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Sorafenib Results Mixed For Advanced Melanoma
CHICAGO The first two randomized trials to assess the addition of sorafenib to chemotherapy for advanced melanoma exhibited mixed results, according to presentations at the annual meeting of the American Society of Clinical Oncology.
A randomized, 17-center, phase II study of 101 chemotherapy-naive patients showed a 50% improvement in progression-free survival and a 62% improvement in time to progression when sorafenib (Nexavar) was added to dacarbazine (DTIC-Dome) compared with dacarbazine plus placebo.
Improved progression-free survival did not translate into a survival benefit, however. "At our last analysis, 65 of 101 patients had died, and there was no difference in median survival between the two study arms," said Dr. David F. McDermott, clinical director of the biologic therapy program at Beth Israel Deaconess Medical Center in Boston.
The second study, the 270-patient, phase III Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial, tested paclitaxel plus carboplatin with or without sorafenib as second-line treatment. The trial produced negative results. Dr. Sanjiv S. Agarwala, chief of medical oncology at St. Luke's Cancer Center in Bethlehem, Pa., reported that sorafenib failed to improve progression-free survival, tumor response rates, or time-to-disease progression in metastatic melanoma patients, whose disease had progressed on a chemotherapy regimen containing dacarbazine or temozolomide (Temodal).
In his discussion of the two trials, Dr. Keith Flaherty said that although the trials had mixed results, the 6-month progression-free survival rate of 41% in the study by Dr. McDermott and colleagues "is truly the high water mark of what we've achieved to date … at least when focusing on this end point." These gains were achieved at a toxicity cost deemed "not unacceptable" by Dr. Flaherty of the division of hematology-oncology at the University of Pennsylvania Health System in Philadelphia.
The multicenter trial by Dr. Agarwala and colleagues did manage to produce data showing that the carboplatin-paclitaxel combination is "relatively active" in patients who have failed front-line chemotherapy containing dacarbazine or temozolomide, according to Dr. Flaherty. "The roughly 30% progression-free survival rate at 6 months is a number that many of us in the field believe is a sign of activity," he said.
"The front-line randomized phase II trial certainly suggests that sorafenib may be active in this setting, and I think the phase III study gives us enough evidence to say that carboplatin-paclitaxel control arm therapy is a perfectly reasonable therapy to offer patients," Dr. Flaherty concluded.
In the dacarbazine with or without sorafenib study, Dr. McDermott and his associates randomized 101 good performance status patients to receive either dacarbazine at 1,000 mg/m2 on day 1 in combination with oral sorafenib 400 mg twice daily, or dacarbazine at 1,000 mg/m2 on day 1 and two placebo tablets twice daily. Tumors were assessed at baseline and every 6 weeks, and treatment was continued until progression or intolerable toxicity.
Dose reductions due to adverse events (including grades 3 and 4 thrombocytopenia, neutropenia, nausea, and CNS hemorrhage) were more common in the sorafenib arm.
"All these toxicities were reversible, and there were no treatment-related deaths. Sorafenib-associated hand-foot syndrome, rash, hypertension, and elevated lipase [were] not greater than [have] been reported in earlier sorafenib trials," Dr. McDermott said.
The 270 chemotherapy-refractory patients in the PRISM trial had stage IV or unresectable stage III melanoma. Half were randomized to receive paclitaxel 225 mg/m2 and carboplatin AUC = 6 on day 1 every 3 weeks plus oral sorafenib 400 mg twice daily on days 2 to 19 every 3 weeks. The other half received the paclitaxel-carboplatin regimen plus an oral placebo. Both groups continued treatment until disease progression or intolerable toxicity.
The difference in progression-free survival between the sorafenib plus chemotherapy and sorafenib plus placebo arms was insignificant at 17.4 weeks and 17.9 weeks, respectively, and there were no tumor responses in either arm, according to Dr. Agarwala.
Neutropenia affected nearly half of patients similarly in both arms, while thrombocytopenia, diarrhea, hand-foot reactions, and rash were higher with sorafenib.
Both trials were sponsored by Bayer, which markets sorafenib. The ongoing Eastern Oncology Cooperative Group trial E2603 is evaluating the same regimen studied by Dr. Agarwala and colleagues in a larger patient population with unresectable locally advanced or stage IV melanoma.
CHICAGO The first two randomized trials to assess the addition of sorafenib to chemotherapy for advanced melanoma exhibited mixed results, according to presentations at the annual meeting of the American Society of Clinical Oncology.
A randomized, 17-center, phase II study of 101 chemotherapy-naive patients showed a 50% improvement in progression-free survival and a 62% improvement in time to progression when sorafenib (Nexavar) was added to dacarbazine (DTIC-Dome) compared with dacarbazine plus placebo.
Improved progression-free survival did not translate into a survival benefit, however. "At our last analysis, 65 of 101 patients had died, and there was no difference in median survival between the two study arms," said Dr. David F. McDermott, clinical director of the biologic therapy program at Beth Israel Deaconess Medical Center in Boston.
The second study, the 270-patient, phase III Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial, tested paclitaxel plus carboplatin with or without sorafenib as second-line treatment. The trial produced negative results. Dr. Sanjiv S. Agarwala, chief of medical oncology at St. Luke's Cancer Center in Bethlehem, Pa., reported that sorafenib failed to improve progression-free survival, tumor response rates, or time-to-disease progression in metastatic melanoma patients, whose disease had progressed on a chemotherapy regimen containing dacarbazine or temozolomide (Temodal).
In his discussion of the two trials, Dr. Keith Flaherty said that although the trials had mixed results, the 6-month progression-free survival rate of 41% in the study by Dr. McDermott and colleagues "is truly the high water mark of what we've achieved to date … at least when focusing on this end point." These gains were achieved at a toxicity cost deemed "not unacceptable" by Dr. Flaherty of the division of hematology-oncology at the University of Pennsylvania Health System in Philadelphia.
The multicenter trial by Dr. Agarwala and colleagues did manage to produce data showing that the carboplatin-paclitaxel combination is "relatively active" in patients who have failed front-line chemotherapy containing dacarbazine or temozolomide, according to Dr. Flaherty. "The roughly 30% progression-free survival rate at 6 months is a number that many of us in the field believe is a sign of activity," he said.
"The front-line randomized phase II trial certainly suggests that sorafenib may be active in this setting, and I think the phase III study gives us enough evidence to say that carboplatin-paclitaxel control arm therapy is a perfectly reasonable therapy to offer patients," Dr. Flaherty concluded.
In the dacarbazine with or without sorafenib study, Dr. McDermott and his associates randomized 101 good performance status patients to receive either dacarbazine at 1,000 mg/m2 on day 1 in combination with oral sorafenib 400 mg twice daily, or dacarbazine at 1,000 mg/m2 on day 1 and two placebo tablets twice daily. Tumors were assessed at baseline and every 6 weeks, and treatment was continued until progression or intolerable toxicity.
Dose reductions due to adverse events (including grades 3 and 4 thrombocytopenia, neutropenia, nausea, and CNS hemorrhage) were more common in the sorafenib arm.
"All these toxicities were reversible, and there were no treatment-related deaths. Sorafenib-associated hand-foot syndrome, rash, hypertension, and elevated lipase [were] not greater than [have] been reported in earlier sorafenib trials," Dr. McDermott said.
The 270 chemotherapy-refractory patients in the PRISM trial had stage IV or unresectable stage III melanoma. Half were randomized to receive paclitaxel 225 mg/m2 and carboplatin AUC = 6 on day 1 every 3 weeks plus oral sorafenib 400 mg twice daily on days 2 to 19 every 3 weeks. The other half received the paclitaxel-carboplatin regimen plus an oral placebo. Both groups continued treatment until disease progression or intolerable toxicity.
The difference in progression-free survival between the sorafenib plus chemotherapy and sorafenib plus placebo arms was insignificant at 17.4 weeks and 17.9 weeks, respectively, and there were no tumor responses in either arm, according to Dr. Agarwala.
Neutropenia affected nearly half of patients similarly in both arms, while thrombocytopenia, diarrhea, hand-foot reactions, and rash were higher with sorafenib.
Both trials were sponsored by Bayer, which markets sorafenib. The ongoing Eastern Oncology Cooperative Group trial E2603 is evaluating the same regimen studied by Dr. Agarwala and colleagues in a larger patient population with unresectable locally advanced or stage IV melanoma.
CHICAGO The first two randomized trials to assess the addition of sorafenib to chemotherapy for advanced melanoma exhibited mixed results, according to presentations at the annual meeting of the American Society of Clinical Oncology.
A randomized, 17-center, phase II study of 101 chemotherapy-naive patients showed a 50% improvement in progression-free survival and a 62% improvement in time to progression when sorafenib (Nexavar) was added to dacarbazine (DTIC-Dome) compared with dacarbazine plus placebo.
Improved progression-free survival did not translate into a survival benefit, however. "At our last analysis, 65 of 101 patients had died, and there was no difference in median survival between the two study arms," said Dr. David F. McDermott, clinical director of the biologic therapy program at Beth Israel Deaconess Medical Center in Boston.
The second study, the 270-patient, phase III Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial, tested paclitaxel plus carboplatin with or without sorafenib as second-line treatment. The trial produced negative results. Dr. Sanjiv S. Agarwala, chief of medical oncology at St. Luke's Cancer Center in Bethlehem, Pa., reported that sorafenib failed to improve progression-free survival, tumor response rates, or time-to-disease progression in metastatic melanoma patients, whose disease had progressed on a chemotherapy regimen containing dacarbazine or temozolomide (Temodal).
In his discussion of the two trials, Dr. Keith Flaherty said that although the trials had mixed results, the 6-month progression-free survival rate of 41% in the study by Dr. McDermott and colleagues "is truly the high water mark of what we've achieved to date … at least when focusing on this end point." These gains were achieved at a toxicity cost deemed "not unacceptable" by Dr. Flaherty of the division of hematology-oncology at the University of Pennsylvania Health System in Philadelphia.
The multicenter trial by Dr. Agarwala and colleagues did manage to produce data showing that the carboplatin-paclitaxel combination is "relatively active" in patients who have failed front-line chemotherapy containing dacarbazine or temozolomide, according to Dr. Flaherty. "The roughly 30% progression-free survival rate at 6 months is a number that many of us in the field believe is a sign of activity," he said.
"The front-line randomized phase II trial certainly suggests that sorafenib may be active in this setting, and I think the phase III study gives us enough evidence to say that carboplatin-paclitaxel control arm therapy is a perfectly reasonable therapy to offer patients," Dr. Flaherty concluded.
In the dacarbazine with or without sorafenib study, Dr. McDermott and his associates randomized 101 good performance status patients to receive either dacarbazine at 1,000 mg/m2 on day 1 in combination with oral sorafenib 400 mg twice daily, or dacarbazine at 1,000 mg/m2 on day 1 and two placebo tablets twice daily. Tumors were assessed at baseline and every 6 weeks, and treatment was continued until progression or intolerable toxicity.
Dose reductions due to adverse events (including grades 3 and 4 thrombocytopenia, neutropenia, nausea, and CNS hemorrhage) were more common in the sorafenib arm.
"All these toxicities were reversible, and there were no treatment-related deaths. Sorafenib-associated hand-foot syndrome, rash, hypertension, and elevated lipase [were] not greater than [have] been reported in earlier sorafenib trials," Dr. McDermott said.
The 270 chemotherapy-refractory patients in the PRISM trial had stage IV or unresectable stage III melanoma. Half were randomized to receive paclitaxel 225 mg/m2 and carboplatin AUC = 6 on day 1 every 3 weeks plus oral sorafenib 400 mg twice daily on days 2 to 19 every 3 weeks. The other half received the paclitaxel-carboplatin regimen plus an oral placebo. Both groups continued treatment until disease progression or intolerable toxicity.
The difference in progression-free survival between the sorafenib plus chemotherapy and sorafenib plus placebo arms was insignificant at 17.4 weeks and 17.9 weeks, respectively, and there were no tumor responses in either arm, according to Dr. Agarwala.
Neutropenia affected nearly half of patients similarly in both arms, while thrombocytopenia, diarrhea, hand-foot reactions, and rash were higher with sorafenib.
Both trials were sponsored by Bayer, which markets sorafenib. The ongoing Eastern Oncology Cooperative Group trial E2603 is evaluating the same regimen studied by Dr. Agarwala and colleagues in a larger patient population with unresectable locally advanced or stage IV melanoma.
Current Options in Stage IV Melanoma Deemed Unsatisfactory
AMSTERDAM Here's just how little progress has occurred in the systemic treatment of metastatic melanoma over the last 3 decades: Today the best therapeutic option for patients with advanced melanoma is to enroll them in a clinical trial of an investigational drug, Dr. Mark R. Middleton said at the 11th World Congress on Cancers of the Skin.
The standard treatment of advanced melanoma has for many years been single-agent dacarbazine (DTIC). None of the numerous multidrug combinations of chemotherapeutic agents or chemotherapeutic agents plus cytotoxic or biologic agents that have been tested have proved more effective than DTIC, only more toxic, he said.
Over the years, though, oncologists have come to realize that they have overestimated how good a drug DTIC is, said Dr. Middleton, a medical oncologist at Cancer Research UK and the University of Oxford (England).
Indeed, while decades-old studies suggested 20% of patients with advanced melanoma experience an objective tumor response to DTIC, more recent large multicenter studies indicate that the true figure is between 1 in 7 and 1 in 10, with no evidence DTIC offers any improvement over supportive care in terms of overall survival, he said at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
This discouraging assessment isn't just one oncologist's view. Dr. Alexander M.M. Eggermont noted during his presentation that the Dutch Cancer Society recently issued an advisory that the No. 1 option in patients with advanced melanoma is to enter them into any new drug development trial, even a phase I trial.
"So phase I studies are the preferred option in stage IV melanoma patients, rather than giving them the usual stuff. I think that's a very important message because that's really what we need to move the field forward," added Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands, and president-elect of the Federation of European Cancer Societies.
AMSTERDAM Here's just how little progress has occurred in the systemic treatment of metastatic melanoma over the last 3 decades: Today the best therapeutic option for patients with advanced melanoma is to enroll them in a clinical trial of an investigational drug, Dr. Mark R. Middleton said at the 11th World Congress on Cancers of the Skin.
The standard treatment of advanced melanoma has for many years been single-agent dacarbazine (DTIC). None of the numerous multidrug combinations of chemotherapeutic agents or chemotherapeutic agents plus cytotoxic or biologic agents that have been tested have proved more effective than DTIC, only more toxic, he said.
Over the years, though, oncologists have come to realize that they have overestimated how good a drug DTIC is, said Dr. Middleton, a medical oncologist at Cancer Research UK and the University of Oxford (England).
Indeed, while decades-old studies suggested 20% of patients with advanced melanoma experience an objective tumor response to DTIC, more recent large multicenter studies indicate that the true figure is between 1 in 7 and 1 in 10, with no evidence DTIC offers any improvement over supportive care in terms of overall survival, he said at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
This discouraging assessment isn't just one oncologist's view. Dr. Alexander M.M. Eggermont noted during his presentation that the Dutch Cancer Society recently issued an advisory that the No. 1 option in patients with advanced melanoma is to enter them into any new drug development trial, even a phase I trial.
"So phase I studies are the preferred option in stage IV melanoma patients, rather than giving them the usual stuff. I think that's a very important message because that's really what we need to move the field forward," added Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands, and president-elect of the Federation of European Cancer Societies.
AMSTERDAM Here's just how little progress has occurred in the systemic treatment of metastatic melanoma over the last 3 decades: Today the best therapeutic option for patients with advanced melanoma is to enroll them in a clinical trial of an investigational drug, Dr. Mark R. Middleton said at the 11th World Congress on Cancers of the Skin.
The standard treatment of advanced melanoma has for many years been single-agent dacarbazine (DTIC). None of the numerous multidrug combinations of chemotherapeutic agents or chemotherapeutic agents plus cytotoxic or biologic agents that have been tested have proved more effective than DTIC, only more toxic, he said.
Over the years, though, oncologists have come to realize that they have overestimated how good a drug DTIC is, said Dr. Middleton, a medical oncologist at Cancer Research UK and the University of Oxford (England).
Indeed, while decades-old studies suggested 20% of patients with advanced melanoma experience an objective tumor response to DTIC, more recent large multicenter studies indicate that the true figure is between 1 in 7 and 1 in 10, with no evidence DTIC offers any improvement over supportive care in terms of overall survival, he said at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
This discouraging assessment isn't just one oncologist's view. Dr. Alexander M.M. Eggermont noted during his presentation that the Dutch Cancer Society recently issued an advisory that the No. 1 option in patients with advanced melanoma is to enter them into any new drug development trial, even a phase I trial.
"So phase I studies are the preferred option in stage IV melanoma patients, rather than giving them the usual stuff. I think that's a very important message because that's really what we need to move the field forward," added Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands, and president-elect of the Federation of European Cancer Societies.
Phase III Trial Activity for Melanoma Is Robust : Biologics being studied include CTLA4 blockers, apoptosis restorers, and antiangiogenesis agents.
AMSTERDAM An unprecedented number of pivotal phase III trials of novel biologic therapies for melanoma are underway or about to start, according to speakers at the 11th World Congress on Cancers of the Skin.
"It's unbelievably busy in the field of melanoma these days," observed Dr. Alexander M.M. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.
Among the biologic agents in phase III clinical trials for melanoma are cytotoxic T lymphocyte antigen 4 (CTLA4) blockers, apoptosis restorers, antiangiogenesis agents, and tyrosine kinase inhibitors. Numerous biologics are in earlier phase studies, including agents that interfere with melanoma's potent ability to repair chemotherapy-induced DNA damage.
"I think the CTLA4 antibodies are the most exciting agents on the horizon," Dr. Eggermont commented at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
Two such agents are in advanced development: ipilimumab, a Medarex/Bristol-Myers Squibb drug, and Pfizer's CP-675,206. Both are fully human monoclonal antibodies given by injection once every several months. CTLA4 blockade takes the brakes off T-cell proliferation, which results in an enhanced immunologic response to the tumor. These agents are in large phase III trialssome of them involving 1,000 advanced melanoma patientsas single-agent therapy, in combination with the alkylating agent dacarbazine (DTIC), as adjuvant therapy in patients with stage III or resected stage IV disease, or in conjunction with peptide vaccine therapy.
Up until now, therapeutic melanoma vaccine development programs have been "remarkably unsuccessful," with no indication of any effect on survival, Dr. Eggermont said. The early evidence suggests CTLA4 blockers may change that.
"We know we can induce immune responses. Many vaccine protocols have shown we can generate and induce T cell populations. The problem is we don't know how to maintain these T cell responses. Maintenance of the immune response is one of the critical barriers to successful development of vaccines. And here anti-CTLA4 is a crucial molecule. I predict it'll play an essential role across the board in vaccine development," he continued.
The phase II trials of CTLA4 blockers in patients with stage IV melanoma have collectively shown confirmed tumor response rates of 10%-15%, with about one-quarter of responses being complete and the remainder being long-lasting partial responses. Another 30%-40% of treated patients have experienced prolonged disease stabilization. There have been documented responses of visceral and brain metastases. The price paid for this anticancer efficacy has come in the form of immune-related adverse events affecting primarily the skin, gastrointestinal, and endocrine systems.
A particularly interesting attribute of the CTLA4 blockers is that more than 60% of confirmed responses have occurred only after more than 12 weeks of therapy. These delayed responses initially showed static or even progressive disease before later developing into partial responses, and in some cases they later evolved into complete responses.
"This is totally new kinetics," Dr. Eggermont noted. "It's different from anything you've ever seen with chemotherapy."
Dr. Céleste Lebbé, professor of dermatology and chief of dermato-oncology at Saint Louis Hospital (Paris) and the University of Paris VII, focused on the other agents in phase III: oblimersen (Genasense) and sorafenib (Nexavar).
▸ Oblimersen: This antisense oligonucleotide downregulates expression of the Bcl-2 protein. Bcl-2 overexpression inhibits apoptosis of cancer cells in response to chemotherapy or radiotherapy. Bcl-2 expression correlates negatively with treatment response and survival.
In a large phase III trial involving 771 patients with unresectable stage III or stage IV melanoma who were randomized to DTIC plus oblimersen or DTIC alone, the combination resulted in significantly better rates of overall response, complete response, durable response lasting more than 6 months, and progression-free survival (J. Clin. Oncol. 2006;24:4738-45).
Oblimersen failed to win regulatory approval in Europe or the United States based upon this study because the trend for improved overall survivalthe primary end pointdidn't achieve significance, but overall survival was significantly better with combination therapy in the 508 patients who had a normal baseline serum lactate dehydrogenase level, which was a prespecified stratification factor. Oblimersen's developer, Genta Inc., plans to conduct a repeat phase III trial, this time restricted to melanoma patients with normal lactate dehydrogenase levels, Dr. Lebbé said.
▸ Sorafenib: This Bayer drug is an antiangiogenesis agent by virtue of its inhibition of vascular endothelial growth factor 2, as well as an inhibitor of the mitogen-activated protein kinase signalling pathway with selectivity for the BRAF mutation present in 70% of melanoma patients. It quickly won regulatory approval in the United States and Europe for the treatment of renal cell carcinoma, and then for hepatocellular carcinoma, the most common malignancy worldwide. (See article on p. 18.)
Although all of this extensive research activity involving new biologic agents for advanced melanoma may look promising, a cautionary note was sounded by Dr. Mark R. Middleton of Cancer UK and the University of Oxford (England), who has witnessed a relentless succession of therapeutic disappointments on the melanoma front during his career in medical oncology.
"In melanoma we already have a wealth of therapeutic options. Untold numbers of drugs have been tested in our patients. Unfortunately, none of them work particularly well. The response rates are pretty dismal compared to those for most other solid tumors," Dr. Middleton observed.
Indeed, numerous combinations of chemotherapeutic agents or chemotherapy drugs and biologicsmainly interferons and interleukinshave been tested over the last 20 years. What these combinations have had in common was a weak therapeutic rationale and impressively high tumor response rates in mostly single-center phase II trials, which failed to translate into any overall survival advantage over DTIC alone in phase III studies.
"It's not that anybody's playing games with their phase-IIs, but naturally with combination regimens that you're trying for the first time you're going to enroll better, fitter patients and overestimate what you can get out of it, particularly if you're using historical controls," he explained.
"I think the definition of promising clinical activity has to be based on survival rather than response rates because we've clearly been caught out by the combination chemotherapy and biochemotherapy stories. It's very, very clear from that experience that the higher response rates haven't translated into survival improvements," Dr. Middleton added.
Dr. Middleton and Dr. Eggermont have received research funding from and are consultants to Schering-Plough.
In addition, Dr. Eggermont is a consultant to Bayer, Boehringer Ingelheim, GlaxoSmithKline, Sanofi Pasteur, Onyx Pharmaceuticals, Genta Inc., and Synta Pharmaceuticals. Dr. Lebbé has received research funding from Novartis.
"The definition of promising clinical activity has to be based on survival rather than response," said Dr. Mark R. Middleton. Bruce Jancin/Elsevier Global Medical News
AMSTERDAM An unprecedented number of pivotal phase III trials of novel biologic therapies for melanoma are underway or about to start, according to speakers at the 11th World Congress on Cancers of the Skin.
"It's unbelievably busy in the field of melanoma these days," observed Dr. Alexander M.M. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.
Among the biologic agents in phase III clinical trials for melanoma are cytotoxic T lymphocyte antigen 4 (CTLA4) blockers, apoptosis restorers, antiangiogenesis agents, and tyrosine kinase inhibitors. Numerous biologics are in earlier phase studies, including agents that interfere with melanoma's potent ability to repair chemotherapy-induced DNA damage.
"I think the CTLA4 antibodies are the most exciting agents on the horizon," Dr. Eggermont commented at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
Two such agents are in advanced development: ipilimumab, a Medarex/Bristol-Myers Squibb drug, and Pfizer's CP-675,206. Both are fully human monoclonal antibodies given by injection once every several months. CTLA4 blockade takes the brakes off T-cell proliferation, which results in an enhanced immunologic response to the tumor. These agents are in large phase III trialssome of them involving 1,000 advanced melanoma patientsas single-agent therapy, in combination with the alkylating agent dacarbazine (DTIC), as adjuvant therapy in patients with stage III or resected stage IV disease, or in conjunction with peptide vaccine therapy.
Up until now, therapeutic melanoma vaccine development programs have been "remarkably unsuccessful," with no indication of any effect on survival, Dr. Eggermont said. The early evidence suggests CTLA4 blockers may change that.
"We know we can induce immune responses. Many vaccine protocols have shown we can generate and induce T cell populations. The problem is we don't know how to maintain these T cell responses. Maintenance of the immune response is one of the critical barriers to successful development of vaccines. And here anti-CTLA4 is a crucial molecule. I predict it'll play an essential role across the board in vaccine development," he continued.
The phase II trials of CTLA4 blockers in patients with stage IV melanoma have collectively shown confirmed tumor response rates of 10%-15%, with about one-quarter of responses being complete and the remainder being long-lasting partial responses. Another 30%-40% of treated patients have experienced prolonged disease stabilization. There have been documented responses of visceral and brain metastases. The price paid for this anticancer efficacy has come in the form of immune-related adverse events affecting primarily the skin, gastrointestinal, and endocrine systems.
A particularly interesting attribute of the CTLA4 blockers is that more than 60% of confirmed responses have occurred only after more than 12 weeks of therapy. These delayed responses initially showed static or even progressive disease before later developing into partial responses, and in some cases they later evolved into complete responses.
"This is totally new kinetics," Dr. Eggermont noted. "It's different from anything you've ever seen with chemotherapy."
Dr. Céleste Lebbé, professor of dermatology and chief of dermato-oncology at Saint Louis Hospital (Paris) and the University of Paris VII, focused on the other agents in phase III: oblimersen (Genasense) and sorafenib (Nexavar).
▸ Oblimersen: This antisense oligonucleotide downregulates expression of the Bcl-2 protein. Bcl-2 overexpression inhibits apoptosis of cancer cells in response to chemotherapy or radiotherapy. Bcl-2 expression correlates negatively with treatment response and survival.
In a large phase III trial involving 771 patients with unresectable stage III or stage IV melanoma who were randomized to DTIC plus oblimersen or DTIC alone, the combination resulted in significantly better rates of overall response, complete response, durable response lasting more than 6 months, and progression-free survival (J. Clin. Oncol. 2006;24:4738-45).
Oblimersen failed to win regulatory approval in Europe or the United States based upon this study because the trend for improved overall survivalthe primary end pointdidn't achieve significance, but overall survival was significantly better with combination therapy in the 508 patients who had a normal baseline serum lactate dehydrogenase level, which was a prespecified stratification factor. Oblimersen's developer, Genta Inc., plans to conduct a repeat phase III trial, this time restricted to melanoma patients with normal lactate dehydrogenase levels, Dr. Lebbé said.
▸ Sorafenib: This Bayer drug is an antiangiogenesis agent by virtue of its inhibition of vascular endothelial growth factor 2, as well as an inhibitor of the mitogen-activated protein kinase signalling pathway with selectivity for the BRAF mutation present in 70% of melanoma patients. It quickly won regulatory approval in the United States and Europe for the treatment of renal cell carcinoma, and then for hepatocellular carcinoma, the most common malignancy worldwide. (See article on p. 18.)
Although all of this extensive research activity involving new biologic agents for advanced melanoma may look promising, a cautionary note was sounded by Dr. Mark R. Middleton of Cancer UK and the University of Oxford (England), who has witnessed a relentless succession of therapeutic disappointments on the melanoma front during his career in medical oncology.
"In melanoma we already have a wealth of therapeutic options. Untold numbers of drugs have been tested in our patients. Unfortunately, none of them work particularly well. The response rates are pretty dismal compared to those for most other solid tumors," Dr. Middleton observed.
Indeed, numerous combinations of chemotherapeutic agents or chemotherapy drugs and biologicsmainly interferons and interleukinshave been tested over the last 20 years. What these combinations have had in common was a weak therapeutic rationale and impressively high tumor response rates in mostly single-center phase II trials, which failed to translate into any overall survival advantage over DTIC alone in phase III studies.
"It's not that anybody's playing games with their phase-IIs, but naturally with combination regimens that you're trying for the first time you're going to enroll better, fitter patients and overestimate what you can get out of it, particularly if you're using historical controls," he explained.
"I think the definition of promising clinical activity has to be based on survival rather than response rates because we've clearly been caught out by the combination chemotherapy and biochemotherapy stories. It's very, very clear from that experience that the higher response rates haven't translated into survival improvements," Dr. Middleton added.
Dr. Middleton and Dr. Eggermont have received research funding from and are consultants to Schering-Plough.
In addition, Dr. Eggermont is a consultant to Bayer, Boehringer Ingelheim, GlaxoSmithKline, Sanofi Pasteur, Onyx Pharmaceuticals, Genta Inc., and Synta Pharmaceuticals. Dr. Lebbé has received research funding from Novartis.
"The definition of promising clinical activity has to be based on survival rather than response," said Dr. Mark R. Middleton. Bruce Jancin/Elsevier Global Medical News
AMSTERDAM An unprecedented number of pivotal phase III trials of novel biologic therapies for melanoma are underway or about to start, according to speakers at the 11th World Congress on Cancers of the Skin.
"It's unbelievably busy in the field of melanoma these days," observed Dr. Alexander M.M. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.
Among the biologic agents in phase III clinical trials for melanoma are cytotoxic T lymphocyte antigen 4 (CTLA4) blockers, apoptosis restorers, antiangiogenesis agents, and tyrosine kinase inhibitors. Numerous biologics are in earlier phase studies, including agents that interfere with melanoma's potent ability to repair chemotherapy-induced DNA damage.
"I think the CTLA4 antibodies are the most exciting agents on the horizon," Dr. Eggermont commented at the congress, which was cosponsored by the Skin Cancer Foundation and Erasmus University.
Two such agents are in advanced development: ipilimumab, a Medarex/Bristol-Myers Squibb drug, and Pfizer's CP-675,206. Both are fully human monoclonal antibodies given by injection once every several months. CTLA4 blockade takes the brakes off T-cell proliferation, which results in an enhanced immunologic response to the tumor. These agents are in large phase III trialssome of them involving 1,000 advanced melanoma patientsas single-agent therapy, in combination with the alkylating agent dacarbazine (DTIC), as adjuvant therapy in patients with stage III or resected stage IV disease, or in conjunction with peptide vaccine therapy.
Up until now, therapeutic melanoma vaccine development programs have been "remarkably unsuccessful," with no indication of any effect on survival, Dr. Eggermont said. The early evidence suggests CTLA4 blockers may change that.
"We know we can induce immune responses. Many vaccine protocols have shown we can generate and induce T cell populations. The problem is we don't know how to maintain these T cell responses. Maintenance of the immune response is one of the critical barriers to successful development of vaccines. And here anti-CTLA4 is a crucial molecule. I predict it'll play an essential role across the board in vaccine development," he continued.
The phase II trials of CTLA4 blockers in patients with stage IV melanoma have collectively shown confirmed tumor response rates of 10%-15%, with about one-quarter of responses being complete and the remainder being long-lasting partial responses. Another 30%-40% of treated patients have experienced prolonged disease stabilization. There have been documented responses of visceral and brain metastases. The price paid for this anticancer efficacy has come in the form of immune-related adverse events affecting primarily the skin, gastrointestinal, and endocrine systems.
A particularly interesting attribute of the CTLA4 blockers is that more than 60% of confirmed responses have occurred only after more than 12 weeks of therapy. These delayed responses initially showed static or even progressive disease before later developing into partial responses, and in some cases they later evolved into complete responses.
"This is totally new kinetics," Dr. Eggermont noted. "It's different from anything you've ever seen with chemotherapy."
Dr. Céleste Lebbé, professor of dermatology and chief of dermato-oncology at Saint Louis Hospital (Paris) and the University of Paris VII, focused on the other agents in phase III: oblimersen (Genasense) and sorafenib (Nexavar).
▸ Oblimersen: This antisense oligonucleotide downregulates expression of the Bcl-2 protein. Bcl-2 overexpression inhibits apoptosis of cancer cells in response to chemotherapy or radiotherapy. Bcl-2 expression correlates negatively with treatment response and survival.
In a large phase III trial involving 771 patients with unresectable stage III or stage IV melanoma who were randomized to DTIC plus oblimersen or DTIC alone, the combination resulted in significantly better rates of overall response, complete response, durable response lasting more than 6 months, and progression-free survival (J. Clin. Oncol. 2006;24:4738-45).
Oblimersen failed to win regulatory approval in Europe or the United States based upon this study because the trend for improved overall survivalthe primary end pointdidn't achieve significance, but overall survival was significantly better with combination therapy in the 508 patients who had a normal baseline serum lactate dehydrogenase level, which was a prespecified stratification factor. Oblimersen's developer, Genta Inc., plans to conduct a repeat phase III trial, this time restricted to melanoma patients with normal lactate dehydrogenase levels, Dr. Lebbé said.
▸ Sorafenib: This Bayer drug is an antiangiogenesis agent by virtue of its inhibition of vascular endothelial growth factor 2, as well as an inhibitor of the mitogen-activated protein kinase signalling pathway with selectivity for the BRAF mutation present in 70% of melanoma patients. It quickly won regulatory approval in the United States and Europe for the treatment of renal cell carcinoma, and then for hepatocellular carcinoma, the most common malignancy worldwide. (See article on p. 18.)
Although all of this extensive research activity involving new biologic agents for advanced melanoma may look promising, a cautionary note was sounded by Dr. Mark R. Middleton of Cancer UK and the University of Oxford (England), who has witnessed a relentless succession of therapeutic disappointments on the melanoma front during his career in medical oncology.
"In melanoma we already have a wealth of therapeutic options. Untold numbers of drugs have been tested in our patients. Unfortunately, none of them work particularly well. The response rates are pretty dismal compared to those for most other solid tumors," Dr. Middleton observed.
Indeed, numerous combinations of chemotherapeutic agents or chemotherapy drugs and biologicsmainly interferons and interleukinshave been tested over the last 20 years. What these combinations have had in common was a weak therapeutic rationale and impressively high tumor response rates in mostly single-center phase II trials, which failed to translate into any overall survival advantage over DTIC alone in phase III studies.
"It's not that anybody's playing games with their phase-IIs, but naturally with combination regimens that you're trying for the first time you're going to enroll better, fitter patients and overestimate what you can get out of it, particularly if you're using historical controls," he explained.
"I think the definition of promising clinical activity has to be based on survival rather than response rates because we've clearly been caught out by the combination chemotherapy and biochemotherapy stories. It's very, very clear from that experience that the higher response rates haven't translated into survival improvements," Dr. Middleton added.
Dr. Middleton and Dr. Eggermont have received research funding from and are consultants to Schering-Plough.
In addition, Dr. Eggermont is a consultant to Bayer, Boehringer Ingelheim, GlaxoSmithKline, Sanofi Pasteur, Onyx Pharmaceuticals, Genta Inc., and Synta Pharmaceuticals. Dr. Lebbé has received research funding from Novartis.
"The definition of promising clinical activity has to be based on survival rather than response," said Dr. Mark R. Middleton. Bruce Jancin/Elsevier Global Medical News
New Anticancer Agents Have Distinctive Toxicities
AMSTERDAM The highly promising new class of investigational anticancer agents known at cytotoxic T-lymphocyte antigen 4 blockers has a characteristic group of side effects of special interest to dermatologists, gastroenterologists, and endocrinologists, Dr. Alexander M.M. Eggermont said at the 11th World Congress on Cancers of the Skin.
Two fully human monoclonal antibodies to CTLA4 are making major waves in oncology circles because of their efficacy in early clinical trials for the treatment of advanced melanoma, a disease which has seen discouragingly little therapeutic progress in the last 3 decades.
But it is apparent that this impressive efficacy comes at the price of what are known in the field as immune-related adverse events, or IRAEs, affecting mainly the dermatologic, gastrointestinal, and endocrinologic domains. The CTLA4 blockers have moved into an extensive program of large phase III clinical trials, so an increasing number of physicians will be confronted with IRAEs, which require prompt diagnosis and intervention, noted Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, and president-elect of the Federation of European Cancer Societies.
CTLA4 is expressed on T cells, where it functions as a fundamental negative regulator of T-cell activation. CTLA4 blockade essentially allows T-cell proliferation, enabling the patient's immune system to mount a more vigorous, prolonged, and effective anticancer responseand, in a sizable minority of cases, trigger IRAEs.
"If you have subclinical autoimmune disease, you may be propelled into clinical disease manifestations because the hand brake is off your T-cell populations," Dr. Eggermont explained at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.
Dermatologic IRAEs take the form of an array of rashes, vitiligo, and pruritic conditions involving specific T-cell infiltrates at the lesion sites. These are usually mild to moderate grade 1 or 2 side effects that resolve with corticosteroid therapy or discontinuation of the biologic agent.
Gastrointestinal IRAEs most often consist of mild to moderate enterocolitis. But occasionally, the colitis is grade 3, marked by bloody diarrhea, or grade 4, involving perforation, which is potentially fatal. Aggressive medical management, often including high doses of steroids, is sometimes required to control these toxicities.
Endocrinologic IRAEs are particularly puzzling, because they involve mainly the pituitary, a gland ordinarily very well protected against autoimmune disease. But a small number of patients with metastatic melanoma or renal cancer who are placed on anti-CTLA4 monoclonal antibody therapyless than 1% thus fardevelop autoimmune hypophysitis.
"You go into an addisonian crisis. It's not a small thing. At the sella turcica, you see a swollen pituitary gland, which will become normal again after you've stopped therapy. You need to intervene here with corticosteroids and hormone substitution," he continued.
The most intriguing thing about the IRAEs is their strong correlation with induction of tumor regression. Investigators at the National Cancer Institute reported on 198 patients with metastatic melanoma or renal cell carcinoma treated with the CTLA4 monoclonal antibody ipilimumab. Twenty-one percent of the treated patients developed grade 3 or 4 autoimmune enterocolitis. The objective tumor response rate was 36% in those melanoma patients with colitis and 11% in those without. Similarly, 35% of renal cell carcinoma patients with colitis had an objective tumor response, compared with just 2% without colitis (J. Clin. Oncol. 2006;24:2283-9).
Dr. Eggermont is a consultant to Bristol-Myers Squibb Co., which together with Medarex Inc., is developing ipilimumab. The other CTLA4 blocker in clinical development is a Pfizer drug known for now as CP-675,206.
Dermatologic adverse events take the form of rashes, vitiligo, and pruritic conditions. DR. EGGERMONT
AMSTERDAM The highly promising new class of investigational anticancer agents known at cytotoxic T-lymphocyte antigen 4 blockers has a characteristic group of side effects of special interest to dermatologists, gastroenterologists, and endocrinologists, Dr. Alexander M.M. Eggermont said at the 11th World Congress on Cancers of the Skin.
Two fully human monoclonal antibodies to CTLA4 are making major waves in oncology circles because of their efficacy in early clinical trials for the treatment of advanced melanoma, a disease which has seen discouragingly little therapeutic progress in the last 3 decades.
But it is apparent that this impressive efficacy comes at the price of what are known in the field as immune-related adverse events, or IRAEs, affecting mainly the dermatologic, gastrointestinal, and endocrinologic domains. The CTLA4 blockers have moved into an extensive program of large phase III clinical trials, so an increasing number of physicians will be confronted with IRAEs, which require prompt diagnosis and intervention, noted Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, and president-elect of the Federation of European Cancer Societies.
CTLA4 is expressed on T cells, where it functions as a fundamental negative regulator of T-cell activation. CTLA4 blockade essentially allows T-cell proliferation, enabling the patient's immune system to mount a more vigorous, prolonged, and effective anticancer responseand, in a sizable minority of cases, trigger IRAEs.
"If you have subclinical autoimmune disease, you may be propelled into clinical disease manifestations because the hand brake is off your T-cell populations," Dr. Eggermont explained at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.
Dermatologic IRAEs take the form of an array of rashes, vitiligo, and pruritic conditions involving specific T-cell infiltrates at the lesion sites. These are usually mild to moderate grade 1 or 2 side effects that resolve with corticosteroid therapy or discontinuation of the biologic agent.
Gastrointestinal IRAEs most often consist of mild to moderate enterocolitis. But occasionally, the colitis is grade 3, marked by bloody diarrhea, or grade 4, involving perforation, which is potentially fatal. Aggressive medical management, often including high doses of steroids, is sometimes required to control these toxicities.
Endocrinologic IRAEs are particularly puzzling, because they involve mainly the pituitary, a gland ordinarily very well protected against autoimmune disease. But a small number of patients with metastatic melanoma or renal cancer who are placed on anti-CTLA4 monoclonal antibody therapyless than 1% thus fardevelop autoimmune hypophysitis.
"You go into an addisonian crisis. It's not a small thing. At the sella turcica, you see a swollen pituitary gland, which will become normal again after you've stopped therapy. You need to intervene here with corticosteroids and hormone substitution," he continued.
The most intriguing thing about the IRAEs is their strong correlation with induction of tumor regression. Investigators at the National Cancer Institute reported on 198 patients with metastatic melanoma or renal cell carcinoma treated with the CTLA4 monoclonal antibody ipilimumab. Twenty-one percent of the treated patients developed grade 3 or 4 autoimmune enterocolitis. The objective tumor response rate was 36% in those melanoma patients with colitis and 11% in those without. Similarly, 35% of renal cell carcinoma patients with colitis had an objective tumor response, compared with just 2% without colitis (J. Clin. Oncol. 2006;24:2283-9).
Dr. Eggermont is a consultant to Bristol-Myers Squibb Co., which together with Medarex Inc., is developing ipilimumab. The other CTLA4 blocker in clinical development is a Pfizer drug known for now as CP-675,206.
Dermatologic adverse events take the form of rashes, vitiligo, and pruritic conditions. DR. EGGERMONT
AMSTERDAM The highly promising new class of investigational anticancer agents known at cytotoxic T-lymphocyte antigen 4 blockers has a characteristic group of side effects of special interest to dermatologists, gastroenterologists, and endocrinologists, Dr. Alexander M.M. Eggermont said at the 11th World Congress on Cancers of the Skin.
Two fully human monoclonal antibodies to CTLA4 are making major waves in oncology circles because of their efficacy in early clinical trials for the treatment of advanced melanoma, a disease which has seen discouragingly little therapeutic progress in the last 3 decades.
But it is apparent that this impressive efficacy comes at the price of what are known in the field as immune-related adverse events, or IRAEs, affecting mainly the dermatologic, gastrointestinal, and endocrinologic domains. The CTLA4 blockers have moved into an extensive program of large phase III clinical trials, so an increasing number of physicians will be confronted with IRAEs, which require prompt diagnosis and intervention, noted Dr. Eggermont, professor and head of surgical oncology at Erasmus University Medical Center, Rotterdam, and president-elect of the Federation of European Cancer Societies.
CTLA4 is expressed on T cells, where it functions as a fundamental negative regulator of T-cell activation. CTLA4 blockade essentially allows T-cell proliferation, enabling the patient's immune system to mount a more vigorous, prolonged, and effective anticancer responseand, in a sizable minority of cases, trigger IRAEs.
"If you have subclinical autoimmune disease, you may be propelled into clinical disease manifestations because the hand brake is off your T-cell populations," Dr. Eggermont explained at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.
Dermatologic IRAEs take the form of an array of rashes, vitiligo, and pruritic conditions involving specific T-cell infiltrates at the lesion sites. These are usually mild to moderate grade 1 or 2 side effects that resolve with corticosteroid therapy or discontinuation of the biologic agent.
Gastrointestinal IRAEs most often consist of mild to moderate enterocolitis. But occasionally, the colitis is grade 3, marked by bloody diarrhea, or grade 4, involving perforation, which is potentially fatal. Aggressive medical management, often including high doses of steroids, is sometimes required to control these toxicities.
Endocrinologic IRAEs are particularly puzzling, because they involve mainly the pituitary, a gland ordinarily very well protected against autoimmune disease. But a small number of patients with metastatic melanoma or renal cancer who are placed on anti-CTLA4 monoclonal antibody therapyless than 1% thus fardevelop autoimmune hypophysitis.
"You go into an addisonian crisis. It's not a small thing. At the sella turcica, you see a swollen pituitary gland, which will become normal again after you've stopped therapy. You need to intervene here with corticosteroids and hormone substitution," he continued.
The most intriguing thing about the IRAEs is their strong correlation with induction of tumor regression. Investigators at the National Cancer Institute reported on 198 patients with metastatic melanoma or renal cell carcinoma treated with the CTLA4 monoclonal antibody ipilimumab. Twenty-one percent of the treated patients developed grade 3 or 4 autoimmune enterocolitis. The objective tumor response rate was 36% in those melanoma patients with colitis and 11% in those without. Similarly, 35% of renal cell carcinoma patients with colitis had an objective tumor response, compared with just 2% without colitis (J. Clin. Oncol. 2006;24:2283-9).
Dr. Eggermont is a consultant to Bristol-Myers Squibb Co., which together with Medarex Inc., is developing ipilimumab. The other CTLA4 blocker in clinical development is a Pfizer drug known for now as CP-675,206.
Dermatologic adverse events take the form of rashes, vitiligo, and pruritic conditions. DR. EGGERMONT
Spontaneous Pneumomediastinum
A previously healthy 22‐year‐old white man presented with acute psychosis after an 11‐day binge of smoking and injecting methamphetamine. The physical exam revealed crepitus over the anterior neck and Hamman's crunch (a crunching sound synchronous with the cardiac cycle and best heard with patient positioned in the left lateral decubitus position). Chest film (Fig. 1) and computerized tomography (Fig. 2) showed pneumomediastinum with extensive subcutaneous emphysema and pneumorrhachis (air in the epidural space).1 An esophogram was normal. Following 48 hours of inpatient observation and oxygen therapy, the neumomediastinum and psychosis resolved.
Spontaneous pneumomediastinum is rare, accounting for 1 in 30,000 emergency department referrals. It is more common among users of illicit substances (ie, amphetamine and methylenedioxymethamphetamine [MDMA/ecstasy]).2 Patients present with chest pain, dyspnea, and the typical physical findings described above.3 Chest imaging confirms the diagnosis.4 Vigorous inhalation during a Valsalva maneuver is thought to rupture terminal alveoli. Gas then enters the lung interstitium and dissects along fascial planes into the hilum and mediastinum and occasionally into the epidural space.5 Thorough investigation rules out other sources of air from the neck, abdomen, or ruptured esophagus (Boerhaave syndrome). Treatment is generally supportive and includes oxygen therapy, reassurance, analgesics, and close monitoring for complications (eg, pneumothorax). Surgical intervention is only necessary if a pneumothorax develops.6 Prognosis is excellent.
- .Spontaneous mediastinal emphysema.Bull Johns Hopkins Hosp.1939;64:1–21.
- ,.Spontaneous pneumomediastinum: a benign curiosity or a significant problem?Chest.2005;3298–3302128.
- ,.Spontaneous pneumomediastinum, pneumothorax and ecstasy abuse.Emerg Med.:2001;13:121–123.
- ,,,,.“Spontaneous Pneumomediastinum.Ann Thorac Surg.2004;78:711–713.
- ,,.Pneumorrhachis secondary to traumatic pneumomediastinum in a child.Pediatr Radiol.2006;36:711–713.
- ,,.Spontaneous pneumomediastinum.Curr Surg.2006;63:351–353.
A previously healthy 22‐year‐old white man presented with acute psychosis after an 11‐day binge of smoking and injecting methamphetamine. The physical exam revealed crepitus over the anterior neck and Hamman's crunch (a crunching sound synchronous with the cardiac cycle and best heard with patient positioned in the left lateral decubitus position). Chest film (Fig. 1) and computerized tomography (Fig. 2) showed pneumomediastinum with extensive subcutaneous emphysema and pneumorrhachis (air in the epidural space).1 An esophogram was normal. Following 48 hours of inpatient observation and oxygen therapy, the neumomediastinum and psychosis resolved.
Spontaneous pneumomediastinum is rare, accounting for 1 in 30,000 emergency department referrals. It is more common among users of illicit substances (ie, amphetamine and methylenedioxymethamphetamine [MDMA/ecstasy]).2 Patients present with chest pain, dyspnea, and the typical physical findings described above.3 Chest imaging confirms the diagnosis.4 Vigorous inhalation during a Valsalva maneuver is thought to rupture terminal alveoli. Gas then enters the lung interstitium and dissects along fascial planes into the hilum and mediastinum and occasionally into the epidural space.5 Thorough investigation rules out other sources of air from the neck, abdomen, or ruptured esophagus (Boerhaave syndrome). Treatment is generally supportive and includes oxygen therapy, reassurance, analgesics, and close monitoring for complications (eg, pneumothorax). Surgical intervention is only necessary if a pneumothorax develops.6 Prognosis is excellent.
A previously healthy 22‐year‐old white man presented with acute psychosis after an 11‐day binge of smoking and injecting methamphetamine. The physical exam revealed crepitus over the anterior neck and Hamman's crunch (a crunching sound synchronous with the cardiac cycle and best heard with patient positioned in the left lateral decubitus position). Chest film (Fig. 1) and computerized tomography (Fig. 2) showed pneumomediastinum with extensive subcutaneous emphysema and pneumorrhachis (air in the epidural space).1 An esophogram was normal. Following 48 hours of inpatient observation and oxygen therapy, the neumomediastinum and psychosis resolved.
Spontaneous pneumomediastinum is rare, accounting for 1 in 30,000 emergency department referrals. It is more common among users of illicit substances (ie, amphetamine and methylenedioxymethamphetamine [MDMA/ecstasy]).2 Patients present with chest pain, dyspnea, and the typical physical findings described above.3 Chest imaging confirms the diagnosis.4 Vigorous inhalation during a Valsalva maneuver is thought to rupture terminal alveoli. Gas then enters the lung interstitium and dissects along fascial planes into the hilum and mediastinum and occasionally into the epidural space.5 Thorough investigation rules out other sources of air from the neck, abdomen, or ruptured esophagus (Boerhaave syndrome). Treatment is generally supportive and includes oxygen therapy, reassurance, analgesics, and close monitoring for complications (eg, pneumothorax). Surgical intervention is only necessary if a pneumothorax develops.6 Prognosis is excellent.
- .Spontaneous mediastinal emphysema.Bull Johns Hopkins Hosp.1939;64:1–21.
- ,.Spontaneous pneumomediastinum: a benign curiosity or a significant problem?Chest.2005;3298–3302128.
- ,.Spontaneous pneumomediastinum, pneumothorax and ecstasy abuse.Emerg Med.:2001;13:121–123.
- ,,,,.“Spontaneous Pneumomediastinum.Ann Thorac Surg.2004;78:711–713.
- ,,.Pneumorrhachis secondary to traumatic pneumomediastinum in a child.Pediatr Radiol.2006;36:711–713.
- ,,.Spontaneous pneumomediastinum.Curr Surg.2006;63:351–353.
- .Spontaneous mediastinal emphysema.Bull Johns Hopkins Hosp.1939;64:1–21.
- ,.Spontaneous pneumomediastinum: a benign curiosity or a significant problem?Chest.2005;3298–3302128.
- ,.Spontaneous pneumomediastinum, pneumothorax and ecstasy abuse.Emerg Med.:2001;13:121–123.
- ,,,,.“Spontaneous Pneumomediastinum.Ann Thorac Surg.2004;78:711–713.
- ,,.Pneumorrhachis secondary to traumatic pneumomediastinum in a child.Pediatr Radiol.2006;36:711–713.
- ,,.Spontaneous pneumomediastinum.Curr Surg.2006;63:351–353.
SHM Workshops on Health Care–Associated Infections and Antimicrobial Resistance / Bush‐Knapp et al.
In the United States, hospitalized patients are at risk of acquiring health careassociated infections that increase morbidity, mortality, length of hospital stay, and cost of care.1 If a health careassociated infection is caused by an antimicrobial‐resistant pathogen, treatment efforts may be further complicated.2, 3 With the decreasing effectiveness of antimicrobials and suboptimal adherence to certain infection control measures, new and multifaceted prevention strategies are necessary to address the problem of health careassociated infections and antimicrobial resistance.410
One strategy that hospitals can use to reduce the incidence of health careassociated infections and antimicrobial resistance is implementation of quality improvement programs. These programs require clinicians to employ techniques, such as root cause analysis (RCA), which investigates contributing factors to an event to prevent reoccurrence, and healthcare failure mode effects analysis (HFMEA), which applies a systematic method of identifying and preventing problems before they occur.1113 Programs and strategies such as these require leadership and adoption within the hospital. Because of their availability and specialized role in the hospital setting, hospitalists are in a unique position to promote and uphold quality improvement efforts.1417 Professional societies, health care organizations, and governmental agencies can play a role in engaging this group of physicians in improving the quality of patient care in hospitals by providing educational programs and materials.18
In 2004, the Society of Hospital Medicine (SHM) collaborated with the Centers for Disease Control and Prevention (CDC) to develop a quality improvement tool kit to reduce antimicrobial resistance and health careassociated infections. The tool kit was based on the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings (Campaign), an educational program targeted at clinicians.19 The SHM/CDC tool kit contained campaign materials, a set of slides about quality improvement, worksheets, and additional materials such as infection control policies and guidelines to supplement a 90‐minute workshop consisting of didactic lectures about antimicrobial resistance, quality improvement initiatives, RCA, and HFMEA; a lecture and case study about intravascular catheter‐related infections; and small‐group activity and discussion. The complete toolkit is now available online via the SHM Antimicrobial Resistance Resource Room at
The purpose of the workshop was to present the tool kit and increase hospitalists' knowledge and awareness about antimicrobial resistance, health careassociated infections, and quality improvement programs. We assessed the workshop participants' familiarity with the Campaign prior to the workshop, perceptions of antimicrobial resistance, knowledge gained as a result of the workshop, and opinions about the usefulness of the workshop.
METHODS
Data were collected from pretests and posttests administered to participants of one of the SHM workshops in May, June, or July 2005 in Denver, Colorado; Boston, Massachusetts; or Portland, Oregon. One SHM physician leader (D.D.D., coauthor of this article) presented all 3 workshops. The workshops were advertised by SHM using E‐mail to local chapter members. Individual sites used a variety of methods to encourage their hospitalists to attend, and participants were provided a complimentary dinner.
Prior to each workshop, participants completed a 10‐question pretest that had been pilot‐tested by hospitalists in other cities. The pretest assessed demographics; perceptions of the problem of antimicrobial resistance using a Likert scale; familiarity with the Campaign; and knowledge of common infection sites, RCA, HFMEA, and antimicrobial resistance prevention measures.
Immediately following each workshop, a 13‐question posttest was administered to participants. This posttest evaluated the workshop and materials using Likert scales, asked for suggestions for future programming using open‐ended questions, and repeated pretest questions to assess changes in perceptions and knowledge.
Data were entered into an Excel spreadsheet and analyzed using descriptive statistics and t tests to compare pre‐ and posttest changes in knowledge. Likert data assessing perceptions were dichotomized into strongly agree versus all other scale responses. Qualitative open‐ended responses were categorized by theme.
RESULTS
A total of 69 SHM members attended the workshops. Of the 69 participants, 65 completed the pretest, 53 completed the posttest, and 50 completed both the pre‐ and the posttests. Only participants who completed both the pretest and the posttest were included in the analyses (n = 21, Denver; n = 11, Boston; n = 18, Portland). Of the 50 participants who completed both the pre‐ and posttests, 44 (88%) classified themselves as hospitalists in practices ranging from 2 to more than 25 physicians. Participants averaged 9.2 years (range = 1‐27 years) in practice and 4.9 years (range = 1‐10 years) as practicing hospitalists, with no significant differences between the 3 groups. Only 17 participants (34%) were familiar with the Campaign prior to the workshop, and there was no significant variation between the 3 workshops. Those familiar with the Campaign had heard about or received the educational materials from colleagues (n = 5), their facilities (n = 4), professional journals (n = 4), medical conferences (n = 4), or the CDC or SHM websites (n = 4).
Overall, most participants strongly agreed with the statement that antimicrobial resistance was a problem nationally, institutionally, and within their individual practices (Table 1). These perceptions did not significantly differ between the pretest and the posttest. However, statistically significant differences were found when comparing perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels; more participants strongly agreed that antimicrobial resistance was a problem nationally than within their institutions (pretest, P = .01; posttest, P = .04) or within their practices (pretest, P < .0001; posttest, P = .01).
| Nationally | Institutionally | Within own practice | ||||
|---|---|---|---|---|---|---|
| Pretest | Posttest | Pretest | Posttest | Pretest | Posttest | |
| ||||||
| Denver (n = 21) | 100% | 100% | 86% | 95% | 67% | 86% |
| Portland (n = 18) | 83% | 94% | 67% | 78% | 67% | 78% |
| Boston (n = 11) | 91% | 82% | 91% | 82% | 91% | 82% |
| Average | 91% | 94% | 81% | 85% | 72% | 82% |
| P value | .28 | .18 | .06 | |||
On the knowledge‐based questions, the overall average test score was 48% on the pretest and 63% on the posttest (P < .0001), with scores varying by question (Table 2). For example, knowledge of quality improvement initiatives/HFMEA was low (an average of 10% correct on the pretest, 48% on the posttest) compared with knowledge about the key prevention strategies from the Campaign to Prevent Antimicrobial Resistance (average of 94% correct on the pretest, 98% on the posttest). Furthermore, scores also varied by workshop location. On the pretest, participants in Boston and Portland scored higher (both 53%) than Denver participants (40%). On the posttest, Portland participants scored the highest (78%) followed by Boston participants (64%) and then Denver participants (50%). Boston and Denver participants differed significantly on pretest knowledge score (P = .04) and Portland and Denver participants differed significantly on posttest knowledge score (P < .0001).
| Question Topic | Pretest average | Posttest average | Percent difference (P value)* |
|---|---|---|---|
| |||
| Quality improvement initiatives/HFMEA Which quality improvement initiative(s) must be performed yearly by all hospitals (JCAHO accreditation requirement)? | 10% | 48% | 38% (P < .0001) |
| Prevention of central venous catheter‐associated bloodstream infections: Key prevention steps for preventing central venous catheter‐associated bloodstream infections include all of the following except: | 62% | 88% | 26% (P = .0001) |
| RCA Which of the following is NOT true about root cause analysis? | 20% | 38% | 18% (P = .01) |
| Campaign to Prevent Antimicrobial Resistance The key prevention strategies from the Campaign to Prevent Antimicrobial Resistance include all of the following except: | 94% | 98% | 4% (P = .32) |
| Common body sites for healthcare‐associated infection: The most common site of hospital‐acquired (nosocomial) infection is: | 52% | 44% | 8% (P = .29) |
| Overall average | 48% | 63% | 15% (P < .0001) |
Overall, 43 participants (85%) rated the workshop as either very good or excellent. All but 1 participant (n = 49, 98%) would encourage a colleague to attend the workshop, giving reasons such as that the workshop outlined a major program in delivering good and safe care, offered great information on antimicrobial resistance and methods of quality improvement systems implementation, assisted in find[ing] new tools for improving hospital practice, and addressed a significant factor in hospitals related to morbidity [and] mortality. When asked for general comments about the workshop and suggestions for future improvements, participants requested more direction, more detail, more discussion, specific examples of antimicrobial resistance, and protocols and processes for implementing quality improvement programs. On a scale from 1 (not useful) to 5 (essential), participants rated the usefulness of each workshop segment: intravascular catheter‐related infections lecture and case study (x̄ = 4.3, range = 3‐5), quality improvement initiatives lecture (x̄ = 4.1, range = 2‐5), background on antimicrobial resistance (x̄ = 3.9, range = 2‐5), RCA lecture (x̄ = 3.9, range = 2‐5), HFMEA lecture (x̄ = 3.8, range = 2‐5), and small‐group discussion (x̄ = 3.4, range = 2‐5). These ratings did not vary significantly between the 3 groups.
CONCLUSIONS
To address antimicrobial resistance and health careassociated infections in the hospital setting, the SHM and CDC developed a tool kit and presented a quality improvement workshop to hospitalists in 3 U.S. cities. Overall, the participants scored significantly higher on the knowledge‐based questions on the posttest than on the pretest, indicating that knowledge improved as a result of the workshop. By providing a format that combined didactic lectures with case‐based education, small‐group activities, and discussion, the SHM workshop may have optimized its ability to increase knowledge, similar to the findings in previous research.2021
There were no significant differences between the 3 groups in years of practice, perceptions of the problem, and overall evaluation of the workshop. However, differences were found in knowledge gained as a result of the workshop. For example, the Denver group scored lower on the knowledge‐based questions than did the Boston group on the pretest and the Portland group on the posttest, indicating that knowledge and learning styles may differ by location. These differences may be attributed to variations in hospital environments, hospital‐based educational programs, or medical school and residency training. Differences like these may impact the effectiveness of a program and should be a consideration in the program development process, especially when a program is national in scope, like the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. In addition, more than 90% of participants correctly identified key prevention strategies of the Campaign, whereas only 34% were familiar with the Campaign itself prior to the workshop. This result may be a result of the key prevention strategies of the Campaign being derived from well‐established and ‐recognized evidence‐based best practices for patient safety and care.
Although knowledge changed as a result of the workshop, overall perceptions of the problem of antimicrobial resistance did not change significantly from pretest to posttest. It is possible this is because changes in perception require a different or more intensive educational approach. This result also may reflect the initial levels of agreement on the pretest, the measurement instrument itself, and/or the inability to detect differences because of the small number of participants.
Difference did exist in perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels. Antimicrobial resistance was perceived to be a greater problem on the national level than on the institutional and practice levels. Other studies also have found that clinicians more strongly agree that antimicrobial resistance is a problem nationally than within their institutions and practices.2224 When antimicrobial resistance is not perceived as a problem within institutions and practices, physicians may be less likely to overcome the barriers to following recommended infection prevention guidelines or to implementing quality improvement projects.4 Therefore, educational and intervention efforts like this workshop should address hospitalists' perceptions of the problem of antimicrobial resistance on the individual level as a first step in motivating them to engage in quality improvement.
Although participants' knowledge scores increased from pretest to posttest, gaps in knowledge remained, as indicated by the significantly improved but low overall posttest scores related to RCA and HFMEA. As hospitalists are in a unique position to promote quality improvement programs, these topic areas should be given more attention in future workshops and in training. Furthermore, by adding more specific questions related to each section of the workshop, associations among presentation style, knowledge gained, and perceived usefulness of each section could be evaluated. For example, the participants significantly increased their scores from pretest to posttest on the catheter‐related knowledge‐based question and rated the lecture and case study on intravascular catheter‐related infections as the most useful sections. Future research may explore these possible relationships to better guide selection of presentation styles and topics to ensure that participants gain knowledge and perceive the sections as useful. In addition, by addressing the feedback from participants, such as offering more detail, examples, and discussion, future workshops may have greater perceived usefulness and be better able to increase the knowledge and awareness of quality improvement programs for the prevention of health careassociated infections and antimicrobial resistance.
Although there were 3 workshops conducted in 3 areas across the United States, the sample size at each site was small, and results may not be representative of hospitalists at large. In addition, power calculations should be considered in future studies to increase the ability to better detect differences between and within groups. Another limitation of this study was that the limited data available and participant anonymity meant it was not possible to follow‐up with participants after the workshop to evaluate whether the knowledge they gained was sustained and/or whether they reported changes in practice. However, possession of knowledge and skills to inform practice does not mean that practice will change; therefore, follow‐up is necessary to determine if this workshop was effective in changing behaviors in the long term.25 Although the SHM workshop improved knowledge, more intensive educational strategies may be necessary to affect perceptions and improve the leadership skills required for implementation of quality improvement programs at an institutional level.
Overall, the SHM workshop was found to be a useful tool for increasing knowledge and outlining methods by which hospitalists can lead, coordinate, or participate in measures to prevent infections and improve patient safety. In addition, through the workshop, the SHM and the CDC have provided an example of how professional societies and government agencies can collaborate to address emerging issues in the health care setting.
- ,,.Impact of nosocomial infection on cost of illness and length of stay in intensive care units.Infect Control Hosp Epidemiol2005;26:281–287.
- .Implementation of strategies to control antimicrobial resistance.Chest.2001;119:405S–411S.
- ,,, et al.Society for Healthcare Epidemiology of America and Infectious Diseases Society of American Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.Clin Infect Dis.1997;25:584–599.
- ,,, et al.Strategies to prevent and control the emergence and spread of antimicrobial‐resistant microorganisms in hospitals: a challenge to hospital leadership.JAMA.1996;275:234–240.
- Centers for Disease Control and Prevention.Guidelines for hand hygiene in health‐care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force.MMWR Recomm Rep.2002;51:1–44.
- .Hospital Infection Control Practices Advisory Committee.Guideline for isolation precautions in hospitals.Infect Control Hosp Epidemiol.1996;17:53–80.
- ,,, et al.SHEA guideline for prevention nosocomial transmission of multidrug‐resistant strains of Staphylococcus aureus and Enterococcus.Infect Control Hosp Epidemiol.2003;24:362–386.
- .Improving adherence to hand hygiene practice: a multidisciplinary approach.Emerg Infect Dis.2001;7:234–240.
- ,,.Alcohol‐based handrub improves compliance with hand hygiene in intensive care units.Arch Intern Med.2002;162:1037–1043.
- ,,, et al.An organizational climate intervention associated with increased handwashing and decreased nosocomial infections.Behav Med.2000;26:14–22.
- ,.Getting to the root of the matter.AHRQ Web M 29:319–330.
- ,,.The Basics of FMEA.New York:Quality Resources;1996.
- .The hospitalist model of care: A positive influence on efficiency, quality of care, and outcomes.Crit Path Cardiol.2004;3:S5–S7.
- .An introduction to the hospitalist model.Ann Intern Med.1999;130:338–342.
- .The impact of hospitalists on medical education and the academic health systems.Ann Intern Med.1999;130:364–367.
- ,,, et al.Hospitalists' perceptions of their residency training needs: Results of a national survey.Am J Med.2001;111:247–254.
- ,,.Preventing the emergence of antimicrobial resistance: A call for action by clinicians, public health officials and patients.JAMA1997;278:944–945.
- Centers for Disease Control and Prevention. Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. 2005. Available at: URL: http://www.cdc.gov/drugresistance/healthcare/default.htm. Accessed November 8,2005.
- ,,, et al.Impact of formal continuing medical education: Do conferences, workshops, rounds and other traditional continuing education activities change physician behavior or health care outcomes?JAMA.1999;282:867–874.
- ,,, et al.Physician preferences for continuing medical education with a focus on the topic of antimicrobial resistance: Society for Healthcare Epidemiology of America.Infect Control Hosp Epidemiol.2001;22:656–660.
- ,,, et al.Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities.Arch Intern Med.2004;164:1662–1668.
- ,,, et al.Antibiotic resistance: a survey of physician perceptions.Arch Intern Med.2002;162:2210–2216.
- ,,, et al.Assessing motivation for physicians to prevent antimicrobial resistance in hospitalized children using the health belief model as a framework.Am J Infect Control.2004;33:175–181.
- .Educational theory into practice: Development of an infection control link nurse programme.Nurs Ed Pract.2001;1:35–41.
In the United States, hospitalized patients are at risk of acquiring health careassociated infections that increase morbidity, mortality, length of hospital stay, and cost of care.1 If a health careassociated infection is caused by an antimicrobial‐resistant pathogen, treatment efforts may be further complicated.2, 3 With the decreasing effectiveness of antimicrobials and suboptimal adherence to certain infection control measures, new and multifaceted prevention strategies are necessary to address the problem of health careassociated infections and antimicrobial resistance.410
One strategy that hospitals can use to reduce the incidence of health careassociated infections and antimicrobial resistance is implementation of quality improvement programs. These programs require clinicians to employ techniques, such as root cause analysis (RCA), which investigates contributing factors to an event to prevent reoccurrence, and healthcare failure mode effects analysis (HFMEA), which applies a systematic method of identifying and preventing problems before they occur.1113 Programs and strategies such as these require leadership and adoption within the hospital. Because of their availability and specialized role in the hospital setting, hospitalists are in a unique position to promote and uphold quality improvement efforts.1417 Professional societies, health care organizations, and governmental agencies can play a role in engaging this group of physicians in improving the quality of patient care in hospitals by providing educational programs and materials.18
In 2004, the Society of Hospital Medicine (SHM) collaborated with the Centers for Disease Control and Prevention (CDC) to develop a quality improvement tool kit to reduce antimicrobial resistance and health careassociated infections. The tool kit was based on the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings (Campaign), an educational program targeted at clinicians.19 The SHM/CDC tool kit contained campaign materials, a set of slides about quality improvement, worksheets, and additional materials such as infection control policies and guidelines to supplement a 90‐minute workshop consisting of didactic lectures about antimicrobial resistance, quality improvement initiatives, RCA, and HFMEA; a lecture and case study about intravascular catheter‐related infections; and small‐group activity and discussion. The complete toolkit is now available online via the SHM Antimicrobial Resistance Resource Room at
The purpose of the workshop was to present the tool kit and increase hospitalists' knowledge and awareness about antimicrobial resistance, health careassociated infections, and quality improvement programs. We assessed the workshop participants' familiarity with the Campaign prior to the workshop, perceptions of antimicrobial resistance, knowledge gained as a result of the workshop, and opinions about the usefulness of the workshop.
METHODS
Data were collected from pretests and posttests administered to participants of one of the SHM workshops in May, June, or July 2005 in Denver, Colorado; Boston, Massachusetts; or Portland, Oregon. One SHM physician leader (D.D.D., coauthor of this article) presented all 3 workshops. The workshops were advertised by SHM using E‐mail to local chapter members. Individual sites used a variety of methods to encourage their hospitalists to attend, and participants were provided a complimentary dinner.
Prior to each workshop, participants completed a 10‐question pretest that had been pilot‐tested by hospitalists in other cities. The pretest assessed demographics; perceptions of the problem of antimicrobial resistance using a Likert scale; familiarity with the Campaign; and knowledge of common infection sites, RCA, HFMEA, and antimicrobial resistance prevention measures.
Immediately following each workshop, a 13‐question posttest was administered to participants. This posttest evaluated the workshop and materials using Likert scales, asked for suggestions for future programming using open‐ended questions, and repeated pretest questions to assess changes in perceptions and knowledge.
Data were entered into an Excel spreadsheet and analyzed using descriptive statistics and t tests to compare pre‐ and posttest changes in knowledge. Likert data assessing perceptions were dichotomized into strongly agree versus all other scale responses. Qualitative open‐ended responses were categorized by theme.
RESULTS
A total of 69 SHM members attended the workshops. Of the 69 participants, 65 completed the pretest, 53 completed the posttest, and 50 completed both the pre‐ and the posttests. Only participants who completed both the pretest and the posttest were included in the analyses (n = 21, Denver; n = 11, Boston; n = 18, Portland). Of the 50 participants who completed both the pre‐ and posttests, 44 (88%) classified themselves as hospitalists in practices ranging from 2 to more than 25 physicians. Participants averaged 9.2 years (range = 1‐27 years) in practice and 4.9 years (range = 1‐10 years) as practicing hospitalists, with no significant differences between the 3 groups. Only 17 participants (34%) were familiar with the Campaign prior to the workshop, and there was no significant variation between the 3 workshops. Those familiar with the Campaign had heard about or received the educational materials from colleagues (n = 5), their facilities (n = 4), professional journals (n = 4), medical conferences (n = 4), or the CDC or SHM websites (n = 4).
Overall, most participants strongly agreed with the statement that antimicrobial resistance was a problem nationally, institutionally, and within their individual practices (Table 1). These perceptions did not significantly differ between the pretest and the posttest. However, statistically significant differences were found when comparing perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels; more participants strongly agreed that antimicrobial resistance was a problem nationally than within their institutions (pretest, P = .01; posttest, P = .04) or within their practices (pretest, P < .0001; posttest, P = .01).
| Nationally | Institutionally | Within own practice | ||||
|---|---|---|---|---|---|---|
| Pretest | Posttest | Pretest | Posttest | Pretest | Posttest | |
| ||||||
| Denver (n = 21) | 100% | 100% | 86% | 95% | 67% | 86% |
| Portland (n = 18) | 83% | 94% | 67% | 78% | 67% | 78% |
| Boston (n = 11) | 91% | 82% | 91% | 82% | 91% | 82% |
| Average | 91% | 94% | 81% | 85% | 72% | 82% |
| P value | .28 | .18 | .06 | |||
On the knowledge‐based questions, the overall average test score was 48% on the pretest and 63% on the posttest (P < .0001), with scores varying by question (Table 2). For example, knowledge of quality improvement initiatives/HFMEA was low (an average of 10% correct on the pretest, 48% on the posttest) compared with knowledge about the key prevention strategies from the Campaign to Prevent Antimicrobial Resistance (average of 94% correct on the pretest, 98% on the posttest). Furthermore, scores also varied by workshop location. On the pretest, participants in Boston and Portland scored higher (both 53%) than Denver participants (40%). On the posttest, Portland participants scored the highest (78%) followed by Boston participants (64%) and then Denver participants (50%). Boston and Denver participants differed significantly on pretest knowledge score (P = .04) and Portland and Denver participants differed significantly on posttest knowledge score (P < .0001).
| Question Topic | Pretest average | Posttest average | Percent difference (P value)* |
|---|---|---|---|
| |||
| Quality improvement initiatives/HFMEA Which quality improvement initiative(s) must be performed yearly by all hospitals (JCAHO accreditation requirement)? | 10% | 48% | 38% (P < .0001) |
| Prevention of central venous catheter‐associated bloodstream infections: Key prevention steps for preventing central venous catheter‐associated bloodstream infections include all of the following except: | 62% | 88% | 26% (P = .0001) |
| RCA Which of the following is NOT true about root cause analysis? | 20% | 38% | 18% (P = .01) |
| Campaign to Prevent Antimicrobial Resistance The key prevention strategies from the Campaign to Prevent Antimicrobial Resistance include all of the following except: | 94% | 98% | 4% (P = .32) |
| Common body sites for healthcare‐associated infection: The most common site of hospital‐acquired (nosocomial) infection is: | 52% | 44% | 8% (P = .29) |
| Overall average | 48% | 63% | 15% (P < .0001) |
Overall, 43 participants (85%) rated the workshop as either very good or excellent. All but 1 participant (n = 49, 98%) would encourage a colleague to attend the workshop, giving reasons such as that the workshop outlined a major program in delivering good and safe care, offered great information on antimicrobial resistance and methods of quality improvement systems implementation, assisted in find[ing] new tools for improving hospital practice, and addressed a significant factor in hospitals related to morbidity [and] mortality. When asked for general comments about the workshop and suggestions for future improvements, participants requested more direction, more detail, more discussion, specific examples of antimicrobial resistance, and protocols and processes for implementing quality improvement programs. On a scale from 1 (not useful) to 5 (essential), participants rated the usefulness of each workshop segment: intravascular catheter‐related infections lecture and case study (x̄ = 4.3, range = 3‐5), quality improvement initiatives lecture (x̄ = 4.1, range = 2‐5), background on antimicrobial resistance (x̄ = 3.9, range = 2‐5), RCA lecture (x̄ = 3.9, range = 2‐5), HFMEA lecture (x̄ = 3.8, range = 2‐5), and small‐group discussion (x̄ = 3.4, range = 2‐5). These ratings did not vary significantly between the 3 groups.
CONCLUSIONS
To address antimicrobial resistance and health careassociated infections in the hospital setting, the SHM and CDC developed a tool kit and presented a quality improvement workshop to hospitalists in 3 U.S. cities. Overall, the participants scored significantly higher on the knowledge‐based questions on the posttest than on the pretest, indicating that knowledge improved as a result of the workshop. By providing a format that combined didactic lectures with case‐based education, small‐group activities, and discussion, the SHM workshop may have optimized its ability to increase knowledge, similar to the findings in previous research.2021
There were no significant differences between the 3 groups in years of practice, perceptions of the problem, and overall evaluation of the workshop. However, differences were found in knowledge gained as a result of the workshop. For example, the Denver group scored lower on the knowledge‐based questions than did the Boston group on the pretest and the Portland group on the posttest, indicating that knowledge and learning styles may differ by location. These differences may be attributed to variations in hospital environments, hospital‐based educational programs, or medical school and residency training. Differences like these may impact the effectiveness of a program and should be a consideration in the program development process, especially when a program is national in scope, like the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. In addition, more than 90% of participants correctly identified key prevention strategies of the Campaign, whereas only 34% were familiar with the Campaign itself prior to the workshop. This result may be a result of the key prevention strategies of the Campaign being derived from well‐established and ‐recognized evidence‐based best practices for patient safety and care.
Although knowledge changed as a result of the workshop, overall perceptions of the problem of antimicrobial resistance did not change significantly from pretest to posttest. It is possible this is because changes in perception require a different or more intensive educational approach. This result also may reflect the initial levels of agreement on the pretest, the measurement instrument itself, and/or the inability to detect differences because of the small number of participants.
Difference did exist in perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels. Antimicrobial resistance was perceived to be a greater problem on the national level than on the institutional and practice levels. Other studies also have found that clinicians more strongly agree that antimicrobial resistance is a problem nationally than within their institutions and practices.2224 When antimicrobial resistance is not perceived as a problem within institutions and practices, physicians may be less likely to overcome the barriers to following recommended infection prevention guidelines or to implementing quality improvement projects.4 Therefore, educational and intervention efforts like this workshop should address hospitalists' perceptions of the problem of antimicrobial resistance on the individual level as a first step in motivating them to engage in quality improvement.
Although participants' knowledge scores increased from pretest to posttest, gaps in knowledge remained, as indicated by the significantly improved but low overall posttest scores related to RCA and HFMEA. As hospitalists are in a unique position to promote quality improvement programs, these topic areas should be given more attention in future workshops and in training. Furthermore, by adding more specific questions related to each section of the workshop, associations among presentation style, knowledge gained, and perceived usefulness of each section could be evaluated. For example, the participants significantly increased their scores from pretest to posttest on the catheter‐related knowledge‐based question and rated the lecture and case study on intravascular catheter‐related infections as the most useful sections. Future research may explore these possible relationships to better guide selection of presentation styles and topics to ensure that participants gain knowledge and perceive the sections as useful. In addition, by addressing the feedback from participants, such as offering more detail, examples, and discussion, future workshops may have greater perceived usefulness and be better able to increase the knowledge and awareness of quality improvement programs for the prevention of health careassociated infections and antimicrobial resistance.
Although there were 3 workshops conducted in 3 areas across the United States, the sample size at each site was small, and results may not be representative of hospitalists at large. In addition, power calculations should be considered in future studies to increase the ability to better detect differences between and within groups. Another limitation of this study was that the limited data available and participant anonymity meant it was not possible to follow‐up with participants after the workshop to evaluate whether the knowledge they gained was sustained and/or whether they reported changes in practice. However, possession of knowledge and skills to inform practice does not mean that practice will change; therefore, follow‐up is necessary to determine if this workshop was effective in changing behaviors in the long term.25 Although the SHM workshop improved knowledge, more intensive educational strategies may be necessary to affect perceptions and improve the leadership skills required for implementation of quality improvement programs at an institutional level.
Overall, the SHM workshop was found to be a useful tool for increasing knowledge and outlining methods by which hospitalists can lead, coordinate, or participate in measures to prevent infections and improve patient safety. In addition, through the workshop, the SHM and the CDC have provided an example of how professional societies and government agencies can collaborate to address emerging issues in the health care setting.
In the United States, hospitalized patients are at risk of acquiring health careassociated infections that increase morbidity, mortality, length of hospital stay, and cost of care.1 If a health careassociated infection is caused by an antimicrobial‐resistant pathogen, treatment efforts may be further complicated.2, 3 With the decreasing effectiveness of antimicrobials and suboptimal adherence to certain infection control measures, new and multifaceted prevention strategies are necessary to address the problem of health careassociated infections and antimicrobial resistance.410
One strategy that hospitals can use to reduce the incidence of health careassociated infections and antimicrobial resistance is implementation of quality improvement programs. These programs require clinicians to employ techniques, such as root cause analysis (RCA), which investigates contributing factors to an event to prevent reoccurrence, and healthcare failure mode effects analysis (HFMEA), which applies a systematic method of identifying and preventing problems before they occur.1113 Programs and strategies such as these require leadership and adoption within the hospital. Because of their availability and specialized role in the hospital setting, hospitalists are in a unique position to promote and uphold quality improvement efforts.1417 Professional societies, health care organizations, and governmental agencies can play a role in engaging this group of physicians in improving the quality of patient care in hospitals by providing educational programs and materials.18
In 2004, the Society of Hospital Medicine (SHM) collaborated with the Centers for Disease Control and Prevention (CDC) to develop a quality improvement tool kit to reduce antimicrobial resistance and health careassociated infections. The tool kit was based on the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings (Campaign), an educational program targeted at clinicians.19 The SHM/CDC tool kit contained campaign materials, a set of slides about quality improvement, worksheets, and additional materials such as infection control policies and guidelines to supplement a 90‐minute workshop consisting of didactic lectures about antimicrobial resistance, quality improvement initiatives, RCA, and HFMEA; a lecture and case study about intravascular catheter‐related infections; and small‐group activity and discussion. The complete toolkit is now available online via the SHM Antimicrobial Resistance Resource Room at
The purpose of the workshop was to present the tool kit and increase hospitalists' knowledge and awareness about antimicrobial resistance, health careassociated infections, and quality improvement programs. We assessed the workshop participants' familiarity with the Campaign prior to the workshop, perceptions of antimicrobial resistance, knowledge gained as a result of the workshop, and opinions about the usefulness of the workshop.
METHODS
Data were collected from pretests and posttests administered to participants of one of the SHM workshops in May, June, or July 2005 in Denver, Colorado; Boston, Massachusetts; or Portland, Oregon. One SHM physician leader (D.D.D., coauthor of this article) presented all 3 workshops. The workshops were advertised by SHM using E‐mail to local chapter members. Individual sites used a variety of methods to encourage their hospitalists to attend, and participants were provided a complimentary dinner.
Prior to each workshop, participants completed a 10‐question pretest that had been pilot‐tested by hospitalists in other cities. The pretest assessed demographics; perceptions of the problem of antimicrobial resistance using a Likert scale; familiarity with the Campaign; and knowledge of common infection sites, RCA, HFMEA, and antimicrobial resistance prevention measures.
Immediately following each workshop, a 13‐question posttest was administered to participants. This posttest evaluated the workshop and materials using Likert scales, asked for suggestions for future programming using open‐ended questions, and repeated pretest questions to assess changes in perceptions and knowledge.
Data were entered into an Excel spreadsheet and analyzed using descriptive statistics and t tests to compare pre‐ and posttest changes in knowledge. Likert data assessing perceptions were dichotomized into strongly agree versus all other scale responses. Qualitative open‐ended responses were categorized by theme.
RESULTS
A total of 69 SHM members attended the workshops. Of the 69 participants, 65 completed the pretest, 53 completed the posttest, and 50 completed both the pre‐ and the posttests. Only participants who completed both the pretest and the posttest were included in the analyses (n = 21, Denver; n = 11, Boston; n = 18, Portland). Of the 50 participants who completed both the pre‐ and posttests, 44 (88%) classified themselves as hospitalists in practices ranging from 2 to more than 25 physicians. Participants averaged 9.2 years (range = 1‐27 years) in practice and 4.9 years (range = 1‐10 years) as practicing hospitalists, with no significant differences between the 3 groups. Only 17 participants (34%) were familiar with the Campaign prior to the workshop, and there was no significant variation between the 3 workshops. Those familiar with the Campaign had heard about or received the educational materials from colleagues (n = 5), their facilities (n = 4), professional journals (n = 4), medical conferences (n = 4), or the CDC or SHM websites (n = 4).
Overall, most participants strongly agreed with the statement that antimicrobial resistance was a problem nationally, institutionally, and within their individual practices (Table 1). These perceptions did not significantly differ between the pretest and the posttest. However, statistically significant differences were found when comparing perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels; more participants strongly agreed that antimicrobial resistance was a problem nationally than within their institutions (pretest, P = .01; posttest, P = .04) or within their practices (pretest, P < .0001; posttest, P = .01).
| Nationally | Institutionally | Within own practice | ||||
|---|---|---|---|---|---|---|
| Pretest | Posttest | Pretest | Posttest | Pretest | Posttest | |
| ||||||
| Denver (n = 21) | 100% | 100% | 86% | 95% | 67% | 86% |
| Portland (n = 18) | 83% | 94% | 67% | 78% | 67% | 78% |
| Boston (n = 11) | 91% | 82% | 91% | 82% | 91% | 82% |
| Average | 91% | 94% | 81% | 85% | 72% | 82% |
| P value | .28 | .18 | .06 | |||
On the knowledge‐based questions, the overall average test score was 48% on the pretest and 63% on the posttest (P < .0001), with scores varying by question (Table 2). For example, knowledge of quality improvement initiatives/HFMEA was low (an average of 10% correct on the pretest, 48% on the posttest) compared with knowledge about the key prevention strategies from the Campaign to Prevent Antimicrobial Resistance (average of 94% correct on the pretest, 98% on the posttest). Furthermore, scores also varied by workshop location. On the pretest, participants in Boston and Portland scored higher (both 53%) than Denver participants (40%). On the posttest, Portland participants scored the highest (78%) followed by Boston participants (64%) and then Denver participants (50%). Boston and Denver participants differed significantly on pretest knowledge score (P = .04) and Portland and Denver participants differed significantly on posttest knowledge score (P < .0001).
| Question Topic | Pretest average | Posttest average | Percent difference (P value)* |
|---|---|---|---|
| |||
| Quality improvement initiatives/HFMEA Which quality improvement initiative(s) must be performed yearly by all hospitals (JCAHO accreditation requirement)? | 10% | 48% | 38% (P < .0001) |
| Prevention of central venous catheter‐associated bloodstream infections: Key prevention steps for preventing central venous catheter‐associated bloodstream infections include all of the following except: | 62% | 88% | 26% (P = .0001) |
| RCA Which of the following is NOT true about root cause analysis? | 20% | 38% | 18% (P = .01) |
| Campaign to Prevent Antimicrobial Resistance The key prevention strategies from the Campaign to Prevent Antimicrobial Resistance include all of the following except: | 94% | 98% | 4% (P = .32) |
| Common body sites for healthcare‐associated infection: The most common site of hospital‐acquired (nosocomial) infection is: | 52% | 44% | 8% (P = .29) |
| Overall average | 48% | 63% | 15% (P < .0001) |
Overall, 43 participants (85%) rated the workshop as either very good or excellent. All but 1 participant (n = 49, 98%) would encourage a colleague to attend the workshop, giving reasons such as that the workshop outlined a major program in delivering good and safe care, offered great information on antimicrobial resistance and methods of quality improvement systems implementation, assisted in find[ing] new tools for improving hospital practice, and addressed a significant factor in hospitals related to morbidity [and] mortality. When asked for general comments about the workshop and suggestions for future improvements, participants requested more direction, more detail, more discussion, specific examples of antimicrobial resistance, and protocols and processes for implementing quality improvement programs. On a scale from 1 (not useful) to 5 (essential), participants rated the usefulness of each workshop segment: intravascular catheter‐related infections lecture and case study (x̄ = 4.3, range = 3‐5), quality improvement initiatives lecture (x̄ = 4.1, range = 2‐5), background on antimicrobial resistance (x̄ = 3.9, range = 2‐5), RCA lecture (x̄ = 3.9, range = 2‐5), HFMEA lecture (x̄ = 3.8, range = 2‐5), and small‐group discussion (x̄ = 3.4, range = 2‐5). These ratings did not vary significantly between the 3 groups.
CONCLUSIONS
To address antimicrobial resistance and health careassociated infections in the hospital setting, the SHM and CDC developed a tool kit and presented a quality improvement workshop to hospitalists in 3 U.S. cities. Overall, the participants scored significantly higher on the knowledge‐based questions on the posttest than on the pretest, indicating that knowledge improved as a result of the workshop. By providing a format that combined didactic lectures with case‐based education, small‐group activities, and discussion, the SHM workshop may have optimized its ability to increase knowledge, similar to the findings in previous research.2021
There were no significant differences between the 3 groups in years of practice, perceptions of the problem, and overall evaluation of the workshop. However, differences were found in knowledge gained as a result of the workshop. For example, the Denver group scored lower on the knowledge‐based questions than did the Boston group on the pretest and the Portland group on the posttest, indicating that knowledge and learning styles may differ by location. These differences may be attributed to variations in hospital environments, hospital‐based educational programs, or medical school and residency training. Differences like these may impact the effectiveness of a program and should be a consideration in the program development process, especially when a program is national in scope, like the CDC's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. In addition, more than 90% of participants correctly identified key prevention strategies of the Campaign, whereas only 34% were familiar with the Campaign itself prior to the workshop. This result may be a result of the key prevention strategies of the Campaign being derived from well‐established and ‐recognized evidence‐based best practices for patient safety and care.
Although knowledge changed as a result of the workshop, overall perceptions of the problem of antimicrobial resistance did not change significantly from pretest to posttest. It is possible this is because changes in perception require a different or more intensive educational approach. This result also may reflect the initial levels of agreement on the pretest, the measurement instrument itself, and/or the inability to detect differences because of the small number of participants.
Difference did exist in perceptions of the problem of antimicrobial resistance at the national, institutional, and practice levels. Antimicrobial resistance was perceived to be a greater problem on the national level than on the institutional and practice levels. Other studies also have found that clinicians more strongly agree that antimicrobial resistance is a problem nationally than within their institutions and practices.2224 When antimicrobial resistance is not perceived as a problem within institutions and practices, physicians may be less likely to overcome the barriers to following recommended infection prevention guidelines or to implementing quality improvement projects.4 Therefore, educational and intervention efforts like this workshop should address hospitalists' perceptions of the problem of antimicrobial resistance on the individual level as a first step in motivating them to engage in quality improvement.
Although participants' knowledge scores increased from pretest to posttest, gaps in knowledge remained, as indicated by the significantly improved but low overall posttest scores related to RCA and HFMEA. As hospitalists are in a unique position to promote quality improvement programs, these topic areas should be given more attention in future workshops and in training. Furthermore, by adding more specific questions related to each section of the workshop, associations among presentation style, knowledge gained, and perceived usefulness of each section could be evaluated. For example, the participants significantly increased their scores from pretest to posttest on the catheter‐related knowledge‐based question and rated the lecture and case study on intravascular catheter‐related infections as the most useful sections. Future research may explore these possible relationships to better guide selection of presentation styles and topics to ensure that participants gain knowledge and perceive the sections as useful. In addition, by addressing the feedback from participants, such as offering more detail, examples, and discussion, future workshops may have greater perceived usefulness and be better able to increase the knowledge and awareness of quality improvement programs for the prevention of health careassociated infections and antimicrobial resistance.
Although there were 3 workshops conducted in 3 areas across the United States, the sample size at each site was small, and results may not be representative of hospitalists at large. In addition, power calculations should be considered in future studies to increase the ability to better detect differences between and within groups. Another limitation of this study was that the limited data available and participant anonymity meant it was not possible to follow‐up with participants after the workshop to evaluate whether the knowledge they gained was sustained and/or whether they reported changes in practice. However, possession of knowledge and skills to inform practice does not mean that practice will change; therefore, follow‐up is necessary to determine if this workshop was effective in changing behaviors in the long term.25 Although the SHM workshop improved knowledge, more intensive educational strategies may be necessary to affect perceptions and improve the leadership skills required for implementation of quality improvement programs at an institutional level.
Overall, the SHM workshop was found to be a useful tool for increasing knowledge and outlining methods by which hospitalists can lead, coordinate, or participate in measures to prevent infections and improve patient safety. In addition, through the workshop, the SHM and the CDC have provided an example of how professional societies and government agencies can collaborate to address emerging issues in the health care setting.
- ,,.Impact of nosocomial infection on cost of illness and length of stay in intensive care units.Infect Control Hosp Epidemiol2005;26:281–287.
- .Implementation of strategies to control antimicrobial resistance.Chest.2001;119:405S–411S.
- ,,, et al.Society for Healthcare Epidemiology of America and Infectious Diseases Society of American Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.Clin Infect Dis.1997;25:584–599.
- ,,, et al.Strategies to prevent and control the emergence and spread of antimicrobial‐resistant microorganisms in hospitals: a challenge to hospital leadership.JAMA.1996;275:234–240.
- Centers for Disease Control and Prevention.Guidelines for hand hygiene in health‐care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force.MMWR Recomm Rep.2002;51:1–44.
- .Hospital Infection Control Practices Advisory Committee.Guideline for isolation precautions in hospitals.Infect Control Hosp Epidemiol.1996;17:53–80.
- ,,, et al.SHEA guideline for prevention nosocomial transmission of multidrug‐resistant strains of Staphylococcus aureus and Enterococcus.Infect Control Hosp Epidemiol.2003;24:362–386.
- .Improving adherence to hand hygiene practice: a multidisciplinary approach.Emerg Infect Dis.2001;7:234–240.
- ,,.Alcohol‐based handrub improves compliance with hand hygiene in intensive care units.Arch Intern Med.2002;162:1037–1043.
- ,,, et al.An organizational climate intervention associated with increased handwashing and decreased nosocomial infections.Behav Med.2000;26:14–22.
- ,.Getting to the root of the matter.AHRQ Web M 29:319–330.
- ,,.The Basics of FMEA.New York:Quality Resources;1996.
- .The hospitalist model of care: A positive influence on efficiency, quality of care, and outcomes.Crit Path Cardiol.2004;3:S5–S7.
- .An introduction to the hospitalist model.Ann Intern Med.1999;130:338–342.
- .The impact of hospitalists on medical education and the academic health systems.Ann Intern Med.1999;130:364–367.
- ,,, et al.Hospitalists' perceptions of their residency training needs: Results of a national survey.Am J Med.2001;111:247–254.
- ,,.Preventing the emergence of antimicrobial resistance: A call for action by clinicians, public health officials and patients.JAMA1997;278:944–945.
- Centers for Disease Control and Prevention. Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. 2005. Available at: URL: http://www.cdc.gov/drugresistance/healthcare/default.htm. Accessed November 8,2005.
- ,,, et al.Impact of formal continuing medical education: Do conferences, workshops, rounds and other traditional continuing education activities change physician behavior or health care outcomes?JAMA.1999;282:867–874.
- ,,, et al.Physician preferences for continuing medical education with a focus on the topic of antimicrobial resistance: Society for Healthcare Epidemiology of America.Infect Control Hosp Epidemiol.2001;22:656–660.
- ,,, et al.Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities.Arch Intern Med.2004;164:1662–1668.
- ,,, et al.Antibiotic resistance: a survey of physician perceptions.Arch Intern Med.2002;162:2210–2216.
- ,,, et al.Assessing motivation for physicians to prevent antimicrobial resistance in hospitalized children using the health belief model as a framework.Am J Infect Control.2004;33:175–181.
- .Educational theory into practice: Development of an infection control link nurse programme.Nurs Ed Pract.2001;1:35–41.
- ,,.Impact of nosocomial infection on cost of illness and length of stay in intensive care units.Infect Control Hosp Epidemiol2005;26:281–287.
- .Implementation of strategies to control antimicrobial resistance.Chest.2001;119:405S–411S.
- ,,, et al.Society for Healthcare Epidemiology of America and Infectious Diseases Society of American Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.Clin Infect Dis.1997;25:584–599.
- ,,, et al.Strategies to prevent and control the emergence and spread of antimicrobial‐resistant microorganisms in hospitals: a challenge to hospital leadership.JAMA.1996;275:234–240.
- Centers for Disease Control and Prevention.Guidelines for hand hygiene in health‐care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force.MMWR Recomm Rep.2002;51:1–44.
- .Hospital Infection Control Practices Advisory Committee.Guideline for isolation precautions in hospitals.Infect Control Hosp Epidemiol.1996;17:53–80.
- ,,, et al.SHEA guideline for prevention nosocomial transmission of multidrug‐resistant strains of Staphylococcus aureus and Enterococcus.Infect Control Hosp Epidemiol.2003;24:362–386.
- .Improving adherence to hand hygiene practice: a multidisciplinary approach.Emerg Infect Dis.2001;7:234–240.
- ,,.Alcohol‐based handrub improves compliance with hand hygiene in intensive care units.Arch Intern Med.2002;162:1037–1043.
- ,,, et al.An organizational climate intervention associated with increased handwashing and decreased nosocomial infections.Behav Med.2000;26:14–22.
- ,.Getting to the root of the matter.AHRQ Web M 29:319–330.
- ,,.The Basics of FMEA.New York:Quality Resources;1996.
- .The hospitalist model of care: A positive influence on efficiency, quality of care, and outcomes.Crit Path Cardiol.2004;3:S5–S7.
- .An introduction to the hospitalist model.Ann Intern Med.1999;130:338–342.
- .The impact of hospitalists on medical education and the academic health systems.Ann Intern Med.1999;130:364–367.
- ,,, et al.Hospitalists' perceptions of their residency training needs: Results of a national survey.Am J Med.2001;111:247–254.
- ,,.Preventing the emergence of antimicrobial resistance: A call for action by clinicians, public health officials and patients.JAMA1997;278:944–945.
- Centers for Disease Control and Prevention. Campaign to Prevent Antimicrobial Resistance in Healthcare Settings. 2005. Available at: URL: http://www.cdc.gov/drugresistance/healthcare/default.htm. Accessed November 8,2005.
- ,,, et al.Impact of formal continuing medical education: Do conferences, workshops, rounds and other traditional continuing education activities change physician behavior or health care outcomes?JAMA.1999;282:867–874.
- ,,, et al.Physician preferences for continuing medical education with a focus on the topic of antimicrobial resistance: Society for Healthcare Epidemiology of America.Infect Control Hosp Epidemiol.2001;22:656–660.
- ,,, et al.Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities.Arch Intern Med.2004;164:1662–1668.
- ,,, et al.Antibiotic resistance: a survey of physician perceptions.Arch Intern Med.2002;162:2210–2216.
- ,,, et al.Assessing motivation for physicians to prevent antimicrobial resistance in hospitalized children using the health belief model as a framework.Am J Infect Control.2004;33:175–181.
- .Educational theory into practice: Development of an infection control link nurse programme.Nurs Ed Pract.2001;1:35–41.
Copyright © 2007 Society of Hospital Medicine
Consequences of Missed Opportunities
A 58‐year‐old man was evaluated for 3 weeks of leg numbness and weakness. His symptoms began with numbness and tingling in the distal left leg that progressed to weakness that impaired his ability to walk. He had no history of trauma or incontinence but endorsed several months of back pain that worsened when lying flat. He had a history of type 2 diabetes mellitus, hepatitis C infection, hypertension, and posttraumatic stress disorder. He had a remote history of intravenous drug use and had quit tobacco 9 years earlier. Medications he was taking included hydrochlorothiazide, rosiglitazone, oxycodone/acetaminophen, baclofen, ibuprofen, and gabapentin.
Internists see this constellation of complaints frequently in an acute care setting. Finding a unifying diagnosis may be difficult initially, so thinking of the symptoms in series is helpful. The complaint of leg weakness and the pattern of numbness should be further elucidated. Is this true weakness, or is it a feeling of instability because of foot numbness? What is the pattern of the numbness? Peripheral neuropathy typically begins in a symmetric stocking pattern (involving the plantar surface of the feet), then progresses to a glove distribution (involving the hands from the fingers distally to the wrist proximally). Such a pattern in a patient with diabetes would be consistent with distal polyneuropathy, a mixed sensory and motor process. Other possible causes of peripheral neuropathy in this patient include HIV, B12 deficiency, and syphilis. These symptoms could be tied to the back pain if this were intervertebral disk disease, a compression fracture, or a lytic lesion in the vertebrae with resulting nerve impingement or if it were epidural spinal cord compression. The lack of bowel or bladder dysfunction speaks against a cauda equina syndrome but does not rule out more cepahalad spinal pathology.
On neurological examination, I would concentrate on differentiating weakness from pain. I would attempt to determine whether the weakness was of central or peripheral nerve etiology. Helpful findings would include increased tone with upper motor lesions and flaccid tone with lower motor lesions, hyperreflexia with upper motor lesions and hyporeflexia with lower motor lesions, a Babinski sign, muscle atrophy or fasciculations, and gait. A rectal examination would also be helpful to assess for deficits in rectal tone, wink reflex, or saddle anesthesia.
All patients with low back pain who have alarm signs of age older than 50, pain duration of more than 1 month, known cancer, lack of relief with conservative measures, or systemic B symptoms should have imaging of the spine. Although plain films may reveal bony abnormalities, computed tomography (CT) is better for evaluating osseous structures and magnetic resonance imaging (MRI) for evaluating pathology in patients suspected of having an infection or a malignancy. I would obtain imaging of the spine in this patient.
The patient was receiving care at an outside clinic for 2 liver lesions discovered on abdominal ultrasound 19 months prior to admission. CT showed that the lesions were 4.0 and 2.3 cm in diameter 17 months prior to admission and 5.0 and 3.0 cm in diameter 5 months prior to admission. No cirrhosis was appreciated on the ultrasound or CT. The patient was referred for CT‐guided biopsy of the larger mass after the second CT, but he became anxious and left before the biopsy was obtained.
This piece of the history is ominous, as it increases the possibility of cancer in our differential. Metastatic disease could provide a unifying diagnosis, explaining the constellation of back pain, leg weakness, and liver lesions. Lung cancer commonly metastasizes to the liver and to bone, so I would obtain a chest x‐ray. Other possible types of cancer in this situation include cancer of the prostate, colon, or thyroid and melanoma. In this patient, who has hepatitis C, hepatocellular carcinoma (HCC) could be the primary etiology, although cirrhosis was not seen on CT and HCC metastasizes to the spine less commonly than do other primary cancers (eg, lung, breast, prostate). Nonetheless, I would obtain an alpha‐fetoprotein level, which would confirm HCC in a patient with liver lesions if it was greater than 200 g/L. Pancreatic cancer has been associated with both type 2 diabetes and liver lesions and could explain his abdominal pain.
There is no comment on the arterial‐phase CT imaging of the liver lesions. Dual‐phase CT scans examine the hepatic arterial and portal vein phases of contrast filling. Triple‐phase CT scans also examine the portal vein influx phase. Both hemangiomas and hypervascular HCCs enhance on the arterial phase, as they derive their blood flow from the hepatic artery. Therefore, arterial‐phase imaging can help to distinguish vascular tumors that flush with contrast, such as hemangiomas, melanoma, and HCC, from less vascular tumors such as pancreatic and colon cancer. Other liver lesions such as focal nodular hyperplasia and adenomas cannot be excluded in this situation as they also may enhance during the arterial phase and can grow over time, as this patient's repeat imaging documented. It seems unlikely that this patient has a liver abscess because he has a paucity of constitutional symptoms and no travel history. The liver lesions seen on initial imaging were larger than 1.0 cm, so I would have favored an earlier biopsy to obtain a tissue diagnosis.
The patient was afebrile, and all other vital signs were normal. He appeared well nourished and anicteric. There was no lymphadenopathy. Cardiac auscultation was regular without murmurs. The lungs were clear. The abdomen was without fluid wave or hepatosplenomegaly and was tender to palpation in the right upper and lower quadrants. There was no midline tenderness to palpation of the spine.
Cranial nerves II‐XII were intact. Lower extremity muscle tone could not be accurately assessed due to splinting from back pain. Strength was 3 of 5 in the left hip extensors and left knee flexors and extensors, and 1 of 5 in the left hip flexors. He had no motor strength in the distal left lower extremity extensors. Bilateral upper extremity and right leg strength were normal. Sensation to light touch, temperature, and pain was decreased circumferentially below the xiphoid. The patient had hyperesthesia in a band around the thorax just above the xiphoid and paresthesia of the perineal area. Left patellar tendon reflexes were brisk, and left ankle jerk was absent, but other reflexes were normal. Toes were down‐going bilaterally. The anal wink was absent, and rectal tone was decreased. Results of the cerebellar exam were normal. Gait could not be assessed.
The results of the exam are notable for not showing the stigmata of end‐stage liver disease. The results of the neurological exam are concerning, with decreased sensation at approximately the T7 level that is almost certainly a result of epidural compression of the spinal cord. Hematogenous metastasis to the vertebrae from one of the tumors mentioned above, with spread into the thecal sac, is the most likely culprit. An epidural abscess is possible because the patient has diabetes and a history of injection drug use.
The thoracic spine is involved in 60% of spinal cord metastases. This patient's left‐sided distal leg weakness is consistent with having corticospinal tract compression and indicates thoracic spine involvement. Flaccid paralysis is classically found in lower motor neuron weakness, but is also seen in the early stages of upper motor neuron pathology. Lesions found above the cauda equina often spare the perineal area, but low thoracic lesions involving the conus medullaris (from T10 to L1) could explain both his loss of anal wink and his decreased rectal tone.
This patient's presentation is unfortunately classic for epidural spinal cord compression. Because the onset of compression is insidious, the diagnosis is often delayed, even in patients with known cancer. Urgent imaging is imperative to evaluate this possibility, as having any meaningful chance of recovery of function depends on rapid relief of the spinal cord compression. I would obtain an emergent MRI of the thoracic and lumbosacral spine.
Laboratory studies showed the following: hemoglobin, 13.1 g/dL; mean corpuscular volume, 80 m3; platelet count, 149,000/L; creatinine, 1.9 mg/dL; aspartate aminotransferase, 66 U/L (5‐35 U/L); alanine aminotransferase, 66 U/L (7‐56 U/L); alkaline phosphatase, 87 U/L (40‐125 U/L); total bilirubin, 1.3 mg/dL; prostate specific antigen (PSA), 1.6 g/dL; and alpha‐fetoprotein (AFP), 10.3 g/L. White cell count, sodium, glucose, calcium, and albumin levels, and prothrombin and partial‐thromboplastin times were within normal ranges.
His liver function tests likely reflect chronic hepatitis C infection. His renal insufficiency could be a result of hypertension, diabetes, or dehydration given that he has been bed‐bound.
Most intriguing are the normal PSA level and only slightly elevated AFP level. PSA is useful for detecting recurrence of prostate cancer or following response of therapy, but the utility of PSA as a screening tool remains controversial in part because of its low specificity. Prostate cancer is the most commonly diagnosed cancer among men and cannot be ruled out by a normal PSA. In a patient with hepatitis C, cirrhosis (which we have not conclusively diagnosed), and a radiologically suspicious liver lesion, an AFP > 200 g/L would be diagnostic of HCC. In this case, however, mildly elevated AFP does not help us to either diagnose or exclude HCC.
The chest x‐ray showed no abnormalities. MRI of the spine revealed lytic lesions in the T7‐T10 vertebral bodies with spinal cord compression at the T7 level (Fig. 1).
A repeat CT scan of the abdomen showed a coarse, nodular liver with 2 heterogeneous, early‐enhancing masses (4.7 4.2 and 3.4 2.4 cm in diameter) with surrounding satellite lesions (Fig. 2).
The enhancement pattern on dual‐phase liver protocol CT was not characteristic of HCC. The left portal vein was not visualized. Splenomegaly and esophageal varices were observed. The adrenal glands showed bilateral, heterogeneous enhancing masses. The epiphrenic, retroperitoneal, and periportal lymph nodes were enlarged. Lytic lesions were seen in the sacrum, left iliac wing, and T7‐T10 vertebral bodies.
Intravenous high‐dose steroids were started. The neurosurgery team advised that no surgical interventions were appropriate because of the patient's poor functional status and the extent of his disease.
It is unfortunate that no neurosurgical interventions could help this patient, especially because we are not yet sure of the final diagnosis. Standard indications for neurosurgical decompression include compression from bone fragments, spinal instability requiring fixation, and lack of response to radiation therapy. Patients must also be able to tolerate surgery. Although evidence supports the use of corticosteroids in reducing edema, inflammation, and neurological deficits in malignant spinal cord compression, there is not consensus on what the optimal dose is. Doses of 16‐100 mg of dexamethasone per day appear to be beneficial, as long as higher doses are rapidly tapered to avoid toxic effects. High‐dose steroids minimize the initial edema but are unlikely to change the long‐term outcome of patients who are nonambulatory on arrival.
The CT scan does not help us distinguish between metastatic cancer and primary HCC. Adrenal metastases are very uncommon in HCC. Lung cancer, however, metastasizes to the liver, adrenal glands, and spine, even without significant pulmonary symptoms. HCC may be seen on CT as a solitary mass, a dominant mass with surrounding satellite lesions, multifocal lesions, or a diffusely infiltrating tumor. This diagnosis now seems more likely given the finding of cirrhosis, which increases the risk of HCC in individuals with hepatitis C infection.
We need to obtain tissue for diagnosis and prognosis and to guide therapy. I would consult with radiology and gastroenterology colleagues about the best location to biopsy, but a bone biopsy should be avoided because the pathologic yield is lower.
The radiology and gastroenterology consultants recommended adrenal biopsy because there was easier posterior access for tissue. A liver biopsy was avoided because of the risk of bleeding with hypervascular masses. Fine‐needle aspiration of the mass in the right adrenal gland was performed. The pathology demonstrated bile production and hexagonal arrangement of cells with endothelial cuffing consistent with hepatocellular carcinoma. The oncology staff was consulted about palliative chemotherapy options. The patient began radiation therapy directed at the T7 lesion compressing the spinal cord. He regained minimal movement of his foot. After discussing treatment options with the oncology staff, the patient declined chemotherapy and was transitioned to hospice, where he died 3 weeks later.
COMMENTARY
Hepatocellular carcinoma (HCC) is the third‐leading cause of cancer death and the fifth‐leading cause of cancer worldwide. It causes nearly 1 million deaths annually, and unlike many other cancers, its incidence and mortality rate are rising. Most cases of HCC in Africa and Asia are a result of chronic hepatitis B infection, but in the United States HCC is primarily attributable to hepatitis C infection.1 The annual incidence of HCC in the U.S. population, now about 4 cases per 100,000 people,2 is rising because of the increased prevalence of hepatitis C. Other causes of HCC, such as alcoholic liver disease, hepatitis B infection, and hemochromatosis, have remained stable and have not contributed as significantly to the rising incidence of HCC. For the individual patient, hepatitis C infection conveys a 20‐fold increase in the risk for HCC (2%‐8% risk/year).1 Eighty percent of cases of HCC develop in patients with cirrhosis.3 Unlike patients with hepatitis B infection, persons chronically infected with hepatitis C rarely develop HCC unless they have cirrhosis.
The American Association for the Study of Liver Disease recommends that hepatitis Binfected individuals at high risk for HCC (eg, men older than 40 years and persons with cirrhosis or a family history of HCC) and hepatitis Cinfected individuals with cirrhosis4 be periodically screened for HCC with alpha‐fetoprotein (AFP) and ultrasonography (every 6 months to approximate the doubling time of the tumor5). Using the most commonly reported cutoff for a positive test result for hepatocellular carcinoma (AFP level > 20 g/L) resulted in the following test characteristics: sensitivity, 41%‐65%; specificity, 80%‐94%; positive likelihood ratio, 3.1‐6.8; and negative likelihood ratio, 0.4‐0.6.6 AFP alone is therefore a poor screening test for HCC, and as shown in this case, AFP levels can be normal or only minimally elevated in the setting of diffusely metastatic disease. Ultrasonography alone is only 35%‐87% sensitive in detecting HCC,79 but the combination of AFP and ultrasonography identified 100% of the HCC cases in one small case series.10
For the patient in this case, the optimal clinical pathway would have been to transition from screening to diagnostic measures in a timely manner. Consensus guidelines from the European Association for Study of the Liver in 2001 recommend biopsy of all focal liver lesions that are between 1 and 2 cm.11 The American Association for the Study of Liver Diseases (AASLD) recommends that focal liver lesions between 1 and 2 cm found on ultrasound in cirrhotic livers be followed by 2 dynamic studies: CT, MRI, or contrast ultrasound. If 2 separate studies reveal typical characteristics of HCC, then the lesion should be treated as HCC, and if not typical, then the lesion should be biopsied.4 Although no studies were available to support the recommendations, both the EASL and AASLD advise that lesions greater than 2 cm with demonstrated vascularity on both ultrasonography and CT can be diagnosed as HCC without biopsy and that lesions smaller than 1 cm be monitored.4, 11
Hepatocellular carcinoma can metastasize to almost anywhere in the body by hematologic or lymphatic spread or by direct extension. The most common site for metastases of HCC is the lung. Metastases to the lung arise primarily from arterial emboli and therefore are most common in the lower lobes, where there is greater perfusion.12 The second most common site is intraabdominal lymph nodes. The axial skeleton is the third most common site of metastases and, as in this case, primarily involves the spine.13 Other sites of metastases include the peritoneum, the inferior vena cava and right atrium by direct extension, and, less commonly, the gallbladder and spleen. Autopsy studies of patients with HCC found that 8% had metastases to the adrenal glands, as did this patient.13 Metastasis to the central nervous system is rare.
There were several challenging aspects of this case, including atypical radiologic appearance, an unusual metastatic pattern, and minimally elevated AFP level. This case raises 3 key points that we must remember as clinicians:
-
Patients infected with hepatitis C who are found to have suspicious hepatic lesions should be aggressively evaluated for HCC.
-
Using an AFP level < 20 g/L as a screening test is not helpful because this level can be seen even with widely metastatic disease.
-
Knowledge of available screening tests as well as the many possible manifestations of HCC helps clinicians to diagnose HCC earlier, when the disease is potentially curable.
Acknowledgements
The authors thank Gurpreet Dhaliwal, MD, for reviewing an early version of this manuscript.
- .Hepatocellular carcinoma: epidemiology, risk factors, and screening.Semin Liver Dis.2005;25:143–154.
- American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005. Available at: http://www.cancer.org/docroot/STT/stt_0.asp. Accessed October 17,2005.
- ,,.Hepatocellular carcinoma.Lancet.2003;362:1907–1917.
- ,.Management of hepatocellular carcinoma. AASLD Practice Guideline.Hepatology.2005;42:1208–1236.
- ,,, et al.Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.Gastroenterology.1985;89:259–266.
- ,,.Test characteristics of alpha‐fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C.Ann Intern Med.2003;139:46–50.
- ,,,.Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation.Am J Roentgenol.1998;171:433–435.
- ,,,,.Detection of malignant tumors in end‐stage cirrhotic livers: efficacy of sonography as a screening technique.Am J Roentgenol.1992;159:727–733.
- ,,, et al.The diagnosis of small hepatocellular carcinomas: efficacy of various imaging procedures in 100 patients.Am J Roentgenol.1990;155:49–54
- ,,,,,.Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis.Ann Surg.1998;277:513–518.
- ,,, et al.;EASL Panel of Experts on HCC.Clinical management of hepatocellular carcinoma: conclusions of the Barcelona‐2000 EASL conference: European Association for the Study of the Liver.J Hepatol.2001;35:421–430.
- ,,, et al.Extrahepatic spread of hepatocellular carcinoma: a pictorial review.Eur Radiol.2003;13:874–882.
- ,,,,,.Extrahepatic metastases of hepatocellular carcinoma.Radiology.2000;216:698–703.
A 58‐year‐old man was evaluated for 3 weeks of leg numbness and weakness. His symptoms began with numbness and tingling in the distal left leg that progressed to weakness that impaired his ability to walk. He had no history of trauma or incontinence but endorsed several months of back pain that worsened when lying flat. He had a history of type 2 diabetes mellitus, hepatitis C infection, hypertension, and posttraumatic stress disorder. He had a remote history of intravenous drug use and had quit tobacco 9 years earlier. Medications he was taking included hydrochlorothiazide, rosiglitazone, oxycodone/acetaminophen, baclofen, ibuprofen, and gabapentin.
Internists see this constellation of complaints frequently in an acute care setting. Finding a unifying diagnosis may be difficult initially, so thinking of the symptoms in series is helpful. The complaint of leg weakness and the pattern of numbness should be further elucidated. Is this true weakness, or is it a feeling of instability because of foot numbness? What is the pattern of the numbness? Peripheral neuropathy typically begins in a symmetric stocking pattern (involving the plantar surface of the feet), then progresses to a glove distribution (involving the hands from the fingers distally to the wrist proximally). Such a pattern in a patient with diabetes would be consistent with distal polyneuropathy, a mixed sensory and motor process. Other possible causes of peripheral neuropathy in this patient include HIV, B12 deficiency, and syphilis. These symptoms could be tied to the back pain if this were intervertebral disk disease, a compression fracture, or a lytic lesion in the vertebrae with resulting nerve impingement or if it were epidural spinal cord compression. The lack of bowel or bladder dysfunction speaks against a cauda equina syndrome but does not rule out more cepahalad spinal pathology.
On neurological examination, I would concentrate on differentiating weakness from pain. I would attempt to determine whether the weakness was of central or peripheral nerve etiology. Helpful findings would include increased tone with upper motor lesions and flaccid tone with lower motor lesions, hyperreflexia with upper motor lesions and hyporeflexia with lower motor lesions, a Babinski sign, muscle atrophy or fasciculations, and gait. A rectal examination would also be helpful to assess for deficits in rectal tone, wink reflex, or saddle anesthesia.
All patients with low back pain who have alarm signs of age older than 50, pain duration of more than 1 month, known cancer, lack of relief with conservative measures, or systemic B symptoms should have imaging of the spine. Although plain films may reveal bony abnormalities, computed tomography (CT) is better for evaluating osseous structures and magnetic resonance imaging (MRI) for evaluating pathology in patients suspected of having an infection or a malignancy. I would obtain imaging of the spine in this patient.
The patient was receiving care at an outside clinic for 2 liver lesions discovered on abdominal ultrasound 19 months prior to admission. CT showed that the lesions were 4.0 and 2.3 cm in diameter 17 months prior to admission and 5.0 and 3.0 cm in diameter 5 months prior to admission. No cirrhosis was appreciated on the ultrasound or CT. The patient was referred for CT‐guided biopsy of the larger mass after the second CT, but he became anxious and left before the biopsy was obtained.
This piece of the history is ominous, as it increases the possibility of cancer in our differential. Metastatic disease could provide a unifying diagnosis, explaining the constellation of back pain, leg weakness, and liver lesions. Lung cancer commonly metastasizes to the liver and to bone, so I would obtain a chest x‐ray. Other possible types of cancer in this situation include cancer of the prostate, colon, or thyroid and melanoma. In this patient, who has hepatitis C, hepatocellular carcinoma (HCC) could be the primary etiology, although cirrhosis was not seen on CT and HCC metastasizes to the spine less commonly than do other primary cancers (eg, lung, breast, prostate). Nonetheless, I would obtain an alpha‐fetoprotein level, which would confirm HCC in a patient with liver lesions if it was greater than 200 g/L. Pancreatic cancer has been associated with both type 2 diabetes and liver lesions and could explain his abdominal pain.
There is no comment on the arterial‐phase CT imaging of the liver lesions. Dual‐phase CT scans examine the hepatic arterial and portal vein phases of contrast filling. Triple‐phase CT scans also examine the portal vein influx phase. Both hemangiomas and hypervascular HCCs enhance on the arterial phase, as they derive their blood flow from the hepatic artery. Therefore, arterial‐phase imaging can help to distinguish vascular tumors that flush with contrast, such as hemangiomas, melanoma, and HCC, from less vascular tumors such as pancreatic and colon cancer. Other liver lesions such as focal nodular hyperplasia and adenomas cannot be excluded in this situation as they also may enhance during the arterial phase and can grow over time, as this patient's repeat imaging documented. It seems unlikely that this patient has a liver abscess because he has a paucity of constitutional symptoms and no travel history. The liver lesions seen on initial imaging were larger than 1.0 cm, so I would have favored an earlier biopsy to obtain a tissue diagnosis.
The patient was afebrile, and all other vital signs were normal. He appeared well nourished and anicteric. There was no lymphadenopathy. Cardiac auscultation was regular without murmurs. The lungs were clear. The abdomen was without fluid wave or hepatosplenomegaly and was tender to palpation in the right upper and lower quadrants. There was no midline tenderness to palpation of the spine.
Cranial nerves II‐XII were intact. Lower extremity muscle tone could not be accurately assessed due to splinting from back pain. Strength was 3 of 5 in the left hip extensors and left knee flexors and extensors, and 1 of 5 in the left hip flexors. He had no motor strength in the distal left lower extremity extensors. Bilateral upper extremity and right leg strength were normal. Sensation to light touch, temperature, and pain was decreased circumferentially below the xiphoid. The patient had hyperesthesia in a band around the thorax just above the xiphoid and paresthesia of the perineal area. Left patellar tendon reflexes were brisk, and left ankle jerk was absent, but other reflexes were normal. Toes were down‐going bilaterally. The anal wink was absent, and rectal tone was decreased. Results of the cerebellar exam were normal. Gait could not be assessed.
The results of the exam are notable for not showing the stigmata of end‐stage liver disease. The results of the neurological exam are concerning, with decreased sensation at approximately the T7 level that is almost certainly a result of epidural compression of the spinal cord. Hematogenous metastasis to the vertebrae from one of the tumors mentioned above, with spread into the thecal sac, is the most likely culprit. An epidural abscess is possible because the patient has diabetes and a history of injection drug use.
The thoracic spine is involved in 60% of spinal cord metastases. This patient's left‐sided distal leg weakness is consistent with having corticospinal tract compression and indicates thoracic spine involvement. Flaccid paralysis is classically found in lower motor neuron weakness, but is also seen in the early stages of upper motor neuron pathology. Lesions found above the cauda equina often spare the perineal area, but low thoracic lesions involving the conus medullaris (from T10 to L1) could explain both his loss of anal wink and his decreased rectal tone.
This patient's presentation is unfortunately classic for epidural spinal cord compression. Because the onset of compression is insidious, the diagnosis is often delayed, even in patients with known cancer. Urgent imaging is imperative to evaluate this possibility, as having any meaningful chance of recovery of function depends on rapid relief of the spinal cord compression. I would obtain an emergent MRI of the thoracic and lumbosacral spine.
Laboratory studies showed the following: hemoglobin, 13.1 g/dL; mean corpuscular volume, 80 m3; platelet count, 149,000/L; creatinine, 1.9 mg/dL; aspartate aminotransferase, 66 U/L (5‐35 U/L); alanine aminotransferase, 66 U/L (7‐56 U/L); alkaline phosphatase, 87 U/L (40‐125 U/L); total bilirubin, 1.3 mg/dL; prostate specific antigen (PSA), 1.6 g/dL; and alpha‐fetoprotein (AFP), 10.3 g/L. White cell count, sodium, glucose, calcium, and albumin levels, and prothrombin and partial‐thromboplastin times were within normal ranges.
His liver function tests likely reflect chronic hepatitis C infection. His renal insufficiency could be a result of hypertension, diabetes, or dehydration given that he has been bed‐bound.
Most intriguing are the normal PSA level and only slightly elevated AFP level. PSA is useful for detecting recurrence of prostate cancer or following response of therapy, but the utility of PSA as a screening tool remains controversial in part because of its low specificity. Prostate cancer is the most commonly diagnosed cancer among men and cannot be ruled out by a normal PSA. In a patient with hepatitis C, cirrhosis (which we have not conclusively diagnosed), and a radiologically suspicious liver lesion, an AFP > 200 g/L would be diagnostic of HCC. In this case, however, mildly elevated AFP does not help us to either diagnose or exclude HCC.
The chest x‐ray showed no abnormalities. MRI of the spine revealed lytic lesions in the T7‐T10 vertebral bodies with spinal cord compression at the T7 level (Fig. 1).
A repeat CT scan of the abdomen showed a coarse, nodular liver with 2 heterogeneous, early‐enhancing masses (4.7 4.2 and 3.4 2.4 cm in diameter) with surrounding satellite lesions (Fig. 2).
The enhancement pattern on dual‐phase liver protocol CT was not characteristic of HCC. The left portal vein was not visualized. Splenomegaly and esophageal varices were observed. The adrenal glands showed bilateral, heterogeneous enhancing masses. The epiphrenic, retroperitoneal, and periportal lymph nodes were enlarged. Lytic lesions were seen in the sacrum, left iliac wing, and T7‐T10 vertebral bodies.
Intravenous high‐dose steroids were started. The neurosurgery team advised that no surgical interventions were appropriate because of the patient's poor functional status and the extent of his disease.
It is unfortunate that no neurosurgical interventions could help this patient, especially because we are not yet sure of the final diagnosis. Standard indications for neurosurgical decompression include compression from bone fragments, spinal instability requiring fixation, and lack of response to radiation therapy. Patients must also be able to tolerate surgery. Although evidence supports the use of corticosteroids in reducing edema, inflammation, and neurological deficits in malignant spinal cord compression, there is not consensus on what the optimal dose is. Doses of 16‐100 mg of dexamethasone per day appear to be beneficial, as long as higher doses are rapidly tapered to avoid toxic effects. High‐dose steroids minimize the initial edema but are unlikely to change the long‐term outcome of patients who are nonambulatory on arrival.
The CT scan does not help us distinguish between metastatic cancer and primary HCC. Adrenal metastases are very uncommon in HCC. Lung cancer, however, metastasizes to the liver, adrenal glands, and spine, even without significant pulmonary symptoms. HCC may be seen on CT as a solitary mass, a dominant mass with surrounding satellite lesions, multifocal lesions, or a diffusely infiltrating tumor. This diagnosis now seems more likely given the finding of cirrhosis, which increases the risk of HCC in individuals with hepatitis C infection.
We need to obtain tissue for diagnosis and prognosis and to guide therapy. I would consult with radiology and gastroenterology colleagues about the best location to biopsy, but a bone biopsy should be avoided because the pathologic yield is lower.
The radiology and gastroenterology consultants recommended adrenal biopsy because there was easier posterior access for tissue. A liver biopsy was avoided because of the risk of bleeding with hypervascular masses. Fine‐needle aspiration of the mass in the right adrenal gland was performed. The pathology demonstrated bile production and hexagonal arrangement of cells with endothelial cuffing consistent with hepatocellular carcinoma. The oncology staff was consulted about palliative chemotherapy options. The patient began radiation therapy directed at the T7 lesion compressing the spinal cord. He regained minimal movement of his foot. After discussing treatment options with the oncology staff, the patient declined chemotherapy and was transitioned to hospice, where he died 3 weeks later.
COMMENTARY
Hepatocellular carcinoma (HCC) is the third‐leading cause of cancer death and the fifth‐leading cause of cancer worldwide. It causes nearly 1 million deaths annually, and unlike many other cancers, its incidence and mortality rate are rising. Most cases of HCC in Africa and Asia are a result of chronic hepatitis B infection, but in the United States HCC is primarily attributable to hepatitis C infection.1 The annual incidence of HCC in the U.S. population, now about 4 cases per 100,000 people,2 is rising because of the increased prevalence of hepatitis C. Other causes of HCC, such as alcoholic liver disease, hepatitis B infection, and hemochromatosis, have remained stable and have not contributed as significantly to the rising incidence of HCC. For the individual patient, hepatitis C infection conveys a 20‐fold increase in the risk for HCC (2%‐8% risk/year).1 Eighty percent of cases of HCC develop in patients with cirrhosis.3 Unlike patients with hepatitis B infection, persons chronically infected with hepatitis C rarely develop HCC unless they have cirrhosis.
The American Association for the Study of Liver Disease recommends that hepatitis Binfected individuals at high risk for HCC (eg, men older than 40 years and persons with cirrhosis or a family history of HCC) and hepatitis Cinfected individuals with cirrhosis4 be periodically screened for HCC with alpha‐fetoprotein (AFP) and ultrasonography (every 6 months to approximate the doubling time of the tumor5). Using the most commonly reported cutoff for a positive test result for hepatocellular carcinoma (AFP level > 20 g/L) resulted in the following test characteristics: sensitivity, 41%‐65%; specificity, 80%‐94%; positive likelihood ratio, 3.1‐6.8; and negative likelihood ratio, 0.4‐0.6.6 AFP alone is therefore a poor screening test for HCC, and as shown in this case, AFP levels can be normal or only minimally elevated in the setting of diffusely metastatic disease. Ultrasonography alone is only 35%‐87% sensitive in detecting HCC,79 but the combination of AFP and ultrasonography identified 100% of the HCC cases in one small case series.10
For the patient in this case, the optimal clinical pathway would have been to transition from screening to diagnostic measures in a timely manner. Consensus guidelines from the European Association for Study of the Liver in 2001 recommend biopsy of all focal liver lesions that are between 1 and 2 cm.11 The American Association for the Study of Liver Diseases (AASLD) recommends that focal liver lesions between 1 and 2 cm found on ultrasound in cirrhotic livers be followed by 2 dynamic studies: CT, MRI, or contrast ultrasound. If 2 separate studies reveal typical characteristics of HCC, then the lesion should be treated as HCC, and if not typical, then the lesion should be biopsied.4 Although no studies were available to support the recommendations, both the EASL and AASLD advise that lesions greater than 2 cm with demonstrated vascularity on both ultrasonography and CT can be diagnosed as HCC without biopsy and that lesions smaller than 1 cm be monitored.4, 11
Hepatocellular carcinoma can metastasize to almost anywhere in the body by hematologic or lymphatic spread or by direct extension. The most common site for metastases of HCC is the lung. Metastases to the lung arise primarily from arterial emboli and therefore are most common in the lower lobes, where there is greater perfusion.12 The second most common site is intraabdominal lymph nodes. The axial skeleton is the third most common site of metastases and, as in this case, primarily involves the spine.13 Other sites of metastases include the peritoneum, the inferior vena cava and right atrium by direct extension, and, less commonly, the gallbladder and spleen. Autopsy studies of patients with HCC found that 8% had metastases to the adrenal glands, as did this patient.13 Metastasis to the central nervous system is rare.
There were several challenging aspects of this case, including atypical radiologic appearance, an unusual metastatic pattern, and minimally elevated AFP level. This case raises 3 key points that we must remember as clinicians:
-
Patients infected with hepatitis C who are found to have suspicious hepatic lesions should be aggressively evaluated for HCC.
-
Using an AFP level < 20 g/L as a screening test is not helpful because this level can be seen even with widely metastatic disease.
-
Knowledge of available screening tests as well as the many possible manifestations of HCC helps clinicians to diagnose HCC earlier, when the disease is potentially curable.
Acknowledgements
The authors thank Gurpreet Dhaliwal, MD, for reviewing an early version of this manuscript.
A 58‐year‐old man was evaluated for 3 weeks of leg numbness and weakness. His symptoms began with numbness and tingling in the distal left leg that progressed to weakness that impaired his ability to walk. He had no history of trauma or incontinence but endorsed several months of back pain that worsened when lying flat. He had a history of type 2 diabetes mellitus, hepatitis C infection, hypertension, and posttraumatic stress disorder. He had a remote history of intravenous drug use and had quit tobacco 9 years earlier. Medications he was taking included hydrochlorothiazide, rosiglitazone, oxycodone/acetaminophen, baclofen, ibuprofen, and gabapentin.
Internists see this constellation of complaints frequently in an acute care setting. Finding a unifying diagnosis may be difficult initially, so thinking of the symptoms in series is helpful. The complaint of leg weakness and the pattern of numbness should be further elucidated. Is this true weakness, or is it a feeling of instability because of foot numbness? What is the pattern of the numbness? Peripheral neuropathy typically begins in a symmetric stocking pattern (involving the plantar surface of the feet), then progresses to a glove distribution (involving the hands from the fingers distally to the wrist proximally). Such a pattern in a patient with diabetes would be consistent with distal polyneuropathy, a mixed sensory and motor process. Other possible causes of peripheral neuropathy in this patient include HIV, B12 deficiency, and syphilis. These symptoms could be tied to the back pain if this were intervertebral disk disease, a compression fracture, or a lytic lesion in the vertebrae with resulting nerve impingement or if it were epidural spinal cord compression. The lack of bowel or bladder dysfunction speaks against a cauda equina syndrome but does not rule out more cepahalad spinal pathology.
On neurological examination, I would concentrate on differentiating weakness from pain. I would attempt to determine whether the weakness was of central or peripheral nerve etiology. Helpful findings would include increased tone with upper motor lesions and flaccid tone with lower motor lesions, hyperreflexia with upper motor lesions and hyporeflexia with lower motor lesions, a Babinski sign, muscle atrophy or fasciculations, and gait. A rectal examination would also be helpful to assess for deficits in rectal tone, wink reflex, or saddle anesthesia.
All patients with low back pain who have alarm signs of age older than 50, pain duration of more than 1 month, known cancer, lack of relief with conservative measures, or systemic B symptoms should have imaging of the spine. Although plain films may reveal bony abnormalities, computed tomography (CT) is better for evaluating osseous structures and magnetic resonance imaging (MRI) for evaluating pathology in patients suspected of having an infection or a malignancy. I would obtain imaging of the spine in this patient.
The patient was receiving care at an outside clinic for 2 liver lesions discovered on abdominal ultrasound 19 months prior to admission. CT showed that the lesions were 4.0 and 2.3 cm in diameter 17 months prior to admission and 5.0 and 3.0 cm in diameter 5 months prior to admission. No cirrhosis was appreciated on the ultrasound or CT. The patient was referred for CT‐guided biopsy of the larger mass after the second CT, but he became anxious and left before the biopsy was obtained.
This piece of the history is ominous, as it increases the possibility of cancer in our differential. Metastatic disease could provide a unifying diagnosis, explaining the constellation of back pain, leg weakness, and liver lesions. Lung cancer commonly metastasizes to the liver and to bone, so I would obtain a chest x‐ray. Other possible types of cancer in this situation include cancer of the prostate, colon, or thyroid and melanoma. In this patient, who has hepatitis C, hepatocellular carcinoma (HCC) could be the primary etiology, although cirrhosis was not seen on CT and HCC metastasizes to the spine less commonly than do other primary cancers (eg, lung, breast, prostate). Nonetheless, I would obtain an alpha‐fetoprotein level, which would confirm HCC in a patient with liver lesions if it was greater than 200 g/L. Pancreatic cancer has been associated with both type 2 diabetes and liver lesions and could explain his abdominal pain.
There is no comment on the arterial‐phase CT imaging of the liver lesions. Dual‐phase CT scans examine the hepatic arterial and portal vein phases of contrast filling. Triple‐phase CT scans also examine the portal vein influx phase. Both hemangiomas and hypervascular HCCs enhance on the arterial phase, as they derive their blood flow from the hepatic artery. Therefore, arterial‐phase imaging can help to distinguish vascular tumors that flush with contrast, such as hemangiomas, melanoma, and HCC, from less vascular tumors such as pancreatic and colon cancer. Other liver lesions such as focal nodular hyperplasia and adenomas cannot be excluded in this situation as they also may enhance during the arterial phase and can grow over time, as this patient's repeat imaging documented. It seems unlikely that this patient has a liver abscess because he has a paucity of constitutional symptoms and no travel history. The liver lesions seen on initial imaging were larger than 1.0 cm, so I would have favored an earlier biopsy to obtain a tissue diagnosis.
The patient was afebrile, and all other vital signs were normal. He appeared well nourished and anicteric. There was no lymphadenopathy. Cardiac auscultation was regular without murmurs. The lungs were clear. The abdomen was without fluid wave or hepatosplenomegaly and was tender to palpation in the right upper and lower quadrants. There was no midline tenderness to palpation of the spine.
Cranial nerves II‐XII were intact. Lower extremity muscle tone could not be accurately assessed due to splinting from back pain. Strength was 3 of 5 in the left hip extensors and left knee flexors and extensors, and 1 of 5 in the left hip flexors. He had no motor strength in the distal left lower extremity extensors. Bilateral upper extremity and right leg strength were normal. Sensation to light touch, temperature, and pain was decreased circumferentially below the xiphoid. The patient had hyperesthesia in a band around the thorax just above the xiphoid and paresthesia of the perineal area. Left patellar tendon reflexes were brisk, and left ankle jerk was absent, but other reflexes were normal. Toes were down‐going bilaterally. The anal wink was absent, and rectal tone was decreased. Results of the cerebellar exam were normal. Gait could not be assessed.
The results of the exam are notable for not showing the stigmata of end‐stage liver disease. The results of the neurological exam are concerning, with decreased sensation at approximately the T7 level that is almost certainly a result of epidural compression of the spinal cord. Hematogenous metastasis to the vertebrae from one of the tumors mentioned above, with spread into the thecal sac, is the most likely culprit. An epidural abscess is possible because the patient has diabetes and a history of injection drug use.
The thoracic spine is involved in 60% of spinal cord metastases. This patient's left‐sided distal leg weakness is consistent with having corticospinal tract compression and indicates thoracic spine involvement. Flaccid paralysis is classically found in lower motor neuron weakness, but is also seen in the early stages of upper motor neuron pathology. Lesions found above the cauda equina often spare the perineal area, but low thoracic lesions involving the conus medullaris (from T10 to L1) could explain both his loss of anal wink and his decreased rectal tone.
This patient's presentation is unfortunately classic for epidural spinal cord compression. Because the onset of compression is insidious, the diagnosis is often delayed, even in patients with known cancer. Urgent imaging is imperative to evaluate this possibility, as having any meaningful chance of recovery of function depends on rapid relief of the spinal cord compression. I would obtain an emergent MRI of the thoracic and lumbosacral spine.
Laboratory studies showed the following: hemoglobin, 13.1 g/dL; mean corpuscular volume, 80 m3; platelet count, 149,000/L; creatinine, 1.9 mg/dL; aspartate aminotransferase, 66 U/L (5‐35 U/L); alanine aminotransferase, 66 U/L (7‐56 U/L); alkaline phosphatase, 87 U/L (40‐125 U/L); total bilirubin, 1.3 mg/dL; prostate specific antigen (PSA), 1.6 g/dL; and alpha‐fetoprotein (AFP), 10.3 g/L. White cell count, sodium, glucose, calcium, and albumin levels, and prothrombin and partial‐thromboplastin times were within normal ranges.
His liver function tests likely reflect chronic hepatitis C infection. His renal insufficiency could be a result of hypertension, diabetes, or dehydration given that he has been bed‐bound.
Most intriguing are the normal PSA level and only slightly elevated AFP level. PSA is useful for detecting recurrence of prostate cancer or following response of therapy, but the utility of PSA as a screening tool remains controversial in part because of its low specificity. Prostate cancer is the most commonly diagnosed cancer among men and cannot be ruled out by a normal PSA. In a patient with hepatitis C, cirrhosis (which we have not conclusively diagnosed), and a radiologically suspicious liver lesion, an AFP > 200 g/L would be diagnostic of HCC. In this case, however, mildly elevated AFP does not help us to either diagnose or exclude HCC.
The chest x‐ray showed no abnormalities. MRI of the spine revealed lytic lesions in the T7‐T10 vertebral bodies with spinal cord compression at the T7 level (Fig. 1).
A repeat CT scan of the abdomen showed a coarse, nodular liver with 2 heterogeneous, early‐enhancing masses (4.7 4.2 and 3.4 2.4 cm in diameter) with surrounding satellite lesions (Fig. 2).
The enhancement pattern on dual‐phase liver protocol CT was not characteristic of HCC. The left portal vein was not visualized. Splenomegaly and esophageal varices were observed. The adrenal glands showed bilateral, heterogeneous enhancing masses. The epiphrenic, retroperitoneal, and periportal lymph nodes were enlarged. Lytic lesions were seen in the sacrum, left iliac wing, and T7‐T10 vertebral bodies.
Intravenous high‐dose steroids were started. The neurosurgery team advised that no surgical interventions were appropriate because of the patient's poor functional status and the extent of his disease.
It is unfortunate that no neurosurgical interventions could help this patient, especially because we are not yet sure of the final diagnosis. Standard indications for neurosurgical decompression include compression from bone fragments, spinal instability requiring fixation, and lack of response to radiation therapy. Patients must also be able to tolerate surgery. Although evidence supports the use of corticosteroids in reducing edema, inflammation, and neurological deficits in malignant spinal cord compression, there is not consensus on what the optimal dose is. Doses of 16‐100 mg of dexamethasone per day appear to be beneficial, as long as higher doses are rapidly tapered to avoid toxic effects. High‐dose steroids minimize the initial edema but are unlikely to change the long‐term outcome of patients who are nonambulatory on arrival.
The CT scan does not help us distinguish between metastatic cancer and primary HCC. Adrenal metastases are very uncommon in HCC. Lung cancer, however, metastasizes to the liver, adrenal glands, and spine, even without significant pulmonary symptoms. HCC may be seen on CT as a solitary mass, a dominant mass with surrounding satellite lesions, multifocal lesions, or a diffusely infiltrating tumor. This diagnosis now seems more likely given the finding of cirrhosis, which increases the risk of HCC in individuals with hepatitis C infection.
We need to obtain tissue for diagnosis and prognosis and to guide therapy. I would consult with radiology and gastroenterology colleagues about the best location to biopsy, but a bone biopsy should be avoided because the pathologic yield is lower.
The radiology and gastroenterology consultants recommended adrenal biopsy because there was easier posterior access for tissue. A liver biopsy was avoided because of the risk of bleeding with hypervascular masses. Fine‐needle aspiration of the mass in the right adrenal gland was performed. The pathology demonstrated bile production and hexagonal arrangement of cells with endothelial cuffing consistent with hepatocellular carcinoma. The oncology staff was consulted about palliative chemotherapy options. The patient began radiation therapy directed at the T7 lesion compressing the spinal cord. He regained minimal movement of his foot. After discussing treatment options with the oncology staff, the patient declined chemotherapy and was transitioned to hospice, where he died 3 weeks later.
COMMENTARY
Hepatocellular carcinoma (HCC) is the third‐leading cause of cancer death and the fifth‐leading cause of cancer worldwide. It causes nearly 1 million deaths annually, and unlike many other cancers, its incidence and mortality rate are rising. Most cases of HCC in Africa and Asia are a result of chronic hepatitis B infection, but in the United States HCC is primarily attributable to hepatitis C infection.1 The annual incidence of HCC in the U.S. population, now about 4 cases per 100,000 people,2 is rising because of the increased prevalence of hepatitis C. Other causes of HCC, such as alcoholic liver disease, hepatitis B infection, and hemochromatosis, have remained stable and have not contributed as significantly to the rising incidence of HCC. For the individual patient, hepatitis C infection conveys a 20‐fold increase in the risk for HCC (2%‐8% risk/year).1 Eighty percent of cases of HCC develop in patients with cirrhosis.3 Unlike patients with hepatitis B infection, persons chronically infected with hepatitis C rarely develop HCC unless they have cirrhosis.
The American Association for the Study of Liver Disease recommends that hepatitis Binfected individuals at high risk for HCC (eg, men older than 40 years and persons with cirrhosis or a family history of HCC) and hepatitis Cinfected individuals with cirrhosis4 be periodically screened for HCC with alpha‐fetoprotein (AFP) and ultrasonography (every 6 months to approximate the doubling time of the tumor5). Using the most commonly reported cutoff for a positive test result for hepatocellular carcinoma (AFP level > 20 g/L) resulted in the following test characteristics: sensitivity, 41%‐65%; specificity, 80%‐94%; positive likelihood ratio, 3.1‐6.8; and negative likelihood ratio, 0.4‐0.6.6 AFP alone is therefore a poor screening test for HCC, and as shown in this case, AFP levels can be normal or only minimally elevated in the setting of diffusely metastatic disease. Ultrasonography alone is only 35%‐87% sensitive in detecting HCC,79 but the combination of AFP and ultrasonography identified 100% of the HCC cases in one small case series.10
For the patient in this case, the optimal clinical pathway would have been to transition from screening to diagnostic measures in a timely manner. Consensus guidelines from the European Association for Study of the Liver in 2001 recommend biopsy of all focal liver lesions that are between 1 and 2 cm.11 The American Association for the Study of Liver Diseases (AASLD) recommends that focal liver lesions between 1 and 2 cm found on ultrasound in cirrhotic livers be followed by 2 dynamic studies: CT, MRI, or contrast ultrasound. If 2 separate studies reveal typical characteristics of HCC, then the lesion should be treated as HCC, and if not typical, then the lesion should be biopsied.4 Although no studies were available to support the recommendations, both the EASL and AASLD advise that lesions greater than 2 cm with demonstrated vascularity on both ultrasonography and CT can be diagnosed as HCC without biopsy and that lesions smaller than 1 cm be monitored.4, 11
Hepatocellular carcinoma can metastasize to almost anywhere in the body by hematologic or lymphatic spread or by direct extension. The most common site for metastases of HCC is the lung. Metastases to the lung arise primarily from arterial emboli and therefore are most common in the lower lobes, where there is greater perfusion.12 The second most common site is intraabdominal lymph nodes. The axial skeleton is the third most common site of metastases and, as in this case, primarily involves the spine.13 Other sites of metastases include the peritoneum, the inferior vena cava and right atrium by direct extension, and, less commonly, the gallbladder and spleen. Autopsy studies of patients with HCC found that 8% had metastases to the adrenal glands, as did this patient.13 Metastasis to the central nervous system is rare.
There were several challenging aspects of this case, including atypical radiologic appearance, an unusual metastatic pattern, and minimally elevated AFP level. This case raises 3 key points that we must remember as clinicians:
-
Patients infected with hepatitis C who are found to have suspicious hepatic lesions should be aggressively evaluated for HCC.
-
Using an AFP level < 20 g/L as a screening test is not helpful because this level can be seen even with widely metastatic disease.
-
Knowledge of available screening tests as well as the many possible manifestations of HCC helps clinicians to diagnose HCC earlier, when the disease is potentially curable.
Acknowledgements
The authors thank Gurpreet Dhaliwal, MD, for reviewing an early version of this manuscript.
- .Hepatocellular carcinoma: epidemiology, risk factors, and screening.Semin Liver Dis.2005;25:143–154.
- American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005. Available at: http://www.cancer.org/docroot/STT/stt_0.asp. Accessed October 17,2005.
- ,,.Hepatocellular carcinoma.Lancet.2003;362:1907–1917.
- ,.Management of hepatocellular carcinoma. AASLD Practice Guideline.Hepatology.2005;42:1208–1236.
- ,,, et al.Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.Gastroenterology.1985;89:259–266.
- ,,.Test characteristics of alpha‐fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C.Ann Intern Med.2003;139:46–50.
- ,,,.Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation.Am J Roentgenol.1998;171:433–435.
- ,,,,.Detection of malignant tumors in end‐stage cirrhotic livers: efficacy of sonography as a screening technique.Am J Roentgenol.1992;159:727–733.
- ,,, et al.The diagnosis of small hepatocellular carcinomas: efficacy of various imaging procedures in 100 patients.Am J Roentgenol.1990;155:49–54
- ,,,,,.Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis.Ann Surg.1998;277:513–518.
- ,,, et al.;EASL Panel of Experts on HCC.Clinical management of hepatocellular carcinoma: conclusions of the Barcelona‐2000 EASL conference: European Association for the Study of the Liver.J Hepatol.2001;35:421–430.
- ,,, et al.Extrahepatic spread of hepatocellular carcinoma: a pictorial review.Eur Radiol.2003;13:874–882.
- ,,,,,.Extrahepatic metastases of hepatocellular carcinoma.Radiology.2000;216:698–703.
- .Hepatocellular carcinoma: epidemiology, risk factors, and screening.Semin Liver Dis.2005;25:143–154.
- American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005. Available at: http://www.cancer.org/docroot/STT/stt_0.asp. Accessed October 17,2005.
- ,,.Hepatocellular carcinoma.Lancet.2003;362:1907–1917.
- ,.Management of hepatocellular carcinoma. AASLD Practice Guideline.Hepatology.2005;42:1208–1236.
- ,,, et al.Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.Gastroenterology.1985;89:259–266.
- ,,.Test characteristics of alpha‐fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C.Ann Intern Med.2003;139:46–50.
- ,,,.Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation.Am J Roentgenol.1998;171:433–435.
- ,,,,.Detection of malignant tumors in end‐stage cirrhotic livers: efficacy of sonography as a screening technique.Am J Roentgenol.1992;159:727–733.
- ,,, et al.The diagnosis of small hepatocellular carcinomas: efficacy of various imaging procedures in 100 patients.Am J Roentgenol.1990;155:49–54
- ,,,,,.Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis.Ann Surg.1998;277:513–518.
- ,,, et al.;EASL Panel of Experts on HCC.Clinical management of hepatocellular carcinoma: conclusions of the Barcelona‐2000 EASL conference: European Association for the Study of the Liver.J Hepatol.2001;35:421–430.
- ,,, et al.Extrahepatic spread of hepatocellular carcinoma: a pictorial review.Eur Radiol.2003;13:874–882.
- ,,,,,.Extrahepatic metastases of hepatocellular carcinoma.Radiology.2000;216:698–703.
Management of Blood Pressure after Stroke
Hospitalists are on the front lines of care for patients with cerebrovascular accidents. After the first steps in acute stroke management occur in the emergency room, care is frequently transferred to the hospitalist. This review focuses on the evidence‐based management of blood pressure following acute ischemic stroke. Management of blood pressure after stroke is still controversial, and current consensus statement guidelines acknowledge that optimal treatment has not yet been established.1, 2 As such, it is essential to understand the changes in normal homeostatic physiologic processes that occur after stroke and their subsequent effects on neurologic function. Only then can the appropriate blood pressure target and antihypertensive regimen be chosen.
Physiology of Cerebral Perfusion
Once a stroke has occurred and perfusion to a section of brain tissue has been acutely compromised, systemic pressure tends to rise. This rise is presumably due in part to increased adrenergic tone and activation of the renin‐aldosterone system and potentially is part of Cushing's reflex in cases in which intracranial pressure is elevated.3 The increase in mean arterial pressure may represent a protective response. In the first major study on the topic, in 1981, on admission for stroke mean blood pressure was 163/90 mm Hg for patients without a history of hypertension and 214/118 mm Hg for patients who had been treated for hypertension previously.4 This rise in blood pressure in response to endogenous mechanisms is attenuated over the first 24 hours, and even without intervention, blood pressure tends to fall spontaneously over the next 10 days.47
Under normal circumstances, cerebral blood flow (CBF) is tightly autoregulated across a wide range of cerebral perfusion pressures by alteration in cerebrovascular resistance via arteriolar constriction.89 This allows CBF to remain constant even if cerebral perfusion pressure (CPP) fluctuates from 60 to 150 mm Hg.9 In patients with chronic hypertension, autoregulation works best with blood pressure in a higher range because of vascular smooth muscle hypertrophy and structural changes in the cerebral vessels (see Table 1).
| Cerebral blood flow (CBF) of 50‐70 mL/100 g/minnormal |
| CBF of 20‐50 mL/100 g/minreduced flow compensated for by increased oxygen extraction |
| CBF of 15‐20 mL/100 g/minneuronal quiescence |
| CBF < 15 mL/100 g/minneuronal death |
After an acute ischemic stroke, autoregulation is lost, and local CBF becomes linearly associated with cerebral perfusion pressure. Loss of autoregulation occurs because of several local factors as a result of the infarct. Acidosis and hypoxia in the region of the stroke lead to vasodilatation in the perfusing vessels.9 This may improve local circulation in collateral vessels as a response to the obstruction in the primary supplying artery, but the consequence of maximal vasodilatation is loss of the ability to autoregulate. Normal CPP is driven by the mean arterial pressure minus the intracranial pressure. However, if intracranial vessels have lost the ability to accommodate changes in perfusion pressure, then blood flow to the area of injury becomes linearly correlated with mean arterial pressure.
Surrounding a central core of irreversible necrosis may be a zone of at‐risk tissue that is susceptible to reduction below the threshold of viability in response to any decrement in systemic mean blood pressure.11 This critical concept in stroke management is referred to as the peri‐infarct penumbra (see Fig. 1 and Table 2).
| Mean arterial pressure (MAP) = ⅔ diastolic blood pressure (DBP) + ⅓ systolic blood pressure (SBP) |
| Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) intracranial pressure (ICP) |
| Cerebral blood flow (CBF) = cerebral perfusion pressure (CPP)/cerebrovascular resistance (CVR) |
Blood Pressure Management after Stroke
The presence of a systemic blood pressure‐dependent peri‐infarct penumbra that might be compromised by blood pressure reduction and thus extend the infarct is the principal argument for allowing permissive hypertension. This is bolstered by the observation that decreases in blood pressure in the first 24 hours are associated with a significant risk of poor neurologic outcome.6 In their an observational study Vlcek et al. found that a greater than 25% drop in diastolic blood pressure (DBP) was associated with a 4‐fold risk of severe disability.5 In a 2003 observational study Oliveria et al. found that reduction in systolic blood pressure (SBP) in the first 24 hours was independently associated with poor outcomes, with a doubling of the risk for poor outcomes for every 10% drop in systolic blood pressure.6 In both these studies, the worsened outcome did not depend on whether the drop was spontaneous or induced by medications. Case reports suggest that large drops in blood pressure can be catastrophic and that even moderate lowering of blood pressure after acute stroke can be associated with clinical deterioration.8, 12
The primary argument for lowering blood pressure after an acute stroke hinges on secondary prevention of new ischemic events, minimization of cerebral edema, and prevention of hemorrhagic conversion. It has long been recognized that hypertension itself is a risk factor for stroke13 and that reduction in chronic hypertension is part of secondary prevention for cerebrovascular accidents.14 Further, hypertension is the most common risk factor for intracerebral hemorrhage, and it would stand to reason that damage to the brain parenchyma from ischemic stroke would increase the risk of pressure‐induced bleeding in an acute setting.15
Because there are compelling theoretical arguments both for and against lowering blood pressure after an acute stroke, it is necessary to look at the results of randomized clinical trials for guidance in weighing the risks and benefits. The overall goal of blood pressure management is to maximize perfusion to the ischemic penumbra while minimizing the hypertensive risk of hemorrhagic transformation.
Lisk et al. conducted a small randomized trial in 1993 of antihypertensive therapy versus placebo after ischemic stroke looking at SPECT perfusion and found lower CBF if mean arterial pressure (MAP) dropped more than 16%.16 This is in contrast with the results of a 1997 randomized trial of perindopril after cerebrovascular accident that found no decrease in Doppler CBF despite a 10% decrease in blood pressure in the active treatment group.17 Neither study was powered to detect significant differences in clinical outcome.
Early randomized controlled trials of antihypertensive agents after acute stroke investigated neuroprotection via mechanisms other than the antihypertensive effect. Nimodipine, a dihydropyridine derivative thought to prevent neuronal death via blockade of calcium channels, has been studied extensively.1820 A meta‐analysis of the 9 early trials of nimodipine, from 1988 to 1992, suggested that nimodipine was potentially beneficial in neurologic score and functional outcome only if used within the first 12 hours and that it could be harmful if started after 24 hours.21 Two additional studies were done in 1994 using both intravenous and oral nimodipine formulations. They demonstrated worsened neurologic function and higher mortality, respectively, which was hypothesized to be a result of the detrimental hemodynamic effects of nimodipine.18, 22
The BEST trial used beta‐blockers in the early period after acute stroke and failed to find benefit, whereas the FIST trial had similar results with the calcium channel blocker flunarizine.23, 24 The ACCESS trial in 2003 was a prospective, randomized, controlled trial using oral candesartan in the first 24 hours after stroke.25 It did find improved mortality in the candesartan arm after 1 year, yet there were no significant differences in blood pressure between candesartan and placebo. Thus, the improved outcome was presumed to be a result of mechanisms other than antihypertensive effect.
Some significant caveats should be kept in mind when interpreting the results of these studies. None of the trials was designed to titrate blood pressure to a prespecified goal in a prospective randomized fashion. It is also difficult to tease out the effect of the active medical intervention from the effect of spontaneous drops in blood pressure, and many trials did not find a significant difference in blood pressure between the medication and placebo groups. A large randomized trial to evaluate interventions to a predefined blood pressure target is needed.
The Cochrane Stroke Group reviewed 32 trials involving 5368 patients and concluded there was not enough evidence to reliably evaluate the effect of altering blood pressure on outcomes.3
Recommendations for Treatment of Hypertension in Acute Stroke
The decision of when to initiate antihypertensive therapy has not been clearly delineated. However, most experts agree that blood pressure targets need to take into account whether thrombolytics are used. The available data provide little evidence that lowering blood pressure decreases adverse events; however, there is some evidence that lowering blood pressure can worsen outcomes by expanding the area of ischemia. Thus, in treating most acute ischemic strokes, antihypertensive therapy can and should be withheld. The exception to this is stroke in a patient with comorbid hypertensive organ damage such as myocardial infarction, aortic dissection, acute hypertensive renal failure, pulmonary edema, or encephalopathy. The consensus statement of the American Stroke Association is to withhold treatment until blood pressure exceeds 220/120 mm Hg,1 roughly corresponding to a MAP of 150 mm Hg, the normal upper limit of cerebral autoregulation. Treatment optimally should be titratable in order to avoid overcorrection, preferably with minimal cerebral venodilatation effect. The parenteral agents labetolol, fenoldopam, nicardipine, and nitroprusside are most commonly used. A disadvantage of nitrates or nitroprusside is that their venodilating effect may raise intracranial pressure. Clonidine may induce central nervous system depression, which can complicate interpretation of the mental status of a patient with an acute neurologic event. Sublingual nifedipine should be avoided because of its well‐documented tendency to cause overcorrection of blood pressure.26 No large direct comparison trial has evaluated which of these antihypertensive agents is superior in clinical outcomes. For the hospitalist, choice of antihypertensive agent should be driven by a need for rapid control of blood pressure to target without overcorrection (see Table 3). Issues such as intracranial pressure, heart rate, and comorbidities may also play a role in choice of medication.
| Not eligible for thrombolytic therapy | |
|---|---|
| |
| Systolic < 220 or diastolic < 120 | Observe unless other end‐organ involvement (aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy) |
| Systolic > 220 or diastolic 121‐140 | Aim for 10%‐15% reduction in blood pressure |
| Labetalol 10‐20 mg IV over 1‐2 minutes; repeat or double every 10 minutes; maximum 300 mg | |
| or | |
| Nicardipine 5 mg/hour IV; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| or | |
| Nitroprusside 0.5 g/kg/minute IV; titrate to goal | |
| Diastolic > 140 | Aim for 10%‐15% reduction in blood pressure |
| Nitroprusside 0.5 g/kg/minute IV; titrate to desired blood pressure | |
| Eligible for thrombolytic therapy | |
| Pretreatment | |
| Systolic > 185 or diastolic > 110 | Labetalol 10‐20mg IV |
| May repeat 1 or Nitropaste 1‐2 inches | |
| During and after tPA | |
| Systolic 180‐230 or Diastolic 105‐120 | Labetalol 10 mg |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute | |
| Systolic > 230 or diastolic 121‐140 | Labetalol 10mg IV |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute or | |
| Nicardipine 5 mg/hour; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| If not at goal with labetalol or nicardipine, consider nitroprusside | |
| Diastolic>140 | Nitroprusside 0.5 g/kg/minute IV infusion; titrate to desired blood pressure |
The risk of hemorrhagic conversion is greater when thrombolysis is used for the treatment of cerebrovascular accident, in the NINDS trial rising from 0.6% in patients receiving a placebo to 6.4% in patients receiving tPA.27 Given that the goal of thrombolysis is to restore perfusion through the previously blocked vessel and that the risk of hemorrhage rises after thrombolysis, the balance between maintaining CPP and decreasing the risk of bleeding shifts toward maintaining a lower blood pressure postthrombolysis. The NINDS thrombolytic trial required patients to have a blood pressure less than 185/110 mm Hg to be included.27 Once a thrombolytic had been administered, the permitted maximum blood pressure dropped to 180/105 mm Hg. Blood pressure needs to be monitored closely, initially every 15 minutes for 2 hours, then every 30 minutes for the next 6 hours, and then hourly until the end of the first 24 hours. After this, blood pressure monitoring intervals can be more spaced out depending on the need for active antihypertensive therapy.28 However, arterial punctures for invasive monitoring are not recommended if thrombolytics are administered. Review of the experience of the NINDS trial suggests that approximately one third of patients receiving thrombolytics will require pharmacologic therapy to reach the recommended blood pressure goals in the first 24 hours.28
Although guidelines for the management of blood pressure after cerebrovascular accident from major organizations such as the American Stroke Association and the European Stroke Initiative are published and widely quoted in reviews of stroke management, physician adherence to these guidelines is poor.1, 2933 A 2002 review of prescribing practices in a Canadian hospital found excessive reduction of blood pressure in 60% of patients where nitroglycerin was used, and sublingual nifedipine was still the second most commonly prescribed medication.34 A similar 2004 study by Lindenauer et al. found that only 26% of patients who had antihypertensive medication initiated in the hospital met consensus guidelines for therapy.35
Induced Hypertension
Hypotension should be avoided after acute stroke. Observational studies have demonstrated an increased mortality rate of patients who present with hypotension.42 Patients with acute ischemic stroke and loss of autoregulation may have impaired tolerance to even mild levels of hypotension.8 First‐line therapy for hypotension after stroke is volume resuscitation and optimization of cardiac function by correcting arrhythmias.1 If this should fail, vasopressor support is advisable to avoid ongoing hypotension and cerebral hypoperfusion.
The same physiologic arguments that favor permissively managing high blood pressure and avoiding hypotension raise the question of whether inducing hypertension through the use of vasopressors might improve outcomes of stroke. This hypothesis has been bolstered by animal studies and imaging data that suggest improved perfusion to the area of injury with vasopressor‐induced hypertension.3638 However, there are concerns that this strategy may increase edema and hemorrhage and create the potential for vasopressor‐induced myocardial ischemia or arrhythmias. Although the results of small trials have appeared promising, particularly for patients with large vessel stenosis, at this point induced hypertension is still considered experimental until the results of larger randomized, controlled trials provide greater support for this procedure.1, 3941
Chronic Blood Pressure Control for Secondary Prevention of Stroke
Multiple trials have demonstrated that interventions to treat chronic hypertension can reduce the rate of future strokes.14, 43, 44 The PROGRESS trial demonstrated that blood pressure reduction with combination therapy decreased stroke recurrence by 43%.43 Clearly long‐term blood pressure control is a vital component of secondary prevention of stroke. Based on the results of the PROGRESS and ACCESS trials, it is suggested that angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers, potentially with additional diuretic therapy, are beneficial in the treatment of chronic hypertension following cerebrovascular accident.25, 42 The issue of optimal medication class is not settled. Recommendations are to treat chronically elevated blood pressure to lower and maintain it at less than 140/80 mm Hg. Because there is no single threshold level of blood pressure beyond which the risk of cerebrovascular disease increases, reduction below this cut point may still offer incremental benefit.13, 45, 46 The timing of initiation of therapy to reach secondary‐prevention goals is not addressed in current guidelines, although some authors recommend waiting days to weeks after an acute stroke before starting therapy.1, 37 For a patient who remains hypertensive at discharge, it is incumbent on the hospitalist to communicate the plan for initiation of antihypertensive agents to the patient and the primary care physician in order to ensure that this critical secondary prevention measure is addressed.
Areas of Ambiguity and Need for Future Research
Within an evidence‐guided practice, there are still many areas for which the evidence to date does not answer important clinical questions about patient management. Whether a patient's prestroke baseline blood pressure should be considered in individualizing blood pressure goals is unclear, as is the question of whether to continue or hold previous chronic antihypertensive therapy. Given the many stroke subtypes, from tiny lacunar infarcts with little collateralization to massive malignant middle‐cerebral infarctions, should blood pressure management be individualized according to the likely size and duration of the peri‐infarct penumbra? Research is needed to determine whether reducing blood pressure to a specific target will improve outcome and the optimal timing of therapy to achieve secondary prevention goals. Finally, using the concept of the penumbra as the theoretical physiologic basis for current blood pressure recommendations, there exists a potential for rapidly evolving neuroimaging techniques to help define the presence, size, and duration of the penumbra to guide these decisions.
CONCLUSIONS
Management of blood pressure after acute ischemic stroke differs from that of many other hypertensive conditions because of the need to preserve perfusion of the peri‐infarct penumbra. Evidence to date suggests little benefit and potential harm from acutely lowering blood pressure after stroke, although there have not been large randomized trials examining outcomes when blood pressure is lowered to a prespecified goal. Current consensus guidelines suggest that blood pressure may be managed permissively up to 220/120 mm Hg when thrombolysis is not administered and to 180/105 mm Hg when thrombolysis is performed. Data suggest that low‐dose antihypertensive therapy such as ACE inhibitors or angiotensin receptor blockers may be safe in the acute setting if pressure is reduced by less than 10%‐15%.17, 25 However, the evidence is not sufficiently strong for this practice to be routinely recommended. At this point, it is recommended that hypotension be aggressively treated; however, induced hypertension remains a promising but unproven therapy. Evidence is strong that long‐term blood pressure control is key to secondary prevention of stroke, but the timing of its initiation remains poorly determined.
- ,,, et al.Guidelines for the early management of patients with ischemic stroke.Stroke.2003;34:1056–1083.
- ,,,.Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update.Stroke.2005;36:916–921.
- Blood Pressure in Acute Stroke Collaboration (BASC).Vasoactive drugs for acute strokeCochrane Database Syst Rev.2004;1:CD002839.
- ,.Blood pressure after stroke.JAMA.1981;246:2177–2180.
- ,,,,,.Association between course of blood pressure within the first 24 hours and functional recovery after acute ischemic stroke.Ann Emerg Med.2003;42:619–626.
- ,,,,,.Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset.Neurology.2003;61:1047–1050.
- ,,,, et al.Blood pressure during the first minutes of focal cerebral ischemia.Ann Emerg Med.1993;22:1438–1443.
- ,,,,.Stroke precipitated by moderate blood pressure reduction.J Emerg Med.2000;19:339–346.
- .Hemodynamics and metabolism in ischemic cerebrovascular disease.Neurologic Clinics.1992;10(1):31–48.
- ,.The 5 Ps of acute ischemic stroke treatment: parenchyma, pipes, perfusion, penumbra, and prevention of complications.South Med J.2003;96:336–341.
- .Viability Thresholds and the Penumbra of Focal Ischemia.Annals of Neurology.1994;36:557–565.
- ,,.Hazards of therapy for excessive hypertension in acute stroke.Acta Med Scand.1980;207:253–257.
- Prospective Studies Collaboration.Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies.Lancet.2002;360:1903–1913.
- ,,,.Secondary prevention of ischemic cerebrovascular disease. What is the evidence?Angiology.2005;56:539–552.
- ,,.Intracerebral hemorrhage.Emerg Med Clin North Am.2002;20:631–655.
- ,,, et al.Should hypertension be treated after acute stroke?Arch Neurol.1993;50:855–862.
- ,,.Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke.Stroke.1997;28:580–583.
- ,,,,.Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke.Cerebrovasc Dis.1994;4:204–210.
- The American Nimodipine Study Group.Clinical trial of nimodipine in acute ischemic stroke.Stroke.1992;23(1):3–8.
- ,,, et al.Placebo‐controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction.Stroke.1990;21:1023–1028.
- ,,, et al.Meta‐analysis of oral nimodipine trials in acute ischemic stroke.Cerebrovasc Dis.1994;4:197–203.
- ,,, et al.A randomized, double‐blind, placebo‐controlled trial of nimodipine in acute ischemic hemispheric stroke.Stroke.1994;25:1348–1353.
- ,,,.Low dose B blockade in acute stroke (“BEST” trial): an evaluationBMJ.1988;296:737–741.
- ,,, et al.Flunarizine in stroke treatment (FIST): a double‐blind, placebo‐controlled trial in Scandinavia and the Netherlands.Acta Neurol Scand.1996;93:56–60.
- ,,, et al.The ACCESS study: Evaluation of acute candesartan cilexetil therapy in stroke survivors.Stroke.2003;34:1699–1703.
- .FDA gives Calcium channel blockers clean bill of health but warns of short‐acting nifedipine hazards.JAMA.1996;275:1638.
- The National Institute of Neurological Disorders and Stroke rt‐PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,, et al.Hypertension and its treatment in the NINDS rt‐PA Stroke Trial.Stroke.1998;29:1504–1509.
- ,.Optimizing blood pressure in neurologic emergencies.Neurocrit Care.2004;1:287–299.
- .Management of acute stroke.South M J.2003;96:380–385.
- .Management of acute stroke.Lancet Neurol.2002;1(1):41–50.
- ,.Acute ischemic stroke: emergent evaluation and management.Emerg Med Clin North Am.2002;20:609–630.
- ,.Post‐emergency department management of stroke.Emerg Med Clin North Am.2002;20:687–702.
- ,,.Blood pressure management in acute stroke: comparison of current guidelines with prescribing patterns.Can J Neurol Sci.2002;29(2):125–131.
- ,,,,,.Use of antihypertensive agents in the management of patients with acute ischemic stroke.Neurology.2004;63:318–323.
- ,,,.Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats.Surg Neurol.1996;46:229–234.
- ,,,.Effects of induced hypertension on intracranial pressure and flow velocities of the middle cerebral arteries in patients with large hemispheric stroke.Stroke.2002;33:998–1004.
- ,,,.Induced hypertension improves cerebral blood flow in acute ischemic stroke.Neurology.2005;64:1979.
- ,,,,.A pilot study of drug induced hypertension for treatment of acute stroke.Neurology.2001;56:1210–1213.
- ,,,,,.Pharmacologic elevation of blood pressure in acute stroke: clinical effects and safety.Stroke.1997;28:2133–2138.
- ,,,,.Feasibility and safety of norephinephrine‐induced arterial hypertension in acute ischemic stroke.Neurology.2004;62:1193–1195.
- ,,,,.Initial emergency department blood pressure as predictor of survival after acute ischemic stroke.Neurology.2005;65:1179–1183.
- The PROGRESS Collaborative Group.Randomized trial of a perindopril‐based blood‐pressure‐lowering regimen among 6105 individuals with previous stroke of transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,, et al.Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke.JAMA.2000;284:465–471.
- ,.Treatment of chronic hypertension for the prevention of stroke.South Med J.2003;96:359–362.
- ,,,.Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study.JAMA.1996;276:1269–1278.
Hospitalists are on the front lines of care for patients with cerebrovascular accidents. After the first steps in acute stroke management occur in the emergency room, care is frequently transferred to the hospitalist. This review focuses on the evidence‐based management of blood pressure following acute ischemic stroke. Management of blood pressure after stroke is still controversial, and current consensus statement guidelines acknowledge that optimal treatment has not yet been established.1, 2 As such, it is essential to understand the changes in normal homeostatic physiologic processes that occur after stroke and their subsequent effects on neurologic function. Only then can the appropriate blood pressure target and antihypertensive regimen be chosen.
Physiology of Cerebral Perfusion
Once a stroke has occurred and perfusion to a section of brain tissue has been acutely compromised, systemic pressure tends to rise. This rise is presumably due in part to increased adrenergic tone and activation of the renin‐aldosterone system and potentially is part of Cushing's reflex in cases in which intracranial pressure is elevated.3 The increase in mean arterial pressure may represent a protective response. In the first major study on the topic, in 1981, on admission for stroke mean blood pressure was 163/90 mm Hg for patients without a history of hypertension and 214/118 mm Hg for patients who had been treated for hypertension previously.4 This rise in blood pressure in response to endogenous mechanisms is attenuated over the first 24 hours, and even without intervention, blood pressure tends to fall spontaneously over the next 10 days.47
Under normal circumstances, cerebral blood flow (CBF) is tightly autoregulated across a wide range of cerebral perfusion pressures by alteration in cerebrovascular resistance via arteriolar constriction.89 This allows CBF to remain constant even if cerebral perfusion pressure (CPP) fluctuates from 60 to 150 mm Hg.9 In patients with chronic hypertension, autoregulation works best with blood pressure in a higher range because of vascular smooth muscle hypertrophy and structural changes in the cerebral vessels (see Table 1).
| Cerebral blood flow (CBF) of 50‐70 mL/100 g/minnormal |
| CBF of 20‐50 mL/100 g/minreduced flow compensated for by increased oxygen extraction |
| CBF of 15‐20 mL/100 g/minneuronal quiescence |
| CBF < 15 mL/100 g/minneuronal death |
After an acute ischemic stroke, autoregulation is lost, and local CBF becomes linearly associated with cerebral perfusion pressure. Loss of autoregulation occurs because of several local factors as a result of the infarct. Acidosis and hypoxia in the region of the stroke lead to vasodilatation in the perfusing vessels.9 This may improve local circulation in collateral vessels as a response to the obstruction in the primary supplying artery, but the consequence of maximal vasodilatation is loss of the ability to autoregulate. Normal CPP is driven by the mean arterial pressure minus the intracranial pressure. However, if intracranial vessels have lost the ability to accommodate changes in perfusion pressure, then blood flow to the area of injury becomes linearly correlated with mean arterial pressure.
Surrounding a central core of irreversible necrosis may be a zone of at‐risk tissue that is susceptible to reduction below the threshold of viability in response to any decrement in systemic mean blood pressure.11 This critical concept in stroke management is referred to as the peri‐infarct penumbra (see Fig. 1 and Table 2).
| Mean arterial pressure (MAP) = ⅔ diastolic blood pressure (DBP) + ⅓ systolic blood pressure (SBP) |
| Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) intracranial pressure (ICP) |
| Cerebral blood flow (CBF) = cerebral perfusion pressure (CPP)/cerebrovascular resistance (CVR) |
Blood Pressure Management after Stroke
The presence of a systemic blood pressure‐dependent peri‐infarct penumbra that might be compromised by blood pressure reduction and thus extend the infarct is the principal argument for allowing permissive hypertension. This is bolstered by the observation that decreases in blood pressure in the first 24 hours are associated with a significant risk of poor neurologic outcome.6 In their an observational study Vlcek et al. found that a greater than 25% drop in diastolic blood pressure (DBP) was associated with a 4‐fold risk of severe disability.5 In a 2003 observational study Oliveria et al. found that reduction in systolic blood pressure (SBP) in the first 24 hours was independently associated with poor outcomes, with a doubling of the risk for poor outcomes for every 10% drop in systolic blood pressure.6 In both these studies, the worsened outcome did not depend on whether the drop was spontaneous or induced by medications. Case reports suggest that large drops in blood pressure can be catastrophic and that even moderate lowering of blood pressure after acute stroke can be associated with clinical deterioration.8, 12
The primary argument for lowering blood pressure after an acute stroke hinges on secondary prevention of new ischemic events, minimization of cerebral edema, and prevention of hemorrhagic conversion. It has long been recognized that hypertension itself is a risk factor for stroke13 and that reduction in chronic hypertension is part of secondary prevention for cerebrovascular accidents.14 Further, hypertension is the most common risk factor for intracerebral hemorrhage, and it would stand to reason that damage to the brain parenchyma from ischemic stroke would increase the risk of pressure‐induced bleeding in an acute setting.15
Because there are compelling theoretical arguments both for and against lowering blood pressure after an acute stroke, it is necessary to look at the results of randomized clinical trials for guidance in weighing the risks and benefits. The overall goal of blood pressure management is to maximize perfusion to the ischemic penumbra while minimizing the hypertensive risk of hemorrhagic transformation.
Lisk et al. conducted a small randomized trial in 1993 of antihypertensive therapy versus placebo after ischemic stroke looking at SPECT perfusion and found lower CBF if mean arterial pressure (MAP) dropped more than 16%.16 This is in contrast with the results of a 1997 randomized trial of perindopril after cerebrovascular accident that found no decrease in Doppler CBF despite a 10% decrease in blood pressure in the active treatment group.17 Neither study was powered to detect significant differences in clinical outcome.
Early randomized controlled trials of antihypertensive agents after acute stroke investigated neuroprotection via mechanisms other than the antihypertensive effect. Nimodipine, a dihydropyridine derivative thought to prevent neuronal death via blockade of calcium channels, has been studied extensively.1820 A meta‐analysis of the 9 early trials of nimodipine, from 1988 to 1992, suggested that nimodipine was potentially beneficial in neurologic score and functional outcome only if used within the first 12 hours and that it could be harmful if started after 24 hours.21 Two additional studies were done in 1994 using both intravenous and oral nimodipine formulations. They demonstrated worsened neurologic function and higher mortality, respectively, which was hypothesized to be a result of the detrimental hemodynamic effects of nimodipine.18, 22
The BEST trial used beta‐blockers in the early period after acute stroke and failed to find benefit, whereas the FIST trial had similar results with the calcium channel blocker flunarizine.23, 24 The ACCESS trial in 2003 was a prospective, randomized, controlled trial using oral candesartan in the first 24 hours after stroke.25 It did find improved mortality in the candesartan arm after 1 year, yet there were no significant differences in blood pressure between candesartan and placebo. Thus, the improved outcome was presumed to be a result of mechanisms other than antihypertensive effect.
Some significant caveats should be kept in mind when interpreting the results of these studies. None of the trials was designed to titrate blood pressure to a prespecified goal in a prospective randomized fashion. It is also difficult to tease out the effect of the active medical intervention from the effect of spontaneous drops in blood pressure, and many trials did not find a significant difference in blood pressure between the medication and placebo groups. A large randomized trial to evaluate interventions to a predefined blood pressure target is needed.
The Cochrane Stroke Group reviewed 32 trials involving 5368 patients and concluded there was not enough evidence to reliably evaluate the effect of altering blood pressure on outcomes.3
Recommendations for Treatment of Hypertension in Acute Stroke
The decision of when to initiate antihypertensive therapy has not been clearly delineated. However, most experts agree that blood pressure targets need to take into account whether thrombolytics are used. The available data provide little evidence that lowering blood pressure decreases adverse events; however, there is some evidence that lowering blood pressure can worsen outcomes by expanding the area of ischemia. Thus, in treating most acute ischemic strokes, antihypertensive therapy can and should be withheld. The exception to this is stroke in a patient with comorbid hypertensive organ damage such as myocardial infarction, aortic dissection, acute hypertensive renal failure, pulmonary edema, or encephalopathy. The consensus statement of the American Stroke Association is to withhold treatment until blood pressure exceeds 220/120 mm Hg,1 roughly corresponding to a MAP of 150 mm Hg, the normal upper limit of cerebral autoregulation. Treatment optimally should be titratable in order to avoid overcorrection, preferably with minimal cerebral venodilatation effect. The parenteral agents labetolol, fenoldopam, nicardipine, and nitroprusside are most commonly used. A disadvantage of nitrates or nitroprusside is that their venodilating effect may raise intracranial pressure. Clonidine may induce central nervous system depression, which can complicate interpretation of the mental status of a patient with an acute neurologic event. Sublingual nifedipine should be avoided because of its well‐documented tendency to cause overcorrection of blood pressure.26 No large direct comparison trial has evaluated which of these antihypertensive agents is superior in clinical outcomes. For the hospitalist, choice of antihypertensive agent should be driven by a need for rapid control of blood pressure to target without overcorrection (see Table 3). Issues such as intracranial pressure, heart rate, and comorbidities may also play a role in choice of medication.
| Not eligible for thrombolytic therapy | |
|---|---|
| |
| Systolic < 220 or diastolic < 120 | Observe unless other end‐organ involvement (aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy) |
| Systolic > 220 or diastolic 121‐140 | Aim for 10%‐15% reduction in blood pressure |
| Labetalol 10‐20 mg IV over 1‐2 minutes; repeat or double every 10 minutes; maximum 300 mg | |
| or | |
| Nicardipine 5 mg/hour IV; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| or | |
| Nitroprusside 0.5 g/kg/minute IV; titrate to goal | |
| Diastolic > 140 | Aim for 10%‐15% reduction in blood pressure |
| Nitroprusside 0.5 g/kg/minute IV; titrate to desired blood pressure | |
| Eligible for thrombolytic therapy | |
| Pretreatment | |
| Systolic > 185 or diastolic > 110 | Labetalol 10‐20mg IV |
| May repeat 1 or Nitropaste 1‐2 inches | |
| During and after tPA | |
| Systolic 180‐230 or Diastolic 105‐120 | Labetalol 10 mg |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute | |
| Systolic > 230 or diastolic 121‐140 | Labetalol 10mg IV |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute or | |
| Nicardipine 5 mg/hour; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| If not at goal with labetalol or nicardipine, consider nitroprusside | |
| Diastolic>140 | Nitroprusside 0.5 g/kg/minute IV infusion; titrate to desired blood pressure |
The risk of hemorrhagic conversion is greater when thrombolysis is used for the treatment of cerebrovascular accident, in the NINDS trial rising from 0.6% in patients receiving a placebo to 6.4% in patients receiving tPA.27 Given that the goal of thrombolysis is to restore perfusion through the previously blocked vessel and that the risk of hemorrhage rises after thrombolysis, the balance between maintaining CPP and decreasing the risk of bleeding shifts toward maintaining a lower blood pressure postthrombolysis. The NINDS thrombolytic trial required patients to have a blood pressure less than 185/110 mm Hg to be included.27 Once a thrombolytic had been administered, the permitted maximum blood pressure dropped to 180/105 mm Hg. Blood pressure needs to be monitored closely, initially every 15 minutes for 2 hours, then every 30 minutes for the next 6 hours, and then hourly until the end of the first 24 hours. After this, blood pressure monitoring intervals can be more spaced out depending on the need for active antihypertensive therapy.28 However, arterial punctures for invasive monitoring are not recommended if thrombolytics are administered. Review of the experience of the NINDS trial suggests that approximately one third of patients receiving thrombolytics will require pharmacologic therapy to reach the recommended blood pressure goals in the first 24 hours.28
Although guidelines for the management of blood pressure after cerebrovascular accident from major organizations such as the American Stroke Association and the European Stroke Initiative are published and widely quoted in reviews of stroke management, physician adherence to these guidelines is poor.1, 2933 A 2002 review of prescribing practices in a Canadian hospital found excessive reduction of blood pressure in 60% of patients where nitroglycerin was used, and sublingual nifedipine was still the second most commonly prescribed medication.34 A similar 2004 study by Lindenauer et al. found that only 26% of patients who had antihypertensive medication initiated in the hospital met consensus guidelines for therapy.35
Induced Hypertension
Hypotension should be avoided after acute stroke. Observational studies have demonstrated an increased mortality rate of patients who present with hypotension.42 Patients with acute ischemic stroke and loss of autoregulation may have impaired tolerance to even mild levels of hypotension.8 First‐line therapy for hypotension after stroke is volume resuscitation and optimization of cardiac function by correcting arrhythmias.1 If this should fail, vasopressor support is advisable to avoid ongoing hypotension and cerebral hypoperfusion.
The same physiologic arguments that favor permissively managing high blood pressure and avoiding hypotension raise the question of whether inducing hypertension through the use of vasopressors might improve outcomes of stroke. This hypothesis has been bolstered by animal studies and imaging data that suggest improved perfusion to the area of injury with vasopressor‐induced hypertension.3638 However, there are concerns that this strategy may increase edema and hemorrhage and create the potential for vasopressor‐induced myocardial ischemia or arrhythmias. Although the results of small trials have appeared promising, particularly for patients with large vessel stenosis, at this point induced hypertension is still considered experimental until the results of larger randomized, controlled trials provide greater support for this procedure.1, 3941
Chronic Blood Pressure Control for Secondary Prevention of Stroke
Multiple trials have demonstrated that interventions to treat chronic hypertension can reduce the rate of future strokes.14, 43, 44 The PROGRESS trial demonstrated that blood pressure reduction with combination therapy decreased stroke recurrence by 43%.43 Clearly long‐term blood pressure control is a vital component of secondary prevention of stroke. Based on the results of the PROGRESS and ACCESS trials, it is suggested that angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers, potentially with additional diuretic therapy, are beneficial in the treatment of chronic hypertension following cerebrovascular accident.25, 42 The issue of optimal medication class is not settled. Recommendations are to treat chronically elevated blood pressure to lower and maintain it at less than 140/80 mm Hg. Because there is no single threshold level of blood pressure beyond which the risk of cerebrovascular disease increases, reduction below this cut point may still offer incremental benefit.13, 45, 46 The timing of initiation of therapy to reach secondary‐prevention goals is not addressed in current guidelines, although some authors recommend waiting days to weeks after an acute stroke before starting therapy.1, 37 For a patient who remains hypertensive at discharge, it is incumbent on the hospitalist to communicate the plan for initiation of antihypertensive agents to the patient and the primary care physician in order to ensure that this critical secondary prevention measure is addressed.
Areas of Ambiguity and Need for Future Research
Within an evidence‐guided practice, there are still many areas for which the evidence to date does not answer important clinical questions about patient management. Whether a patient's prestroke baseline blood pressure should be considered in individualizing blood pressure goals is unclear, as is the question of whether to continue or hold previous chronic antihypertensive therapy. Given the many stroke subtypes, from tiny lacunar infarcts with little collateralization to massive malignant middle‐cerebral infarctions, should blood pressure management be individualized according to the likely size and duration of the peri‐infarct penumbra? Research is needed to determine whether reducing blood pressure to a specific target will improve outcome and the optimal timing of therapy to achieve secondary prevention goals. Finally, using the concept of the penumbra as the theoretical physiologic basis for current blood pressure recommendations, there exists a potential for rapidly evolving neuroimaging techniques to help define the presence, size, and duration of the penumbra to guide these decisions.
CONCLUSIONS
Management of blood pressure after acute ischemic stroke differs from that of many other hypertensive conditions because of the need to preserve perfusion of the peri‐infarct penumbra. Evidence to date suggests little benefit and potential harm from acutely lowering blood pressure after stroke, although there have not been large randomized trials examining outcomes when blood pressure is lowered to a prespecified goal. Current consensus guidelines suggest that blood pressure may be managed permissively up to 220/120 mm Hg when thrombolysis is not administered and to 180/105 mm Hg when thrombolysis is performed. Data suggest that low‐dose antihypertensive therapy such as ACE inhibitors or angiotensin receptor blockers may be safe in the acute setting if pressure is reduced by less than 10%‐15%.17, 25 However, the evidence is not sufficiently strong for this practice to be routinely recommended. At this point, it is recommended that hypotension be aggressively treated; however, induced hypertension remains a promising but unproven therapy. Evidence is strong that long‐term blood pressure control is key to secondary prevention of stroke, but the timing of its initiation remains poorly determined.
Hospitalists are on the front lines of care for patients with cerebrovascular accidents. After the first steps in acute stroke management occur in the emergency room, care is frequently transferred to the hospitalist. This review focuses on the evidence‐based management of blood pressure following acute ischemic stroke. Management of blood pressure after stroke is still controversial, and current consensus statement guidelines acknowledge that optimal treatment has not yet been established.1, 2 As such, it is essential to understand the changes in normal homeostatic physiologic processes that occur after stroke and their subsequent effects on neurologic function. Only then can the appropriate blood pressure target and antihypertensive regimen be chosen.
Physiology of Cerebral Perfusion
Once a stroke has occurred and perfusion to a section of brain tissue has been acutely compromised, systemic pressure tends to rise. This rise is presumably due in part to increased adrenergic tone and activation of the renin‐aldosterone system and potentially is part of Cushing's reflex in cases in which intracranial pressure is elevated.3 The increase in mean arterial pressure may represent a protective response. In the first major study on the topic, in 1981, on admission for stroke mean blood pressure was 163/90 mm Hg for patients without a history of hypertension and 214/118 mm Hg for patients who had been treated for hypertension previously.4 This rise in blood pressure in response to endogenous mechanisms is attenuated over the first 24 hours, and even without intervention, blood pressure tends to fall spontaneously over the next 10 days.47
Under normal circumstances, cerebral blood flow (CBF) is tightly autoregulated across a wide range of cerebral perfusion pressures by alteration in cerebrovascular resistance via arteriolar constriction.89 This allows CBF to remain constant even if cerebral perfusion pressure (CPP) fluctuates from 60 to 150 mm Hg.9 In patients with chronic hypertension, autoregulation works best with blood pressure in a higher range because of vascular smooth muscle hypertrophy and structural changes in the cerebral vessels (see Table 1).
| Cerebral blood flow (CBF) of 50‐70 mL/100 g/minnormal |
| CBF of 20‐50 mL/100 g/minreduced flow compensated for by increased oxygen extraction |
| CBF of 15‐20 mL/100 g/minneuronal quiescence |
| CBF < 15 mL/100 g/minneuronal death |
After an acute ischemic stroke, autoregulation is lost, and local CBF becomes linearly associated with cerebral perfusion pressure. Loss of autoregulation occurs because of several local factors as a result of the infarct. Acidosis and hypoxia in the region of the stroke lead to vasodilatation in the perfusing vessels.9 This may improve local circulation in collateral vessels as a response to the obstruction in the primary supplying artery, but the consequence of maximal vasodilatation is loss of the ability to autoregulate. Normal CPP is driven by the mean arterial pressure minus the intracranial pressure. However, if intracranial vessels have lost the ability to accommodate changes in perfusion pressure, then blood flow to the area of injury becomes linearly correlated with mean arterial pressure.
Surrounding a central core of irreversible necrosis may be a zone of at‐risk tissue that is susceptible to reduction below the threshold of viability in response to any decrement in systemic mean blood pressure.11 This critical concept in stroke management is referred to as the peri‐infarct penumbra (see Fig. 1 and Table 2).
| Mean arterial pressure (MAP) = ⅔ diastolic blood pressure (DBP) + ⅓ systolic blood pressure (SBP) |
| Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) intracranial pressure (ICP) |
| Cerebral blood flow (CBF) = cerebral perfusion pressure (CPP)/cerebrovascular resistance (CVR) |
Blood Pressure Management after Stroke
The presence of a systemic blood pressure‐dependent peri‐infarct penumbra that might be compromised by blood pressure reduction and thus extend the infarct is the principal argument for allowing permissive hypertension. This is bolstered by the observation that decreases in blood pressure in the first 24 hours are associated with a significant risk of poor neurologic outcome.6 In their an observational study Vlcek et al. found that a greater than 25% drop in diastolic blood pressure (DBP) was associated with a 4‐fold risk of severe disability.5 In a 2003 observational study Oliveria et al. found that reduction in systolic blood pressure (SBP) in the first 24 hours was independently associated with poor outcomes, with a doubling of the risk for poor outcomes for every 10% drop in systolic blood pressure.6 In both these studies, the worsened outcome did not depend on whether the drop was spontaneous or induced by medications. Case reports suggest that large drops in blood pressure can be catastrophic and that even moderate lowering of blood pressure after acute stroke can be associated with clinical deterioration.8, 12
The primary argument for lowering blood pressure after an acute stroke hinges on secondary prevention of new ischemic events, minimization of cerebral edema, and prevention of hemorrhagic conversion. It has long been recognized that hypertension itself is a risk factor for stroke13 and that reduction in chronic hypertension is part of secondary prevention for cerebrovascular accidents.14 Further, hypertension is the most common risk factor for intracerebral hemorrhage, and it would stand to reason that damage to the brain parenchyma from ischemic stroke would increase the risk of pressure‐induced bleeding in an acute setting.15
Because there are compelling theoretical arguments both for and against lowering blood pressure after an acute stroke, it is necessary to look at the results of randomized clinical trials for guidance in weighing the risks and benefits. The overall goal of blood pressure management is to maximize perfusion to the ischemic penumbra while minimizing the hypertensive risk of hemorrhagic transformation.
Lisk et al. conducted a small randomized trial in 1993 of antihypertensive therapy versus placebo after ischemic stroke looking at SPECT perfusion and found lower CBF if mean arterial pressure (MAP) dropped more than 16%.16 This is in contrast with the results of a 1997 randomized trial of perindopril after cerebrovascular accident that found no decrease in Doppler CBF despite a 10% decrease in blood pressure in the active treatment group.17 Neither study was powered to detect significant differences in clinical outcome.
Early randomized controlled trials of antihypertensive agents after acute stroke investigated neuroprotection via mechanisms other than the antihypertensive effect. Nimodipine, a dihydropyridine derivative thought to prevent neuronal death via blockade of calcium channels, has been studied extensively.1820 A meta‐analysis of the 9 early trials of nimodipine, from 1988 to 1992, suggested that nimodipine was potentially beneficial in neurologic score and functional outcome only if used within the first 12 hours and that it could be harmful if started after 24 hours.21 Two additional studies were done in 1994 using both intravenous and oral nimodipine formulations. They demonstrated worsened neurologic function and higher mortality, respectively, which was hypothesized to be a result of the detrimental hemodynamic effects of nimodipine.18, 22
The BEST trial used beta‐blockers in the early period after acute stroke and failed to find benefit, whereas the FIST trial had similar results with the calcium channel blocker flunarizine.23, 24 The ACCESS trial in 2003 was a prospective, randomized, controlled trial using oral candesartan in the first 24 hours after stroke.25 It did find improved mortality in the candesartan arm after 1 year, yet there were no significant differences in blood pressure between candesartan and placebo. Thus, the improved outcome was presumed to be a result of mechanisms other than antihypertensive effect.
Some significant caveats should be kept in mind when interpreting the results of these studies. None of the trials was designed to titrate blood pressure to a prespecified goal in a prospective randomized fashion. It is also difficult to tease out the effect of the active medical intervention from the effect of spontaneous drops in blood pressure, and many trials did not find a significant difference in blood pressure between the medication and placebo groups. A large randomized trial to evaluate interventions to a predefined blood pressure target is needed.
The Cochrane Stroke Group reviewed 32 trials involving 5368 patients and concluded there was not enough evidence to reliably evaluate the effect of altering blood pressure on outcomes.3
Recommendations for Treatment of Hypertension in Acute Stroke
The decision of when to initiate antihypertensive therapy has not been clearly delineated. However, most experts agree that blood pressure targets need to take into account whether thrombolytics are used. The available data provide little evidence that lowering blood pressure decreases adverse events; however, there is some evidence that lowering blood pressure can worsen outcomes by expanding the area of ischemia. Thus, in treating most acute ischemic strokes, antihypertensive therapy can and should be withheld. The exception to this is stroke in a patient with comorbid hypertensive organ damage such as myocardial infarction, aortic dissection, acute hypertensive renal failure, pulmonary edema, or encephalopathy. The consensus statement of the American Stroke Association is to withhold treatment until blood pressure exceeds 220/120 mm Hg,1 roughly corresponding to a MAP of 150 mm Hg, the normal upper limit of cerebral autoregulation. Treatment optimally should be titratable in order to avoid overcorrection, preferably with minimal cerebral venodilatation effect. The parenteral agents labetolol, fenoldopam, nicardipine, and nitroprusside are most commonly used. A disadvantage of nitrates or nitroprusside is that their venodilating effect may raise intracranial pressure. Clonidine may induce central nervous system depression, which can complicate interpretation of the mental status of a patient with an acute neurologic event. Sublingual nifedipine should be avoided because of its well‐documented tendency to cause overcorrection of blood pressure.26 No large direct comparison trial has evaluated which of these antihypertensive agents is superior in clinical outcomes. For the hospitalist, choice of antihypertensive agent should be driven by a need for rapid control of blood pressure to target without overcorrection (see Table 3). Issues such as intracranial pressure, heart rate, and comorbidities may also play a role in choice of medication.
| Not eligible for thrombolytic therapy | |
|---|---|
| |
| Systolic < 220 or diastolic < 120 | Observe unless other end‐organ involvement (aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy) |
| Systolic > 220 or diastolic 121‐140 | Aim for 10%‐15% reduction in blood pressure |
| Labetalol 10‐20 mg IV over 1‐2 minutes; repeat or double every 10 minutes; maximum 300 mg | |
| or | |
| Nicardipine 5 mg/hour IV; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| or | |
| Nitroprusside 0.5 g/kg/minute IV; titrate to goal | |
| Diastolic > 140 | Aim for 10%‐15% reduction in blood pressure |
| Nitroprusside 0.5 g/kg/minute IV; titrate to desired blood pressure | |
| Eligible for thrombolytic therapy | |
| Pretreatment | |
| Systolic > 185 or diastolic > 110 | Labetalol 10‐20mg IV |
| May repeat 1 or Nitropaste 1‐2 inches | |
| During and after tPA | |
| Systolic 180‐230 or Diastolic 105‐120 | Labetalol 10 mg |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute | |
| Systolic > 230 or diastolic 121‐140 | Labetalol 10mg IV |
| May repeat or double labetalol every 10‐20 minutes to a maximum dose of 300 mg or give bolus and start drip at 2‐8 mg/minute or | |
| Nicardipine 5 mg/hour; titrate by 2.5 mg every 5 minutes; maximum 15 mg/hour | |
| If not at goal with labetalol or nicardipine, consider nitroprusside | |
| Diastolic>140 | Nitroprusside 0.5 g/kg/minute IV infusion; titrate to desired blood pressure |
The risk of hemorrhagic conversion is greater when thrombolysis is used for the treatment of cerebrovascular accident, in the NINDS trial rising from 0.6% in patients receiving a placebo to 6.4% in patients receiving tPA.27 Given that the goal of thrombolysis is to restore perfusion through the previously blocked vessel and that the risk of hemorrhage rises after thrombolysis, the balance between maintaining CPP and decreasing the risk of bleeding shifts toward maintaining a lower blood pressure postthrombolysis. The NINDS thrombolytic trial required patients to have a blood pressure less than 185/110 mm Hg to be included.27 Once a thrombolytic had been administered, the permitted maximum blood pressure dropped to 180/105 mm Hg. Blood pressure needs to be monitored closely, initially every 15 minutes for 2 hours, then every 30 minutes for the next 6 hours, and then hourly until the end of the first 24 hours. After this, blood pressure monitoring intervals can be more spaced out depending on the need for active antihypertensive therapy.28 However, arterial punctures for invasive monitoring are not recommended if thrombolytics are administered. Review of the experience of the NINDS trial suggests that approximately one third of patients receiving thrombolytics will require pharmacologic therapy to reach the recommended blood pressure goals in the first 24 hours.28
Although guidelines for the management of blood pressure after cerebrovascular accident from major organizations such as the American Stroke Association and the European Stroke Initiative are published and widely quoted in reviews of stroke management, physician adherence to these guidelines is poor.1, 2933 A 2002 review of prescribing practices in a Canadian hospital found excessive reduction of blood pressure in 60% of patients where nitroglycerin was used, and sublingual nifedipine was still the second most commonly prescribed medication.34 A similar 2004 study by Lindenauer et al. found that only 26% of patients who had antihypertensive medication initiated in the hospital met consensus guidelines for therapy.35
Induced Hypertension
Hypotension should be avoided after acute stroke. Observational studies have demonstrated an increased mortality rate of patients who present with hypotension.42 Patients with acute ischemic stroke and loss of autoregulation may have impaired tolerance to even mild levels of hypotension.8 First‐line therapy for hypotension after stroke is volume resuscitation and optimization of cardiac function by correcting arrhythmias.1 If this should fail, vasopressor support is advisable to avoid ongoing hypotension and cerebral hypoperfusion.
The same physiologic arguments that favor permissively managing high blood pressure and avoiding hypotension raise the question of whether inducing hypertension through the use of vasopressors might improve outcomes of stroke. This hypothesis has been bolstered by animal studies and imaging data that suggest improved perfusion to the area of injury with vasopressor‐induced hypertension.3638 However, there are concerns that this strategy may increase edema and hemorrhage and create the potential for vasopressor‐induced myocardial ischemia or arrhythmias. Although the results of small trials have appeared promising, particularly for patients with large vessel stenosis, at this point induced hypertension is still considered experimental until the results of larger randomized, controlled trials provide greater support for this procedure.1, 3941
Chronic Blood Pressure Control for Secondary Prevention of Stroke
Multiple trials have demonstrated that interventions to treat chronic hypertension can reduce the rate of future strokes.14, 43, 44 The PROGRESS trial demonstrated that blood pressure reduction with combination therapy decreased stroke recurrence by 43%.43 Clearly long‐term blood pressure control is a vital component of secondary prevention of stroke. Based on the results of the PROGRESS and ACCESS trials, it is suggested that angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers, potentially with additional diuretic therapy, are beneficial in the treatment of chronic hypertension following cerebrovascular accident.25, 42 The issue of optimal medication class is not settled. Recommendations are to treat chronically elevated blood pressure to lower and maintain it at less than 140/80 mm Hg. Because there is no single threshold level of blood pressure beyond which the risk of cerebrovascular disease increases, reduction below this cut point may still offer incremental benefit.13, 45, 46 The timing of initiation of therapy to reach secondary‐prevention goals is not addressed in current guidelines, although some authors recommend waiting days to weeks after an acute stroke before starting therapy.1, 37 For a patient who remains hypertensive at discharge, it is incumbent on the hospitalist to communicate the plan for initiation of antihypertensive agents to the patient and the primary care physician in order to ensure that this critical secondary prevention measure is addressed.
Areas of Ambiguity and Need for Future Research
Within an evidence‐guided practice, there are still many areas for which the evidence to date does not answer important clinical questions about patient management. Whether a patient's prestroke baseline blood pressure should be considered in individualizing blood pressure goals is unclear, as is the question of whether to continue or hold previous chronic antihypertensive therapy. Given the many stroke subtypes, from tiny lacunar infarcts with little collateralization to massive malignant middle‐cerebral infarctions, should blood pressure management be individualized according to the likely size and duration of the peri‐infarct penumbra? Research is needed to determine whether reducing blood pressure to a specific target will improve outcome and the optimal timing of therapy to achieve secondary prevention goals. Finally, using the concept of the penumbra as the theoretical physiologic basis for current blood pressure recommendations, there exists a potential for rapidly evolving neuroimaging techniques to help define the presence, size, and duration of the penumbra to guide these decisions.
CONCLUSIONS
Management of blood pressure after acute ischemic stroke differs from that of many other hypertensive conditions because of the need to preserve perfusion of the peri‐infarct penumbra. Evidence to date suggests little benefit and potential harm from acutely lowering blood pressure after stroke, although there have not been large randomized trials examining outcomes when blood pressure is lowered to a prespecified goal. Current consensus guidelines suggest that blood pressure may be managed permissively up to 220/120 mm Hg when thrombolysis is not administered and to 180/105 mm Hg when thrombolysis is performed. Data suggest that low‐dose antihypertensive therapy such as ACE inhibitors or angiotensin receptor blockers may be safe in the acute setting if pressure is reduced by less than 10%‐15%.17, 25 However, the evidence is not sufficiently strong for this practice to be routinely recommended. At this point, it is recommended that hypotension be aggressively treated; however, induced hypertension remains a promising but unproven therapy. Evidence is strong that long‐term blood pressure control is key to secondary prevention of stroke, but the timing of its initiation remains poorly determined.
- ,,, et al.Guidelines for the early management of patients with ischemic stroke.Stroke.2003;34:1056–1083.
- ,,,.Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update.Stroke.2005;36:916–921.
- Blood Pressure in Acute Stroke Collaboration (BASC).Vasoactive drugs for acute strokeCochrane Database Syst Rev.2004;1:CD002839.
- ,.Blood pressure after stroke.JAMA.1981;246:2177–2180.
- ,,,,,.Association between course of blood pressure within the first 24 hours and functional recovery after acute ischemic stroke.Ann Emerg Med.2003;42:619–626.
- ,,,,,.Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset.Neurology.2003;61:1047–1050.
- ,,,, et al.Blood pressure during the first minutes of focal cerebral ischemia.Ann Emerg Med.1993;22:1438–1443.
- ,,,,.Stroke precipitated by moderate blood pressure reduction.J Emerg Med.2000;19:339–346.
- .Hemodynamics and metabolism in ischemic cerebrovascular disease.Neurologic Clinics.1992;10(1):31–48.
- ,.The 5 Ps of acute ischemic stroke treatment: parenchyma, pipes, perfusion, penumbra, and prevention of complications.South Med J.2003;96:336–341.
- .Viability Thresholds and the Penumbra of Focal Ischemia.Annals of Neurology.1994;36:557–565.
- ,,.Hazards of therapy for excessive hypertension in acute stroke.Acta Med Scand.1980;207:253–257.
- Prospective Studies Collaboration.Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies.Lancet.2002;360:1903–1913.
- ,,,.Secondary prevention of ischemic cerebrovascular disease. What is the evidence?Angiology.2005;56:539–552.
- ,,.Intracerebral hemorrhage.Emerg Med Clin North Am.2002;20:631–655.
- ,,, et al.Should hypertension be treated after acute stroke?Arch Neurol.1993;50:855–862.
- ,,.Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke.Stroke.1997;28:580–583.
- ,,,,.Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke.Cerebrovasc Dis.1994;4:204–210.
- The American Nimodipine Study Group.Clinical trial of nimodipine in acute ischemic stroke.Stroke.1992;23(1):3–8.
- ,,, et al.Placebo‐controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction.Stroke.1990;21:1023–1028.
- ,,, et al.Meta‐analysis of oral nimodipine trials in acute ischemic stroke.Cerebrovasc Dis.1994;4:197–203.
- ,,, et al.A randomized, double‐blind, placebo‐controlled trial of nimodipine in acute ischemic hemispheric stroke.Stroke.1994;25:1348–1353.
- ,,,.Low dose B blockade in acute stroke (“BEST” trial): an evaluationBMJ.1988;296:737–741.
- ,,, et al.Flunarizine in stroke treatment (FIST): a double‐blind, placebo‐controlled trial in Scandinavia and the Netherlands.Acta Neurol Scand.1996;93:56–60.
- ,,, et al.The ACCESS study: Evaluation of acute candesartan cilexetil therapy in stroke survivors.Stroke.2003;34:1699–1703.
- .FDA gives Calcium channel blockers clean bill of health but warns of short‐acting nifedipine hazards.JAMA.1996;275:1638.
- The National Institute of Neurological Disorders and Stroke rt‐PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,, et al.Hypertension and its treatment in the NINDS rt‐PA Stroke Trial.Stroke.1998;29:1504–1509.
- ,.Optimizing blood pressure in neurologic emergencies.Neurocrit Care.2004;1:287–299.
- .Management of acute stroke.South M J.2003;96:380–385.
- .Management of acute stroke.Lancet Neurol.2002;1(1):41–50.
- ,.Acute ischemic stroke: emergent evaluation and management.Emerg Med Clin North Am.2002;20:609–630.
- ,.Post‐emergency department management of stroke.Emerg Med Clin North Am.2002;20:687–702.
- ,,.Blood pressure management in acute stroke: comparison of current guidelines with prescribing patterns.Can J Neurol Sci.2002;29(2):125–131.
- ,,,,,.Use of antihypertensive agents in the management of patients with acute ischemic stroke.Neurology.2004;63:318–323.
- ,,,.Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats.Surg Neurol.1996;46:229–234.
- ,,,.Effects of induced hypertension on intracranial pressure and flow velocities of the middle cerebral arteries in patients with large hemispheric stroke.Stroke.2002;33:998–1004.
- ,,,.Induced hypertension improves cerebral blood flow in acute ischemic stroke.Neurology.2005;64:1979.
- ,,,,.A pilot study of drug induced hypertension for treatment of acute stroke.Neurology.2001;56:1210–1213.
- ,,,,,.Pharmacologic elevation of blood pressure in acute stroke: clinical effects and safety.Stroke.1997;28:2133–2138.
- ,,,,.Feasibility and safety of norephinephrine‐induced arterial hypertension in acute ischemic stroke.Neurology.2004;62:1193–1195.
- ,,,,.Initial emergency department blood pressure as predictor of survival after acute ischemic stroke.Neurology.2005;65:1179–1183.
- The PROGRESS Collaborative Group.Randomized trial of a perindopril‐based blood‐pressure‐lowering regimen among 6105 individuals with previous stroke of transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,, et al.Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke.JAMA.2000;284:465–471.
- ,.Treatment of chronic hypertension for the prevention of stroke.South Med J.2003;96:359–362.
- ,,,.Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study.JAMA.1996;276:1269–1278.
- ,,, et al.Guidelines for the early management of patients with ischemic stroke.Stroke.2003;34:1056–1083.
- ,,,.Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update.Stroke.2005;36:916–921.
- Blood Pressure in Acute Stroke Collaboration (BASC).Vasoactive drugs for acute strokeCochrane Database Syst Rev.2004;1:CD002839.
- ,.Blood pressure after stroke.JAMA.1981;246:2177–2180.
- ,,,,,.Association between course of blood pressure within the first 24 hours and functional recovery after acute ischemic stroke.Ann Emerg Med.2003;42:619–626.
- ,,,,,.Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset.Neurology.2003;61:1047–1050.
- ,,,, et al.Blood pressure during the first minutes of focal cerebral ischemia.Ann Emerg Med.1993;22:1438–1443.
- ,,,,.Stroke precipitated by moderate blood pressure reduction.J Emerg Med.2000;19:339–346.
- .Hemodynamics and metabolism in ischemic cerebrovascular disease.Neurologic Clinics.1992;10(1):31–48.
- ,.The 5 Ps of acute ischemic stroke treatment: parenchyma, pipes, perfusion, penumbra, and prevention of complications.South Med J.2003;96:336–341.
- .Viability Thresholds and the Penumbra of Focal Ischemia.Annals of Neurology.1994;36:557–565.
- ,,.Hazards of therapy for excessive hypertension in acute stroke.Acta Med Scand.1980;207:253–257.
- Prospective Studies Collaboration.Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies.Lancet.2002;360:1903–1913.
- ,,,.Secondary prevention of ischemic cerebrovascular disease. What is the evidence?Angiology.2005;56:539–552.
- ,,.Intracerebral hemorrhage.Emerg Med Clin North Am.2002;20:631–655.
- ,,, et al.Should hypertension be treated after acute stroke?Arch Neurol.1993;50:855–862.
- ,,.Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke.Stroke.1997;28:580–583.
- ,,,,.Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke.Cerebrovasc Dis.1994;4:204–210.
- The American Nimodipine Study Group.Clinical trial of nimodipine in acute ischemic stroke.Stroke.1992;23(1):3–8.
- ,,, et al.Placebo‐controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction.Stroke.1990;21:1023–1028.
- ,,, et al.Meta‐analysis of oral nimodipine trials in acute ischemic stroke.Cerebrovasc Dis.1994;4:197–203.
- ,,, et al.A randomized, double‐blind, placebo‐controlled trial of nimodipine in acute ischemic hemispheric stroke.Stroke.1994;25:1348–1353.
- ,,,.Low dose B blockade in acute stroke (“BEST” trial): an evaluationBMJ.1988;296:737–741.
- ,,, et al.Flunarizine in stroke treatment (FIST): a double‐blind, placebo‐controlled trial in Scandinavia and the Netherlands.Acta Neurol Scand.1996;93:56–60.
- ,,, et al.The ACCESS study: Evaluation of acute candesartan cilexetil therapy in stroke survivors.Stroke.2003;34:1699–1703.
- .FDA gives Calcium channel blockers clean bill of health but warns of short‐acting nifedipine hazards.JAMA.1996;275:1638.
- The National Institute of Neurological Disorders and Stroke rt‐PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,, et al.Hypertension and its treatment in the NINDS rt‐PA Stroke Trial.Stroke.1998;29:1504–1509.
- ,.Optimizing blood pressure in neurologic emergencies.Neurocrit Care.2004;1:287–299.
- .Management of acute stroke.South M J.2003;96:380–385.
- .Management of acute stroke.Lancet Neurol.2002;1(1):41–50.
- ,.Acute ischemic stroke: emergent evaluation and management.Emerg Med Clin North Am.2002;20:609–630.
- ,.Post‐emergency department management of stroke.Emerg Med Clin North Am.2002;20:687–702.
- ,,.Blood pressure management in acute stroke: comparison of current guidelines with prescribing patterns.Can J Neurol Sci.2002;29(2):125–131.
- ,,,,,.Use of antihypertensive agents in the management of patients with acute ischemic stroke.Neurology.2004;63:318–323.
- ,,,.Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats.Surg Neurol.1996;46:229–234.
- ,,,.Effects of induced hypertension on intracranial pressure and flow velocities of the middle cerebral arteries in patients with large hemispheric stroke.Stroke.2002;33:998–1004.
- ,,,.Induced hypertension improves cerebral blood flow in acute ischemic stroke.Neurology.2005;64:1979.
- ,,,,.A pilot study of drug induced hypertension for treatment of acute stroke.Neurology.2001;56:1210–1213.
- ,,,,,.Pharmacologic elevation of blood pressure in acute stroke: clinical effects and safety.Stroke.1997;28:2133–2138.
- ,,,,.Feasibility and safety of norephinephrine‐induced arterial hypertension in acute ischemic stroke.Neurology.2004;62:1193–1195.
- ,,,,.Initial emergency department blood pressure as predictor of survival after acute ischemic stroke.Neurology.2005;65:1179–1183.
- The PROGRESS Collaborative Group.Randomized trial of a perindopril‐based blood‐pressure‐lowering regimen among 6105 individuals with previous stroke of transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,, et al.Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke.JAMA.2000;284:465–471.
- ,.Treatment of chronic hypertension for the prevention of stroke.South Med J.2003;96:359–362.
- ,,,.Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study.JAMA.1996;276:1269–1278.
Suppurative complications and upper airway obstruction in infectious mononucleosis
A 17‐year‐old female patient presented to the emergency department reporting having fever, sore throat, and pain with swallowing for several days. The result of her rapid strep screen was negative. She had an elevated white blood cell count, mildly elevated AST and ALT levels, and a positive result from a heterophile antibody test (BBL Monoslide). She was diagnosed with infectious mononucleosis. Given her inability to tolerate oral fluids, she was admitted to the hospital for intravenous hydration. After 3 days of receiving methylprednisolone intravenously, she had worsening throat pain, progressive neck swelling, difficulty handling her secretions, and new respiratory symptoms. During the examination, she was sitting upright in bed in moderate respiratory distress. She had kissing, exudative tonsils with palatal and uvular edema. Examination of her neck showed significantly enlarged anterior and posterior cervical lymph nodes without fluctuance. Her lung exam revealed subcostal retractions with transmitted upper airway sounds but good aeration. The edge of her liver and spleen tip were palpable.
Because of the rapid progression of symptoms while on medical therapy, computed tomography (CT) of the neck was performed. Sagittal reconstructions showed adenoidal hypertrophy compromising her nasopharynx, and massive tonsillar enlargement causing nearly complete obstruction of her oropharyngeal airway (Fig. 1), with airway narrowing to less than 2.5 mm in axial images. Bilateral low‐density lesions within the paratonsillar regions were suggestive of abscesses and retropharyngeal soft‐tissue swelling was consistent with phlegmon (Fig. 2). The patient was taken to the operating room for an emergent tonsillectomy. Bilateral peritonsillar abscesses were drained, pus was sent for culture, and her tonsils were excised. Cultures from the abscesses grew Streptococcus milleri. The patient was discharged home 2 days later to complete a 2‐week course of oral clindamycin.
Most patients with infectious mononucleosis (IM) have a benign, self‐limited course. However, a wide range of severe complications have been described including airway obstruction, splenic rupture, meningoencephalitis, Guillain‐Barr syndrome, peritonsillar abscess, and hemolytic anemia.1, 2 Upper‐airway obstruction results from lymphoid hyperplasia throughout Waldeyer's ring, with associated soft‐tissue edema. As many as 25% of patients hospitalized for IM will have some degree of airway obstruction.2, 3 Peritonsillar abscesses (PTAs) occur in approximately 1% of hospitalized patients with IM and may further obstruct the airway.4 Most commonly, peritonsillar abscesses are polymicrobial, having both aerobic and anaerobic bacteria. In a study of young adults with peritonsillar abscesses from all causes, Streptococcus pyogenes was the most common aerobe, found in nearly half of isolates; Streptococcus milleri, the bacterium isolated from our patient, was the second most common organism, found in approximately 25% of these abscesses.5 One prior case of airway obstruction from IM complicated by bilateral peritonsillar abscesses has been reported6; however, this patient was not reported to have concomitant retropharyngeal infection, as was noted in our patient.
Guidelines suggest that patients with mild, uncomplicated IM should be managed with supportive care alone; current recommendations are that steroids be prescribed only for specific complications of IM, including upper‐airway obstruction.7 Protocols for steroid regimens include initial prednisone doses ranging from 20 to 80 mg/day, with most advocating that they be tapered off over 1‐2 weeks.7, 8
Some of the controversy about the routine use of steroids in IM is related to concern for potential infectious complications associated with immunosuppression. In a small case series, Handler et al. proposed that there is an association between steroid therapy and the development of peritonsillar abscesses.9 However, this has not been tested in controlled trials, and the results of more recent studies do not support an increased likelihood of PTA in patients with infectious mononucleosis treated with corticosteroids.10, 11 Therefore, given that it has documented benefits and no proven adverse consequences, steroid therapy is uniformly recommended for patients with upper‐airway obstruction secondary to infectious mononucleosis. However, use of steroids also mandates careful monitoring for signs or symptoms suggestive of secondary bacterial infection.
For patients whose symptoms progress despite medical management including steroid therapy, surgical intervention may be required. Both tracheostomy and tonsillectomy during acute infection, sometimes referred to as hot tonsillectomy, have been reported as surgical options for airway obstruction in IM, the latter having emerged as the preferred treatment.3 Such treatment allows for drainage of any infectious collections, as well as removal of obstructing lymphoid tissue as indicated.
In conclusion, enlargement of tonsils and adenoids with associated edema in infectious mononucleosis can lead to upper‐airway obstruction. Patients with evidence of such obstruction should be treated with a tapering course of corticosteroids. Peritonsillar abscesses and deep neck infections are also severe complications of IM and can cause further respiratory compromise. In cases where medical therapy is not effective, such as with our patient, evaluation for peritonsillar abscess and need for possible acute tonsillectomy may be required.
- .Acute complications of Epstein‐Barr virus infectious mononucleosis.Curr Opin Pediatr.2000;12(3):263–268.
- ,.Complications of infection with Epstein‐Barr virus during childhood: a study of children admitted to the hospital.Pediatr Infect Dis.1984;3:304–307.
- ,.The management of severe infectious mononucleosis tonsillitis and upper airway obstruction.J Laryngol Otol.2001;115:973–977.
- ,,.Otolaryngological complications in infectious mononucleosis.J Laryngol Otol.1984;98:999–1001.
- ,,.Bacteriologic findings in peritonsillar abscesses in young adults.Clin Infect Dis.1993;16(suppl 4):S292–S298.
- ,.Infectious mononucleosis and bilateral peritonsillar abscesses resulting in airway obstruction.J Laryngol Otol.1998;112:1186–1188.
- ,,, et al.Guidelines for the use of systemic glucocorticosteroids in the management of selected infections.Working Group on Steroid Use, Antimicrobial Agents Committee, Infectious Diseases Society of America.J Infect Dis.1992;165(1):1–13.
- ,Narula AA Steroids for airway problems in glandular fever.J Laryngol Otol.1987;10:673–675.
- ,.Peritonsillar abscess: a complication of corticosteroid treatment in infectious mononucleosis.Int J Pediatr Otorhinolaryngol.1979;1(3):265–268.
- ,,.Corticosteroids and peritonsillar abscess formation in infectious mononucleosis.J Laryngol Otol.2004;118:459–461.
- ,,.Otolaryngologic Clinical Patterns in Pediatric Infectious Mononucleosis.Am J Otolaryngol.1996;17:397–400.
A 17‐year‐old female patient presented to the emergency department reporting having fever, sore throat, and pain with swallowing for several days. The result of her rapid strep screen was negative. She had an elevated white blood cell count, mildly elevated AST and ALT levels, and a positive result from a heterophile antibody test (BBL Monoslide). She was diagnosed with infectious mononucleosis. Given her inability to tolerate oral fluids, she was admitted to the hospital for intravenous hydration. After 3 days of receiving methylprednisolone intravenously, she had worsening throat pain, progressive neck swelling, difficulty handling her secretions, and new respiratory symptoms. During the examination, she was sitting upright in bed in moderate respiratory distress. She had kissing, exudative tonsils with palatal and uvular edema. Examination of her neck showed significantly enlarged anterior and posterior cervical lymph nodes without fluctuance. Her lung exam revealed subcostal retractions with transmitted upper airway sounds but good aeration. The edge of her liver and spleen tip were palpable.
Because of the rapid progression of symptoms while on medical therapy, computed tomography (CT) of the neck was performed. Sagittal reconstructions showed adenoidal hypertrophy compromising her nasopharynx, and massive tonsillar enlargement causing nearly complete obstruction of her oropharyngeal airway (Fig. 1), with airway narrowing to less than 2.5 mm in axial images. Bilateral low‐density lesions within the paratonsillar regions were suggestive of abscesses and retropharyngeal soft‐tissue swelling was consistent with phlegmon (Fig. 2). The patient was taken to the operating room for an emergent tonsillectomy. Bilateral peritonsillar abscesses were drained, pus was sent for culture, and her tonsils were excised. Cultures from the abscesses grew Streptococcus milleri. The patient was discharged home 2 days later to complete a 2‐week course of oral clindamycin.
Most patients with infectious mononucleosis (IM) have a benign, self‐limited course. However, a wide range of severe complications have been described including airway obstruction, splenic rupture, meningoencephalitis, Guillain‐Barr syndrome, peritonsillar abscess, and hemolytic anemia.1, 2 Upper‐airway obstruction results from lymphoid hyperplasia throughout Waldeyer's ring, with associated soft‐tissue edema. As many as 25% of patients hospitalized for IM will have some degree of airway obstruction.2, 3 Peritonsillar abscesses (PTAs) occur in approximately 1% of hospitalized patients with IM and may further obstruct the airway.4 Most commonly, peritonsillar abscesses are polymicrobial, having both aerobic and anaerobic bacteria. In a study of young adults with peritonsillar abscesses from all causes, Streptococcus pyogenes was the most common aerobe, found in nearly half of isolates; Streptococcus milleri, the bacterium isolated from our patient, was the second most common organism, found in approximately 25% of these abscesses.5 One prior case of airway obstruction from IM complicated by bilateral peritonsillar abscesses has been reported6; however, this patient was not reported to have concomitant retropharyngeal infection, as was noted in our patient.
Guidelines suggest that patients with mild, uncomplicated IM should be managed with supportive care alone; current recommendations are that steroids be prescribed only for specific complications of IM, including upper‐airway obstruction.7 Protocols for steroid regimens include initial prednisone doses ranging from 20 to 80 mg/day, with most advocating that they be tapered off over 1‐2 weeks.7, 8
Some of the controversy about the routine use of steroids in IM is related to concern for potential infectious complications associated with immunosuppression. In a small case series, Handler et al. proposed that there is an association between steroid therapy and the development of peritonsillar abscesses.9 However, this has not been tested in controlled trials, and the results of more recent studies do not support an increased likelihood of PTA in patients with infectious mononucleosis treated with corticosteroids.10, 11 Therefore, given that it has documented benefits and no proven adverse consequences, steroid therapy is uniformly recommended for patients with upper‐airway obstruction secondary to infectious mononucleosis. However, use of steroids also mandates careful monitoring for signs or symptoms suggestive of secondary bacterial infection.
For patients whose symptoms progress despite medical management including steroid therapy, surgical intervention may be required. Both tracheostomy and tonsillectomy during acute infection, sometimes referred to as hot tonsillectomy, have been reported as surgical options for airway obstruction in IM, the latter having emerged as the preferred treatment.3 Such treatment allows for drainage of any infectious collections, as well as removal of obstructing lymphoid tissue as indicated.
In conclusion, enlargement of tonsils and adenoids with associated edema in infectious mononucleosis can lead to upper‐airway obstruction. Patients with evidence of such obstruction should be treated with a tapering course of corticosteroids. Peritonsillar abscesses and deep neck infections are also severe complications of IM and can cause further respiratory compromise. In cases where medical therapy is not effective, such as with our patient, evaluation for peritonsillar abscess and need for possible acute tonsillectomy may be required.
A 17‐year‐old female patient presented to the emergency department reporting having fever, sore throat, and pain with swallowing for several days. The result of her rapid strep screen was negative. She had an elevated white blood cell count, mildly elevated AST and ALT levels, and a positive result from a heterophile antibody test (BBL Monoslide). She was diagnosed with infectious mononucleosis. Given her inability to tolerate oral fluids, she was admitted to the hospital for intravenous hydration. After 3 days of receiving methylprednisolone intravenously, she had worsening throat pain, progressive neck swelling, difficulty handling her secretions, and new respiratory symptoms. During the examination, she was sitting upright in bed in moderate respiratory distress. She had kissing, exudative tonsils with palatal and uvular edema. Examination of her neck showed significantly enlarged anterior and posterior cervical lymph nodes without fluctuance. Her lung exam revealed subcostal retractions with transmitted upper airway sounds but good aeration. The edge of her liver and spleen tip were palpable.
Because of the rapid progression of symptoms while on medical therapy, computed tomography (CT) of the neck was performed. Sagittal reconstructions showed adenoidal hypertrophy compromising her nasopharynx, and massive tonsillar enlargement causing nearly complete obstruction of her oropharyngeal airway (Fig. 1), with airway narrowing to less than 2.5 mm in axial images. Bilateral low‐density lesions within the paratonsillar regions were suggestive of abscesses and retropharyngeal soft‐tissue swelling was consistent with phlegmon (Fig. 2). The patient was taken to the operating room for an emergent tonsillectomy. Bilateral peritonsillar abscesses were drained, pus was sent for culture, and her tonsils were excised. Cultures from the abscesses grew Streptococcus milleri. The patient was discharged home 2 days later to complete a 2‐week course of oral clindamycin.
Most patients with infectious mononucleosis (IM) have a benign, self‐limited course. However, a wide range of severe complications have been described including airway obstruction, splenic rupture, meningoencephalitis, Guillain‐Barr syndrome, peritonsillar abscess, and hemolytic anemia.1, 2 Upper‐airway obstruction results from lymphoid hyperplasia throughout Waldeyer's ring, with associated soft‐tissue edema. As many as 25% of patients hospitalized for IM will have some degree of airway obstruction.2, 3 Peritonsillar abscesses (PTAs) occur in approximately 1% of hospitalized patients with IM and may further obstruct the airway.4 Most commonly, peritonsillar abscesses are polymicrobial, having both aerobic and anaerobic bacteria. In a study of young adults with peritonsillar abscesses from all causes, Streptococcus pyogenes was the most common aerobe, found in nearly half of isolates; Streptococcus milleri, the bacterium isolated from our patient, was the second most common organism, found in approximately 25% of these abscesses.5 One prior case of airway obstruction from IM complicated by bilateral peritonsillar abscesses has been reported6; however, this patient was not reported to have concomitant retropharyngeal infection, as was noted in our patient.
Guidelines suggest that patients with mild, uncomplicated IM should be managed with supportive care alone; current recommendations are that steroids be prescribed only for specific complications of IM, including upper‐airway obstruction.7 Protocols for steroid regimens include initial prednisone doses ranging from 20 to 80 mg/day, with most advocating that they be tapered off over 1‐2 weeks.7, 8
Some of the controversy about the routine use of steroids in IM is related to concern for potential infectious complications associated with immunosuppression. In a small case series, Handler et al. proposed that there is an association between steroid therapy and the development of peritonsillar abscesses.9 However, this has not been tested in controlled trials, and the results of more recent studies do not support an increased likelihood of PTA in patients with infectious mononucleosis treated with corticosteroids.10, 11 Therefore, given that it has documented benefits and no proven adverse consequences, steroid therapy is uniformly recommended for patients with upper‐airway obstruction secondary to infectious mononucleosis. However, use of steroids also mandates careful monitoring for signs or symptoms suggestive of secondary bacterial infection.
For patients whose symptoms progress despite medical management including steroid therapy, surgical intervention may be required. Both tracheostomy and tonsillectomy during acute infection, sometimes referred to as hot tonsillectomy, have been reported as surgical options for airway obstruction in IM, the latter having emerged as the preferred treatment.3 Such treatment allows for drainage of any infectious collections, as well as removal of obstructing lymphoid tissue as indicated.
In conclusion, enlargement of tonsils and adenoids with associated edema in infectious mononucleosis can lead to upper‐airway obstruction. Patients with evidence of such obstruction should be treated with a tapering course of corticosteroids. Peritonsillar abscesses and deep neck infections are also severe complications of IM and can cause further respiratory compromise. In cases where medical therapy is not effective, such as with our patient, evaluation for peritonsillar abscess and need for possible acute tonsillectomy may be required.
- .Acute complications of Epstein‐Barr virus infectious mononucleosis.Curr Opin Pediatr.2000;12(3):263–268.
- ,.Complications of infection with Epstein‐Barr virus during childhood: a study of children admitted to the hospital.Pediatr Infect Dis.1984;3:304–307.
- ,.The management of severe infectious mononucleosis tonsillitis and upper airway obstruction.J Laryngol Otol.2001;115:973–977.
- ,,.Otolaryngological complications in infectious mononucleosis.J Laryngol Otol.1984;98:999–1001.
- ,,.Bacteriologic findings in peritonsillar abscesses in young adults.Clin Infect Dis.1993;16(suppl 4):S292–S298.
- ,.Infectious mononucleosis and bilateral peritonsillar abscesses resulting in airway obstruction.J Laryngol Otol.1998;112:1186–1188.
- ,,, et al.Guidelines for the use of systemic glucocorticosteroids in the management of selected infections.Working Group on Steroid Use, Antimicrobial Agents Committee, Infectious Diseases Society of America.J Infect Dis.1992;165(1):1–13.
- ,Narula AA Steroids for airway problems in glandular fever.J Laryngol Otol.1987;10:673–675.
- ,.Peritonsillar abscess: a complication of corticosteroid treatment in infectious mononucleosis.Int J Pediatr Otorhinolaryngol.1979;1(3):265–268.
- ,,.Corticosteroids and peritonsillar abscess formation in infectious mononucleosis.J Laryngol Otol.2004;118:459–461.
- ,,.Otolaryngologic Clinical Patterns in Pediatric Infectious Mononucleosis.Am J Otolaryngol.1996;17:397–400.
- .Acute complications of Epstein‐Barr virus infectious mononucleosis.Curr Opin Pediatr.2000;12(3):263–268.
- ,.Complications of infection with Epstein‐Barr virus during childhood: a study of children admitted to the hospital.Pediatr Infect Dis.1984;3:304–307.
- ,.The management of severe infectious mononucleosis tonsillitis and upper airway obstruction.J Laryngol Otol.2001;115:973–977.
- ,,.Otolaryngological complications in infectious mononucleosis.J Laryngol Otol.1984;98:999–1001.
- ,,.Bacteriologic findings in peritonsillar abscesses in young adults.Clin Infect Dis.1993;16(suppl 4):S292–S298.
- ,.Infectious mononucleosis and bilateral peritonsillar abscesses resulting in airway obstruction.J Laryngol Otol.1998;112:1186–1188.
- ,,, et al.Guidelines for the use of systemic glucocorticosteroids in the management of selected infections.Working Group on Steroid Use, Antimicrobial Agents Committee, Infectious Diseases Society of America.J Infect Dis.1992;165(1):1–13.
- ,Narula AA Steroids for airway problems in glandular fever.J Laryngol Otol.1987;10:673–675.
- ,.Peritonsillar abscess: a complication of corticosteroid treatment in infectious mononucleosis.Int J Pediatr Otorhinolaryngol.1979;1(3):265–268.
- ,,.Corticosteroids and peritonsillar abscess formation in infectious mononucleosis.J Laryngol Otol.2004;118:459–461.
- ,,.Otolaryngologic Clinical Patterns in Pediatric Infectious Mononucleosis.Am J Otolaryngol.1996;17:397–400.
Hypoglycemia in Hospitalized Patients / Garg et al.
Glycemic control in hospitalized patients is receiving greater attention. The American Diabetes Association and the American College of Endocrinology recently issued a joint consensus statement on the need to implement tight blood glucose (BG) control in hospitalized patients.1, 2 The Joint Commission on Accreditation of Healthcare Organizations (JACHO) has developed an Advanced Inpatient Diabetes Care Certification Program for hospitals. However, despite all these efforts, it has been difficult to change how well glucose is controlled.3 A major hurdle in implementing glycemic control strategies is the prevalent fear of hypoglycemia among hospital staff. Although there are multiple protocols for insulin treatment,47 guidelines for the prevention and treatment of hypoglycemia are lacking. Once a hypoglycemic episode has occurred, reducing the dosage of diabetes medications may reduce subsequent episodes. This study was conducted to assess whether diabetes medications were decreased following an episode of hypoglycemia that led to treatment with intravenous (IV) dextrose.
METHODS
Data were collected by the Diabetes Subcommittee of the Pharmacy and Therapeutics Committee as part of a quality improvement initiative. Hypoglycemic episodes were identified by computerized orders for 50% dextrose solution. All orders in a 1‐month period (June 2006) were collected. Characteristics of patients experiencing these episodes were identified from the electronic medical records (EMR). The following data were collected: age, sex, history of diabetes, serum creatinine, diabetes medications at time of hypoglycemia, blood glucose at time of hypoglycemia, and all BG values in the 24 hours before hypoglycemia. BG values included those obtained in the laboratory as well as those obtained by bedside blood glucose testing. Treatment changes made right when the hypoglycemic episode occurred (immediate) and within 24 hours of the hypoglycemic episode (subsequent) were evaluated by 2 diabetes specialists, a board‐certified endocrinologist and a nurse‐practitioner working on the diabetes management service. The 2 practitioners regularly work together, but the data were evaluated independently. Because there are no specific guidelines, the appropriateness of change in treatment was based on general guidelines and experience. For example, if hypoglycemia developed while a patient was on insulin infusion therapy, it was appropriate to stop the drip when the episode of hypoglycemia occurred and to restart it at a lower rate according to the insulin infusion protocol. No subsequent changes would have been made in a situation such as this, and it was deemed appropriate. However, if a patient developed hypoglycemia while on subcutaneous (SC) insulin and then insulin was either completely discontinued or no change was made in subsequent orders, it was deemed inappropriate. The 2 diabetes specialists agreed in 87% of cases (kappa = 0.68, 95% CI 0.53‐0.84). In the 13% of cases in which the diabetes specialists had different opinions, they conferred to reach agreement. In patients with more than 1 episode, data related to the first episode were evaluated. Data are presented as means with SDs.
RESULTS
The EMR contained information on time of episode of hypoglycemia and medication changes for 52 patients, all of whom were in the study. Patient characteristics and mean blood glucose level are shown in Table 1. All patients were being treated with insulin when the episode of hypoglycemia occurred: 9 were on intravenous (IV) insulin alone, 3 on IV and subcutaneous (SC) insulin, 30 on scheduled SC insulin, and 10 on sliding‐scale SC insulin alone. Three patients were prescribed sulfonylurea drugs in addition to insulin. Insulin dosage of all 52 patients was held at the time of the hypoglycemic episode. Diabetes specialists agreed with this decision 100% of the time. Only 21 patients (40%) subsequently had reductions made in their treatment dosage, and diabetes specialists agreed with the changes made for 11 of these patients (52%). Thirty‐one patients (60%) had no changes made to their treatment, and diabetes specialists agreed with that decision for 10 of these patients (32%). When diabetes specialists disagreed with a decision, they would have decreased the insulin dose or changed the regimen in a different way. Details on the changes in treatment and whether diabetes specialists agreed with the changes are shown in Table 2. Twenty‐four hours after an episode of hypoglycemia, mean blood glucose of patients whose providers had made changes was 190.7 87.9 mg/dL and that of patients whose providers had not made changes was 122.6 43.2 mg/dL (P = NS). The mean BG of patients for whom the diabetologists agreed with the decision was 110.7 90.3 mg/dL, and that of patients for whom they disagreed with the decision was 139.7 42.8 mg/dL (P = NS).
| Number of patients | 52 |
| Age (years) | 64.8 15.8 |
| Sex (male:female), n | 29:23 |
| Preexisting diabetes, n (%) | |
| No diabetes | 17 (33%) |
| Type 1 diabetes | 9 (17%) |
| Type 2 diabetes | 26 (50%) |
| Serum creatinine (mg/dL) | 2.1 1.9 |
| Serum creatinine 2 mg/dL, n (%) | 21 (40%) |
| BG at time of hypoglycemia (mg/dL) | 52.1 9.3 |
| Mean BG during 24 hours before hypoglycemic episode (mg/dL) | 137.5 57.0 |
| Mean BG during 24 hours after hypoglycemic episode (mg/dL) | 112 74.7 |
| Change | Number of patients receiving change | Number of patients for whom diabetes specialists agreed with change, n (%) |
|---|---|---|
| Basal insulin decreased | 6 | 6 (100%) |
| Basal insulin stopped | 2 | 0 (0%) |
| IV insulin changed to scheduled SC insulin | 2 | 1 (50%) |
| IV insulin to SC sliding‐scale insulin | 1 | 0 (0%) |
| Change in sliding‐scale insulin dose | 3 | 1 (33%) |
| Sliding‐scale insulin stopped | 1 | 1 (100%) |
| IV insulin started | 1 | 1 (100%) |
| Sulfonylurea stopped | 1 | 1 (100%) |
| Scheduled insulin changed to sliding scale | 1 | 0 (0%) |
| Insulin discontinued | 3 | 0 (0%) |
| No change | 31 | 10 (32%) |
DISCUSSION
These results suggest that treatment modification following an episode of hypoglycemia may be suboptimal. These data provide no information about the clinical circumstances leading to the choice of treatment with IV dextrose, as opposed to oral glucose or glucagon. Presumably, dextrose was chosen for many patients whom the physician considered to require the most urgent treatment. Appropriately, immediate treatment with insulin was held for all patients. On the other hand, 60% of the patients continued to receive the same insulin dose 24 hours after the hypoglycemic episode. Diabetes specialists judged continuation of the same dose as inappropriate in two thirds of the cases. Even when changes in treatment were made, those changes were judged suboptimal in half the cases. Blood glucose level 24 hours after an episode of hypoglycemia reflects these problems. These findings suggest that opportunities to prevent hypoglycemic episodes in the future are frequently missed. Lack of knowledge and/or guidelines for adjusting insulin dose following an episode of hypoglycemia seemed to have led to suboptimal changes for most patients.
Overall incidence of hypoglycemia (<60 mg/dL) among patients with diabetes admitted to a hospital has been reported to be 23%.8 In patients receiving continuous intravenous insulin infusion, the incidence of hypoglycemia has been variously reported as from 1.2% to 18.7%.9, 10 All insulin infusion protocols have guidelines for the immediate treatment of hypoglycemia and recommend steps to prevent further episodes. Although many hospitals have protocols for immediate action when hypoglycemia occurs (eg, hold insulin, give juice or dextrose), to our knowledge, no specific guidelines exist for adjustment of subcutaneous insulin following an episode of hypoglycemia. The vast majority of patients in a hospital are treated with SC insulin as opposed to IV insulin, and fear of hypoglycemia is a major barrier to intensified therapy. If widely applied, standardized protocols have the potential to be effective in preventing hypoglycemia.9
A limitation of our study was that it was a retrospective data analysis. We did not look at changes in clinical condition, in nutrition, and in other medications that might have led to the episode of hypoglycemia and affected the decision about which antidiabetic medications to treat with. Data on further episodes of hypoglycemia were also not available.
In conclusion, we have shown that treatment changes after an episode of hypoglycemia are chaotic and may be suboptimal. Standardized protocols may be helpful for making effective changes and potentially can reduce the risk of further episodes of hypoglycemia.
- American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control: a call to action.Diabetes Care.2006;29:1955–1962.
- American College of Endocrinology and American Diabetes Association consensus statement on inpatient diabetes and glycemic control.Endocr Pract.2006;12:458–468.
- ,,.Current state of inpatient diabetes burden and care, and goal of the conference.Endocr Pract.2006;12(suppl 3, sddendum):1–10.
- ,,,.Intravenous insulin infusion therapy: indications, methods, and transition to subcutaneous insulin therapy.Endocr Pract.2004;10(suppl 2):71–80.
- ,,,,.Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit.Crit Care Med.2006;34:2974–2978.
- ,,, et al.Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit.Diabetes Care.2004;27:461–467.
- ,,, et al.Efficacy and safety of an insulin infusion protocol in a surgical ICU.J Am Coll Surg.2006;202(1):1–9.
- ,,.Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus.Arch Intern Med.1997;157:545–552.
- ,,, et al.Hospital hypoglycemia: not only treatment but also prevention.Endocr Pract.2004;10(suppl 2):89–99.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
Glycemic control in hospitalized patients is receiving greater attention. The American Diabetes Association and the American College of Endocrinology recently issued a joint consensus statement on the need to implement tight blood glucose (BG) control in hospitalized patients.1, 2 The Joint Commission on Accreditation of Healthcare Organizations (JACHO) has developed an Advanced Inpatient Diabetes Care Certification Program for hospitals. However, despite all these efforts, it has been difficult to change how well glucose is controlled.3 A major hurdle in implementing glycemic control strategies is the prevalent fear of hypoglycemia among hospital staff. Although there are multiple protocols for insulin treatment,47 guidelines for the prevention and treatment of hypoglycemia are lacking. Once a hypoglycemic episode has occurred, reducing the dosage of diabetes medications may reduce subsequent episodes. This study was conducted to assess whether diabetes medications were decreased following an episode of hypoglycemia that led to treatment with intravenous (IV) dextrose.
METHODS
Data were collected by the Diabetes Subcommittee of the Pharmacy and Therapeutics Committee as part of a quality improvement initiative. Hypoglycemic episodes were identified by computerized orders for 50% dextrose solution. All orders in a 1‐month period (June 2006) were collected. Characteristics of patients experiencing these episodes were identified from the electronic medical records (EMR). The following data were collected: age, sex, history of diabetes, serum creatinine, diabetes medications at time of hypoglycemia, blood glucose at time of hypoglycemia, and all BG values in the 24 hours before hypoglycemia. BG values included those obtained in the laboratory as well as those obtained by bedside blood glucose testing. Treatment changes made right when the hypoglycemic episode occurred (immediate) and within 24 hours of the hypoglycemic episode (subsequent) were evaluated by 2 diabetes specialists, a board‐certified endocrinologist and a nurse‐practitioner working on the diabetes management service. The 2 practitioners regularly work together, but the data were evaluated independently. Because there are no specific guidelines, the appropriateness of change in treatment was based on general guidelines and experience. For example, if hypoglycemia developed while a patient was on insulin infusion therapy, it was appropriate to stop the drip when the episode of hypoglycemia occurred and to restart it at a lower rate according to the insulin infusion protocol. No subsequent changes would have been made in a situation such as this, and it was deemed appropriate. However, if a patient developed hypoglycemia while on subcutaneous (SC) insulin and then insulin was either completely discontinued or no change was made in subsequent orders, it was deemed inappropriate. The 2 diabetes specialists agreed in 87% of cases (kappa = 0.68, 95% CI 0.53‐0.84). In the 13% of cases in which the diabetes specialists had different opinions, they conferred to reach agreement. In patients with more than 1 episode, data related to the first episode were evaluated. Data are presented as means with SDs.
RESULTS
The EMR contained information on time of episode of hypoglycemia and medication changes for 52 patients, all of whom were in the study. Patient characteristics and mean blood glucose level are shown in Table 1. All patients were being treated with insulin when the episode of hypoglycemia occurred: 9 were on intravenous (IV) insulin alone, 3 on IV and subcutaneous (SC) insulin, 30 on scheduled SC insulin, and 10 on sliding‐scale SC insulin alone. Three patients were prescribed sulfonylurea drugs in addition to insulin. Insulin dosage of all 52 patients was held at the time of the hypoglycemic episode. Diabetes specialists agreed with this decision 100% of the time. Only 21 patients (40%) subsequently had reductions made in their treatment dosage, and diabetes specialists agreed with the changes made for 11 of these patients (52%). Thirty‐one patients (60%) had no changes made to their treatment, and diabetes specialists agreed with that decision for 10 of these patients (32%). When diabetes specialists disagreed with a decision, they would have decreased the insulin dose or changed the regimen in a different way. Details on the changes in treatment and whether diabetes specialists agreed with the changes are shown in Table 2. Twenty‐four hours after an episode of hypoglycemia, mean blood glucose of patients whose providers had made changes was 190.7 87.9 mg/dL and that of patients whose providers had not made changes was 122.6 43.2 mg/dL (P = NS). The mean BG of patients for whom the diabetologists agreed with the decision was 110.7 90.3 mg/dL, and that of patients for whom they disagreed with the decision was 139.7 42.8 mg/dL (P = NS).
| Number of patients | 52 |
| Age (years) | 64.8 15.8 |
| Sex (male:female), n | 29:23 |
| Preexisting diabetes, n (%) | |
| No diabetes | 17 (33%) |
| Type 1 diabetes | 9 (17%) |
| Type 2 diabetes | 26 (50%) |
| Serum creatinine (mg/dL) | 2.1 1.9 |
| Serum creatinine 2 mg/dL, n (%) | 21 (40%) |
| BG at time of hypoglycemia (mg/dL) | 52.1 9.3 |
| Mean BG during 24 hours before hypoglycemic episode (mg/dL) | 137.5 57.0 |
| Mean BG during 24 hours after hypoglycemic episode (mg/dL) | 112 74.7 |
| Change | Number of patients receiving change | Number of patients for whom diabetes specialists agreed with change, n (%) |
|---|---|---|
| Basal insulin decreased | 6 | 6 (100%) |
| Basal insulin stopped | 2 | 0 (0%) |
| IV insulin changed to scheduled SC insulin | 2 | 1 (50%) |
| IV insulin to SC sliding‐scale insulin | 1 | 0 (0%) |
| Change in sliding‐scale insulin dose | 3 | 1 (33%) |
| Sliding‐scale insulin stopped | 1 | 1 (100%) |
| IV insulin started | 1 | 1 (100%) |
| Sulfonylurea stopped | 1 | 1 (100%) |
| Scheduled insulin changed to sliding scale | 1 | 0 (0%) |
| Insulin discontinued | 3 | 0 (0%) |
| No change | 31 | 10 (32%) |
DISCUSSION
These results suggest that treatment modification following an episode of hypoglycemia may be suboptimal. These data provide no information about the clinical circumstances leading to the choice of treatment with IV dextrose, as opposed to oral glucose or glucagon. Presumably, dextrose was chosen for many patients whom the physician considered to require the most urgent treatment. Appropriately, immediate treatment with insulin was held for all patients. On the other hand, 60% of the patients continued to receive the same insulin dose 24 hours after the hypoglycemic episode. Diabetes specialists judged continuation of the same dose as inappropriate in two thirds of the cases. Even when changes in treatment were made, those changes were judged suboptimal in half the cases. Blood glucose level 24 hours after an episode of hypoglycemia reflects these problems. These findings suggest that opportunities to prevent hypoglycemic episodes in the future are frequently missed. Lack of knowledge and/or guidelines for adjusting insulin dose following an episode of hypoglycemia seemed to have led to suboptimal changes for most patients.
Overall incidence of hypoglycemia (<60 mg/dL) among patients with diabetes admitted to a hospital has been reported to be 23%.8 In patients receiving continuous intravenous insulin infusion, the incidence of hypoglycemia has been variously reported as from 1.2% to 18.7%.9, 10 All insulin infusion protocols have guidelines for the immediate treatment of hypoglycemia and recommend steps to prevent further episodes. Although many hospitals have protocols for immediate action when hypoglycemia occurs (eg, hold insulin, give juice or dextrose), to our knowledge, no specific guidelines exist for adjustment of subcutaneous insulin following an episode of hypoglycemia. The vast majority of patients in a hospital are treated with SC insulin as opposed to IV insulin, and fear of hypoglycemia is a major barrier to intensified therapy. If widely applied, standardized protocols have the potential to be effective in preventing hypoglycemia.9
A limitation of our study was that it was a retrospective data analysis. We did not look at changes in clinical condition, in nutrition, and in other medications that might have led to the episode of hypoglycemia and affected the decision about which antidiabetic medications to treat with. Data on further episodes of hypoglycemia were also not available.
In conclusion, we have shown that treatment changes after an episode of hypoglycemia are chaotic and may be suboptimal. Standardized protocols may be helpful for making effective changes and potentially can reduce the risk of further episodes of hypoglycemia.
Glycemic control in hospitalized patients is receiving greater attention. The American Diabetes Association and the American College of Endocrinology recently issued a joint consensus statement on the need to implement tight blood glucose (BG) control in hospitalized patients.1, 2 The Joint Commission on Accreditation of Healthcare Organizations (JACHO) has developed an Advanced Inpatient Diabetes Care Certification Program for hospitals. However, despite all these efforts, it has been difficult to change how well glucose is controlled.3 A major hurdle in implementing glycemic control strategies is the prevalent fear of hypoglycemia among hospital staff. Although there are multiple protocols for insulin treatment,47 guidelines for the prevention and treatment of hypoglycemia are lacking. Once a hypoglycemic episode has occurred, reducing the dosage of diabetes medications may reduce subsequent episodes. This study was conducted to assess whether diabetes medications were decreased following an episode of hypoglycemia that led to treatment with intravenous (IV) dextrose.
METHODS
Data were collected by the Diabetes Subcommittee of the Pharmacy and Therapeutics Committee as part of a quality improvement initiative. Hypoglycemic episodes were identified by computerized orders for 50% dextrose solution. All orders in a 1‐month period (June 2006) were collected. Characteristics of patients experiencing these episodes were identified from the electronic medical records (EMR). The following data were collected: age, sex, history of diabetes, serum creatinine, diabetes medications at time of hypoglycemia, blood glucose at time of hypoglycemia, and all BG values in the 24 hours before hypoglycemia. BG values included those obtained in the laboratory as well as those obtained by bedside blood glucose testing. Treatment changes made right when the hypoglycemic episode occurred (immediate) and within 24 hours of the hypoglycemic episode (subsequent) were evaluated by 2 diabetes specialists, a board‐certified endocrinologist and a nurse‐practitioner working on the diabetes management service. The 2 practitioners regularly work together, but the data were evaluated independently. Because there are no specific guidelines, the appropriateness of change in treatment was based on general guidelines and experience. For example, if hypoglycemia developed while a patient was on insulin infusion therapy, it was appropriate to stop the drip when the episode of hypoglycemia occurred and to restart it at a lower rate according to the insulin infusion protocol. No subsequent changes would have been made in a situation such as this, and it was deemed appropriate. However, if a patient developed hypoglycemia while on subcutaneous (SC) insulin and then insulin was either completely discontinued or no change was made in subsequent orders, it was deemed inappropriate. The 2 diabetes specialists agreed in 87% of cases (kappa = 0.68, 95% CI 0.53‐0.84). In the 13% of cases in which the diabetes specialists had different opinions, they conferred to reach agreement. In patients with more than 1 episode, data related to the first episode were evaluated. Data are presented as means with SDs.
RESULTS
The EMR contained information on time of episode of hypoglycemia and medication changes for 52 patients, all of whom were in the study. Patient characteristics and mean blood glucose level are shown in Table 1. All patients were being treated with insulin when the episode of hypoglycemia occurred: 9 were on intravenous (IV) insulin alone, 3 on IV and subcutaneous (SC) insulin, 30 on scheduled SC insulin, and 10 on sliding‐scale SC insulin alone. Three patients were prescribed sulfonylurea drugs in addition to insulin. Insulin dosage of all 52 patients was held at the time of the hypoglycemic episode. Diabetes specialists agreed with this decision 100% of the time. Only 21 patients (40%) subsequently had reductions made in their treatment dosage, and diabetes specialists agreed with the changes made for 11 of these patients (52%). Thirty‐one patients (60%) had no changes made to their treatment, and diabetes specialists agreed with that decision for 10 of these patients (32%). When diabetes specialists disagreed with a decision, they would have decreased the insulin dose or changed the regimen in a different way. Details on the changes in treatment and whether diabetes specialists agreed with the changes are shown in Table 2. Twenty‐four hours after an episode of hypoglycemia, mean blood glucose of patients whose providers had made changes was 190.7 87.9 mg/dL and that of patients whose providers had not made changes was 122.6 43.2 mg/dL (P = NS). The mean BG of patients for whom the diabetologists agreed with the decision was 110.7 90.3 mg/dL, and that of patients for whom they disagreed with the decision was 139.7 42.8 mg/dL (P = NS).
| Number of patients | 52 |
| Age (years) | 64.8 15.8 |
| Sex (male:female), n | 29:23 |
| Preexisting diabetes, n (%) | |
| No diabetes | 17 (33%) |
| Type 1 diabetes | 9 (17%) |
| Type 2 diabetes | 26 (50%) |
| Serum creatinine (mg/dL) | 2.1 1.9 |
| Serum creatinine 2 mg/dL, n (%) | 21 (40%) |
| BG at time of hypoglycemia (mg/dL) | 52.1 9.3 |
| Mean BG during 24 hours before hypoglycemic episode (mg/dL) | 137.5 57.0 |
| Mean BG during 24 hours after hypoglycemic episode (mg/dL) | 112 74.7 |
| Change | Number of patients receiving change | Number of patients for whom diabetes specialists agreed with change, n (%) |
|---|---|---|
| Basal insulin decreased | 6 | 6 (100%) |
| Basal insulin stopped | 2 | 0 (0%) |
| IV insulin changed to scheduled SC insulin | 2 | 1 (50%) |
| IV insulin to SC sliding‐scale insulin | 1 | 0 (0%) |
| Change in sliding‐scale insulin dose | 3 | 1 (33%) |
| Sliding‐scale insulin stopped | 1 | 1 (100%) |
| IV insulin started | 1 | 1 (100%) |
| Sulfonylurea stopped | 1 | 1 (100%) |
| Scheduled insulin changed to sliding scale | 1 | 0 (0%) |
| Insulin discontinued | 3 | 0 (0%) |
| No change | 31 | 10 (32%) |
DISCUSSION
These results suggest that treatment modification following an episode of hypoglycemia may be suboptimal. These data provide no information about the clinical circumstances leading to the choice of treatment with IV dextrose, as opposed to oral glucose or glucagon. Presumably, dextrose was chosen for many patients whom the physician considered to require the most urgent treatment. Appropriately, immediate treatment with insulin was held for all patients. On the other hand, 60% of the patients continued to receive the same insulin dose 24 hours after the hypoglycemic episode. Diabetes specialists judged continuation of the same dose as inappropriate in two thirds of the cases. Even when changes in treatment were made, those changes were judged suboptimal in half the cases. Blood glucose level 24 hours after an episode of hypoglycemia reflects these problems. These findings suggest that opportunities to prevent hypoglycemic episodes in the future are frequently missed. Lack of knowledge and/or guidelines for adjusting insulin dose following an episode of hypoglycemia seemed to have led to suboptimal changes for most patients.
Overall incidence of hypoglycemia (<60 mg/dL) among patients with diabetes admitted to a hospital has been reported to be 23%.8 In patients receiving continuous intravenous insulin infusion, the incidence of hypoglycemia has been variously reported as from 1.2% to 18.7%.9, 10 All insulin infusion protocols have guidelines for the immediate treatment of hypoglycemia and recommend steps to prevent further episodes. Although many hospitals have protocols for immediate action when hypoglycemia occurs (eg, hold insulin, give juice or dextrose), to our knowledge, no specific guidelines exist for adjustment of subcutaneous insulin following an episode of hypoglycemia. The vast majority of patients in a hospital are treated with SC insulin as opposed to IV insulin, and fear of hypoglycemia is a major barrier to intensified therapy. If widely applied, standardized protocols have the potential to be effective in preventing hypoglycemia.9
A limitation of our study was that it was a retrospective data analysis. We did not look at changes in clinical condition, in nutrition, and in other medications that might have led to the episode of hypoglycemia and affected the decision about which antidiabetic medications to treat with. Data on further episodes of hypoglycemia were also not available.
In conclusion, we have shown that treatment changes after an episode of hypoglycemia are chaotic and may be suboptimal. Standardized protocols may be helpful for making effective changes and potentially can reduce the risk of further episodes of hypoglycemia.
- American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control: a call to action.Diabetes Care.2006;29:1955–1962.
- American College of Endocrinology and American Diabetes Association consensus statement on inpatient diabetes and glycemic control.Endocr Pract.2006;12:458–468.
- ,,.Current state of inpatient diabetes burden and care, and goal of the conference.Endocr Pract.2006;12(suppl 3, sddendum):1–10.
- ,,,.Intravenous insulin infusion therapy: indications, methods, and transition to subcutaneous insulin therapy.Endocr Pract.2004;10(suppl 2):71–80.
- ,,,,.Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit.Crit Care Med.2006;34:2974–2978.
- ,,, et al.Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit.Diabetes Care.2004;27:461–467.
- ,,, et al.Efficacy and safety of an insulin infusion protocol in a surgical ICU.J Am Coll Surg.2006;202(1):1–9.
- ,,.Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus.Arch Intern Med.1997;157:545–552.
- ,,, et al.Hospital hypoglycemia: not only treatment but also prevention.Endocr Pract.2004;10(suppl 2):89–99.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control: a call to action.Diabetes Care.2006;29:1955–1962.
- American College of Endocrinology and American Diabetes Association consensus statement on inpatient diabetes and glycemic control.Endocr Pract.2006;12:458–468.
- ,,.Current state of inpatient diabetes burden and care, and goal of the conference.Endocr Pract.2006;12(suppl 3, sddendum):1–10.
- ,,,.Intravenous insulin infusion therapy: indications, methods, and transition to subcutaneous insulin therapy.Endocr Pract.2004;10(suppl 2):71–80.
- ,,,,.Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit.Crit Care Med.2006;34:2974–2978.
- ,,, et al.Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit.Diabetes Care.2004;27:461–467.
- ,,, et al.Efficacy and safety of an insulin infusion protocol in a surgical ICU.J Am Coll Surg.2006;202(1):1–9.
- ,,.Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus.Arch Intern Med.1997;157:545–552.
- ,,, et al.Hospital hypoglycemia: not only treatment but also prevention.Endocr Pract.2004;10(suppl 2):89–99.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.