abdominal pain despite oral analgesia. SJ was at her surgical follow-up appointment when she passed out in the waiting room. She awoke spontaneously, but she was hypotensive and was taken by ambulance to the emergency room of Hospital B. On examination SJ was very orthostatic. She had blood drawn, and she had an ECG, an abdominal radiograph, and a CT scan of the abdomen and pelvis performed. Her ECG and abdominal imaging were unremarkable. She was found to have an elevated lipase (910 U/dL) and low hemoglobin (9.9 mg/dL), although her anemia was not significantly different from 2 weeks ago. SJ was sent from Hospital B to Hospital C and admitted by Dr. Hospitalist 1 (nighttime, weekend coverage) for dehydration and possible pancreatitis. Dr. Hospitalist 1 initiated intravenous fluids and ordered an ultrasound of the abdomen. Intermittent pneumatic compression devices were ordered for deep vein thrombosis prophylaxis.

The following morning, SJ was seen by Dr. Hospitalist 2 (daytime, weekend coverage). On examination, SJ was noted to have bilateral lower extremity edema. She remained orthostatic despite several liters of saline. Dr. Hospitalist 2 ordered a CT scan of the chest with a PE protocol along with ultrasonography of the legs. SJ’s morning hemoglobin was 8.4 mg/dL and Dr. Hospitalist 2 ordered a blood transfusion. The results of the imaging returned the next day and both the CT and lower extremity ultrasounds were normal. However, the abdominal ultrasound ordered by Dr. Hospitalist 1 incidentally identified an inferior vena cava filter (IVCF) with a small amount of adherent clot.

The next day, SJ was seen by Dr. Hospitalist 3 (daytime, weekday attending). SJ’s hemoglobin was now 10.4 mg/dL and her lipase was normal. Dr. Hospitalist 3 documented that SJ was doing “better,” and that the plan was to wean IV fluids, work with physical therapy, and discharge soon. But SJ continued to complain of abdominal tightness, burning in her legs, and light-headedness with activity. On hospital day 4, Dr. Hospitalist 3 ordered oral antibiotics for possible leg cellulitis. On hospital day 5, SJ passed out briefly during physical therapy and Dr. Hospitalist 3 increased her IV fluids. Over the next 3 days, Dr. Hospitalist 3 stopped and restarted the IV fluids several times.

On hospital day 8, SJ was seen by Dr. Hospitalist 4 (daytime, weekend coverage). SJ remained orthostatic. Dr. Hospitalist 4 ordered a CT of the abdomen to evaluate the IVCF, which identified thrombus material within the IVCF and the entire caudal vena cava, iliac, and femoral vessels. Full-dose anticoagulation was initiated with low-molecular-weight heparin. On hospital day 10, SJ collapsed in physical therapy and lost her pulse. A full code blue response, including systemic TPA administration, failed to revive her and she was pronounced dead. An autopsy was performed and determined pulmonary embolism as the cause of death.

Complaint

SJ’s husband had difficulty reconciling the fact that SJ died so recently after her surgical discharge and that she had been considered “well on her way” to a full recovery. The case was referred to an attorney and subsequent review supported medical negligence and a complaint was filed. The complaint alleged that the Hospitalists (specifically 1, 2, and 3) failed to recognize SJ’s increased risk for thrombosis, failed to diagnose her IVC obstruction, and failed to initiate appropriate treatment in the form of therapeutic anticoagulation. Had the standard of care been followed, the complaint alleged, SJ would not have died.

Scientific principles

Courtesy Wikimedia Commons/BozMo/Creative Commons License

Inferior vena cava obstruction has been reported in 3%-30% of patients following IVC filter placement related to new local thrombus formation, thrombogenicity of the device, trapped embolus, or extension of a more distal DVT cephalad. Patients with inferior vena caval thrombosis (IVCT) may present with a spectrum of signs and symptoms and this variability is a significant part of the challenge of diagnosis. The classic presentation of IVCT includes bilateral lower extremity edema with dilated, visible superficial abdominal veins.

Complaint rebuttal and discussion

The Hospitalists defended themselves by providing reasonable alternatives to the actual diagnosis. SJ had a new ileostomy and orthostasis is common in such patients. Yet SJ did not have documented high stoma outputs and her electrolytes and renal function were inconsistent with hypovolemia.

 

Defense experts also pointed to SJ’s anemia and orthostasis and opined that anticoagulation would be contraindicated until hemorrhage could be ruled out. Yet SJ’s anemia was not significantly different from her surgical discharge and SJ was on anticoagulant DVT prophylaxis her entire surgical hospitalization with even lower levels of hemoglobin.

Plaintiff experts asserted that the Hospitalists should have contacted SJ’s colorectal surgeon if they were reluctant to use anticoagulants to further inform the risks and benefits. Ultimately, the defense had little explanation for the Hospitalists’ collective failure to follow-up on the abdominal ultrasound that demonstrated a small amount of adherent clot.

Conclusion

SJ was at two different hospitals and had four different Hospitalist s in 10 days.

Dr. Hospitalist 1 never saw the radiology films from Hospital B that showed an IVCF. When Dr. Hospitalist 2 began caring for SJ, he was unaware that SJ even had an IVCF or that she had a prior history of PE. Over the weekend, Dr. Hospitalist 2 did not access the labs from Hospital A to see if SJ’s anemia was new or not. Dr. Hospitalist 3 did not know that Dr. Hospitalist 1 ordered an abdominal ultrasound on admission and because the result was not flagged as “abnormal” the small adherent clot on the IVCF was not integrated into SJ’s clinical presentation.

All Hospitalist groups struggle to provide continuity in a system of discontinuity. In this case, important details were missed and it led to a delay in diagnosis and ultimately treatment.

This case was settled for an undisclosed amount on behalf of the plaintiff.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

The story

SJ was a 66-year-old woman with a history of ulcerative colitis (UC) who was recently status post laparoscopic proctocolectomy with ileoanal J pouch and diverting ileostomy 2 weeks ago at Hospital A. At the time of her surgical discharge, she was tolerating an oral diet, but over the next 2 weeks her oral intake declined, she reported feeling light-headed with movement, and she had an increase in abdominal pain despite oral analgesia. SJ was at her surgical follow-up appointment when she passed out in the waiting room. She awoke spontaneously, but she was hypotensive and was taken by ambulance to the emergency room of Hospital B. On examination SJ was very orthostatic. She had blood drawn, and she had an ECG, an abdominal radiograph, and a CT scan of the abdomen and pelvis performed. Her ECG and abdominal imaging were unremarkable. She was found to have an elevated lipase (910 U/dL) and low hemoglobin (9.9 mg/dL), although her anemia was not significantly different from 2 weeks ago. SJ was sent from Hospital B to Hospital C and admitted by Dr. Hospitalist 1 (nighttime, weekend coverage) for dehydration and possible pancreatitis. Dr. Hospitalist 1 initiated intravenous fluids and ordered an ultrasound of the abdomen. Intermittent pneumatic compression devices were ordered for deep vein thrombosis prophylaxis.

The following morning, SJ was seen by Dr. Hospitalist 2 (daytime, weekend coverage). On examination, SJ was noted to have bilateral lower extremity edema. She remained orthostatic despite several liters of saline. Dr. Hospitalist 2 ordered a CT scan of the chest with a PE protocol along with ultrasonography of the legs. SJ’s morning hemoglobin was 8.4 mg/dL and Dr. Hospitalist 2 ordered a blood transfusion. The results of the imaging returned the next day and both the CT and lower extremity ultrasounds were normal. However, the abdominal ultrasound ordered by Dr. Hospitalist 1 incidentally identified an inferior vena cava filter (IVCF) with a small amount of adherent clot.

The next day, SJ was seen by Dr. Hospitalist 3 (daytime, weekday attending). SJ’s hemoglobin was now 10.4 mg/dL and her lipase was normal. Dr. Hospitalist 3 documented that SJ was doing “better,” and that the plan was to wean IV fluids, work with physical therapy, and discharge soon. But SJ continued to complain of abdominal tightness, burning in her legs, and light-headedness with activity. On hospital day 4, Dr. Hospitalist 3 ordered oral antibiotics for possible leg cellulitis. On hospital day 5, SJ passed out briefly during physical therapy and Dr. Hospitalist 3 increased her IV fluids. Over the next 3 days, Dr. Hospitalist 3 stopped and restarted the IV fluids several times.

On hospital day 8, SJ was seen by Dr. Hospitalist 4 (daytime, weekend coverage). SJ remained orthostatic. Dr. Hospitalist 4 ordered a CT of the abdomen to evaluate the IVCF, which identified thrombus material within the IVCF and the entire caudal vena cava, iliac, and femoral vessels. Full-dose anticoagulation was initiated with low-molecular-weight heparin. On hospital day 10, SJ collapsed in physical therapy and lost her pulse. A full code blue response, including systemic TPA administration, failed to revive her and she was pronounced dead. An autopsy was performed and determined pulmonary embolism as the cause of death.

Complaint

SJ’s husband had difficulty reconciling the fact that SJ died so recently after her surgical discharge and that she had been considered “well on her way” to a full recovery. The case was referred to an attorney and subsequent review supported medical negligence and a complaint was filed. The complaint alleged that the Hospitalists (specifically 1, 2, and 3) failed to recognize SJ’s increased risk for thrombosis, failed to diagnose her IVC obstruction, and failed to initiate appropriate treatment in the form of therapeutic anticoagulation. Had the standard of care been followed, the complaint alleged, SJ would not have died.

Scientific principles

Courtesy Wikimedia Commons/BozMo/Creative Commons License

Inferior vena cava obstruction has been reported in 3%-30% of patients following IVC filter placement related to new local thrombus formation, thrombogenicity of the device, trapped embolus, or extension of a more distal DVT cephalad. Patients with inferior vena caval thrombosis (IVCT) may present with a spectrum of signs and symptoms and this variability is a significant part of the challenge of diagnosis. The classic presentation of IVCT includes bilateral lower extremity edema with dilated, visible superficial abdominal veins.

Complaint rebuttal and discussion

The Hospitalists defended themselves by providing reasonable alternatives to the actual diagnosis. SJ had a new ileostomy and orthostasis is common in such patients. Yet SJ did not have documented high stoma outputs and her electrolytes and renal function were inconsistent with hypovolemia.

 

Defense experts also pointed to SJ’s anemia and orthostasis and opined that anticoagulation would be contraindicated until hemorrhage could be ruled out. Yet SJ’s anemia was not significantly different from her surgical discharge and SJ was on anticoagulant DVT prophylaxis her entire surgical hospitalization with even lower levels of hemoglobin.

Plaintiff experts asserted that the Hospitalists should have contacted SJ’s colorectal surgeon if they were reluctant to use anticoagulants to further inform the risks and benefits. Ultimately, the defense had little explanation for the Hospitalists’ collective failure to follow-up on the abdominal ultrasound that demonstrated a small amount of adherent clot.

Conclusion

SJ was at two different hospitals and had four different Hospitalist s in 10 days.

Dr. Hospitalist 1 never saw the radiology films from Hospital B that showed an IVCF. When Dr. Hospitalist 2 began caring for SJ, he was unaware that SJ even had an IVCF or that she had a prior history of PE. Over the weekend, Dr. Hospitalist 2 did not access the labs from Hospital A to see if SJ’s anemia was new or not. Dr. Hospitalist 3 did not know that Dr. Hospitalist 1 ordered an abdominal ultrasound on admission and because the result was not flagged as “abnormal” the small adherent clot on the IVCF was not integrated into SJ’s clinical presentation.

All Hospitalist groups struggle to provide continuity in a system of discontinuity. In this case, important details were missed and it led to a delay in diagnosis and ultimately treatment.

This case was settled for an undisclosed amount on behalf of the plaintiff.

Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at eHospitalist news.com/Lessons.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.