A lack of communication and accountability among healthcare professionals in general, and physicians in particular, jeopardizes quality and safety for our patients who are transitioning across sites of care.1, 2 Our patients, their family caregivers, and our health care professional colleagues on the receiving end of these transfers are often left flying blind without adequate information or direction to make sound clinical decisions.

Beyond our attempts to ensure effective transitions on a professional level, many of the readers of the Journal of Hospital Medicine likely have struggled to ensure seamless transitions for our families, despite the benefits of our training and experience.3 If some of the nation's most respected healthcare leaders are unable to make this work for their loved ones,48 one can only imagine the challenges faced by those without such advantages.

National and local quality collaboratives aimed at improving communication and collaboration across settings have found physicians difficult to engage as partners in these efforts.9 All too often there is a false expectation that these types of activities are best left to nonphysician healthcare professionals on the sending side of the transfer or to those receiving the transfer.10, 11

In this issue of the Journal, we commend the leadership provided by representatives of 6 of the nation's leading physician professional societies to join forces toward the common purpose of articulating physicians' roles and accountability for care delivered during transitions.12 Ensuring effective care transitions is a team sport, yet rarely do we have a clear understanding of who are the other members of our team, how to interact with them, or a clear delineation of their respective roles. Simply stated, this article is a key step to facilitating teamwork across settings among physicians, our interdisciplinary healthcare professional colleagues, our patients, and their family caregivers. These standards clearly convey the type of care we expect for our loved ones.

Drawing from proven strategies used in nonhealthcare industries, the standards assert that the sending provider or institution retains responsibility for the patient's care until the receiving team confirms receipt of the transfer and assumes responsibility. Further, the receiving team is given the opportunity to ask questions and clarify the proposed care plan in recognition of the fact that communication is more than simply the transfer of information. Rather, such communication involves the need to ensure comprehension and provide an opportunity to have a 2‐way dialog. These standards distinguish between the transmission of information and true communication.

The timing of the release of these standards is ideal. As physicians concentrate their practice within particular settings we can no longer rely on casual random interchanges in hospital parking lots or the hospital's physician lounge. Rather, we need to take a more active and reliable approach to ensuring timely and accurate exchanges. These standards cut to the essence of how we communicate with our physician and nonphysician colleagues alike, and in so doing move us away from nonproductive blame and finger‐pointing.

Although the implications for these standards are far reaching in terms of raising the quality bar, they could reach even further with respect to the types of settings they address. These standards need to extend beyond hospitals and the outpatient arena to include nursing homes, rehabilitation facilities, home care agencies, adult day health centers, and other settings where chronic care services are delivered.

Further, the standards devote considerable focus to the transfer of health information. Even with advances in health information exchange technologies, we must recognize that information is necessary but not sufficient for ensuring safe and high‐quality transfers. Implementing these standards will undoubtedly require that we reconfigure our daily workflows.13 The article in this issue by Graumlich et al.14 emphasizes the challenges of how to introduce technology into our daily clinical routines. The standards also open the door for how we can best ensure not just the transmission of information, but also the comprehension of transfer instructions to our patients with attention to health literacy, cognitive ability, and the patient's level of activation.15 Best and Young16 provide valuable action steps for how to address the needs of diverse and underserved populations.

These standards may serve to uncover the fact that most physicians have not received formal training in executing high‐quality care transitions in the role of either the sender or the receiver. Further, few physicians have a mechanism in place to evaluate their performance. The American Board of Internal Medicine and the American Board of Family Practice has developed Maintenance of Certification Practice Improvement Modules (PIM) on care coordination that provide an excellent opportunity to sharpen our skills. The HMO Care Management Workgroup has also attempted to summarize the essential skills necessary to care for patients during transitions.17

Perhaps the greatest value of these standards is that they lay the framework for actionable improvement. Local, state, and national quality collaboratives can immediately incorporate these recommendations into their overall strategy. These standards will likely influence the design and implementation of the Medical Home.18 As national attention focuses on how to operationalize bundled payment approaches and Accountable Care Organizations,19 these standards provide a clear consensus on communication, accountability, and ensuring patient‐centeredness. The standards are an excellent start and provide a framework for further innovation.

One area in particular may be the opportunity to reinvent the format, content, and medium by which essential information is transferred. For example, one might envision the value of producing a scaled down version of the discharge summary with a limited core set of data elements that could be quickly completed and communicated to the next care team via fax, e‐mail, or text messaging.

Complementing new strategies to improve the exchange of health information are opportunities to reconsider the culture within which this communication occurs. Our profession has a long‐standing tradition of not providing directives to our colleagues on the details of clinical management. Hospitalists develop important insights during a patient's hospital stay and are in an ideal position to anticipate potential developments in the subsequent course after discharge. Contrast this with the 5 to 10 minutes that a primary care physician or specialist may have to come up to speed on the hospital and posthospital events in order to manage the patient in the ambulatory arena. Thus, rather than the traditional historical orientation to a discharge summary, one could envision a more future‐orientated document characterized by a series of if‐then statements that outline a series of possible clinical scenarios that may play out over the weeks after discharge along with recommendations for adjustments to the treatment plan.

At a broader level, the release of these standards demonstrate to our communities and to our nation that physicians can join forces to address a particularly complex and challenging aspect of healthcare. Change can indeed come from within our profession rather than being imposed by outside influences such as government administrators, regulatory bodies, or malpractice attorneys. I applaud such efforts and believe that hospitalists will continue to play a central role in national efforts to improve transitions of care.

A lack of communication and accountability among healthcare professionals in general, and physicians in particular, jeopardizes quality and safety for our patients who are transitioning across sites of care.1, 2 Our patients, their family caregivers, and our health care professional colleagues on the receiving end of these transfers are often left flying blind without adequate information or direction to make sound clinical decisions.

Beyond our attempts to ensure effective transitions on a professional level, many of the readers of the Journal of Hospital Medicine likely have struggled to ensure seamless transitions for our families, despite the benefits of our training and experience.3 If some of the nation's most respected healthcare leaders are unable to make this work for their loved ones,48 one can only imagine the challenges faced by those without such advantages.

National and local quality collaboratives aimed at improving communication and collaboration across settings have found physicians difficult to engage as partners in these efforts.9 All too often there is a false expectation that these types of activities are best left to nonphysician healthcare professionals on the sending side of the transfer or to those receiving the transfer.10, 11

In this issue of the Journal, we commend the leadership provided by representatives of 6 of the nation's leading physician professional societies to join forces toward the common purpose of articulating physicians' roles and accountability for care delivered during transitions.12 Ensuring effective care transitions is a team sport, yet rarely do we have a clear understanding of who are the other members of our team, how to interact with them, or a clear delineation of their respective roles. Simply stated, this article is a key step to facilitating teamwork across settings among physicians, our interdisciplinary healthcare professional colleagues, our patients, and their family caregivers. These standards clearly convey the type of care we expect for our loved ones.

Drawing from proven strategies used in nonhealthcare industries, the standards assert that the sending provider or institution retains responsibility for the patient's care until the receiving team confirms receipt of the transfer and assumes responsibility. Further, the receiving team is given the opportunity to ask questions and clarify the proposed care plan in recognition of the fact that communication is more than simply the transfer of information. Rather, such communication involves the need to ensure comprehension and provide an opportunity to have a 2‐way dialog. These standards distinguish between the transmission of information and true communication.

The timing of the release of these standards is ideal. As physicians concentrate their practice within particular settings we can no longer rely on casual random interchanges in hospital parking lots or the hospital's physician lounge. Rather, we need to take a more active and reliable approach to ensuring timely and accurate exchanges. These standards cut to the essence of how we communicate with our physician and nonphysician colleagues alike, and in so doing move us away from nonproductive blame and finger‐pointing.

Although the implications for these standards are far reaching in terms of raising the quality bar, they could reach even further with respect to the types of settings they address. These standards need to extend beyond hospitals and the outpatient arena to include nursing homes, rehabilitation facilities, home care agencies, adult day health centers, and other settings where chronic care services are delivered.

Further, the standards devote considerable focus to the transfer of health information. Even with advances in health information exchange technologies, we must recognize that information is necessary but not sufficient for ensuring safe and high‐quality transfers. Implementing these standards will undoubtedly require that we reconfigure our daily workflows.13 The article in this issue by Graumlich et al.14 emphasizes the challenges of how to introduce technology into our daily clinical routines. The standards also open the door for how we can best ensure not just the transmission of information, but also the comprehension of transfer instructions to our patients with attention to health literacy, cognitive ability, and the patient's level of activation.15 Best and Young16 provide valuable action steps for how to address the needs of diverse and underserved populations.

These standards may serve to uncover the fact that most physicians have not received formal training in executing high‐quality care transitions in the role of either the sender or the receiver. Further, few physicians have a mechanism in place to evaluate their performance. The American Board of Internal Medicine and the American Board of Family Practice has developed Maintenance of Certification Practice Improvement Modules (PIM) on care coordination that provide an excellent opportunity to sharpen our skills. The HMO Care Management Workgroup has also attempted to summarize the essential skills necessary to care for patients during transitions.17

Perhaps the greatest value of these standards is that they lay the framework for actionable improvement. Local, state, and national quality collaboratives can immediately incorporate these recommendations into their overall strategy. These standards will likely influence the design and implementation of the Medical Home.18 As national attention focuses on how to operationalize bundled payment approaches and Accountable Care Organizations,19 these standards provide a clear consensus on communication, accountability, and ensuring patient‐centeredness. The standards are an excellent start and provide a framework for further innovation.

One area in particular may be the opportunity to reinvent the format, content, and medium by which essential information is transferred. For example, one might envision the value of producing a scaled down version of the discharge summary with a limited core set of data elements that could be quickly completed and communicated to the next care team via fax, e‐mail, or text messaging.

Complementing new strategies to improve the exchange of health information are opportunities to reconsider the culture within which this communication occurs. Our profession has a long‐standing tradition of not providing directives to our colleagues on the details of clinical management. Hospitalists develop important insights during a patient's hospital stay and are in an ideal position to anticipate potential developments in the subsequent course after discharge. Contrast this with the 5 to 10 minutes that a primary care physician or specialist may have to come up to speed on the hospital and posthospital events in order to manage the patient in the ambulatory arena. Thus, rather than the traditional historical orientation to a discharge summary, one could envision a more future‐orientated document characterized by a series of if‐then statements that outline a series of possible clinical scenarios that may play out over the weeks after discharge along with recommendations for adjustments to the treatment plan.

At a broader level, the release of these standards demonstrate to our communities and to our nation that physicians can join forces to address a particularly complex and challenging aspect of healthcare. Change can indeed come from within our profession rather than being imposed by outside influences such as government administrators, regulatory bodies, or malpractice attorneys. I applaud such efforts and believe that hospitalists will continue to play a central role in national efforts to improve transitions of care.

A lack of communication and accountability among healthcare professionals in general, and physicians in particular, jeopardizes quality and safety for our patients who are transitioning across sites of care.1, 2 Our patients, their family caregivers, and our health care professional colleagues on the receiving end of these transfers are often left flying blind without adequate information or direction to make sound clinical decisions.

Beyond our attempts to ensure effective transitions on a professional level, many of the readers of the Journal of Hospital Medicine likely have struggled to ensure seamless transitions for our families, despite the benefits of our training and experience.3 If some of the nation's most respected healthcare leaders are unable to make this work for their loved ones,48 one can only imagine the challenges faced by those without such advantages.

National and local quality collaboratives aimed at improving communication and collaboration across settings have found physicians difficult to engage as partners in these efforts.9 All too often there is a false expectation that these types of activities are best left to nonphysician healthcare professionals on the sending side of the transfer or to those receiving the transfer.10, 11

In this issue of the Journal, we commend the leadership provided by representatives of 6 of the nation's leading physician professional societies to join forces toward the common purpose of articulating physicians' roles and accountability for care delivered during transitions.12 Ensuring effective care transitions is a team sport, yet rarely do we have a clear understanding of who are the other members of our team, how to interact with them, or a clear delineation of their respective roles. Simply stated, this article is a key step to facilitating teamwork across settings among physicians, our interdisciplinary healthcare professional colleagues, our patients, and their family caregivers. These standards clearly convey the type of care we expect for our loved ones.

Drawing from proven strategies used in nonhealthcare industries, the standards assert that the sending provider or institution retains responsibility for the patient's care until the receiving team confirms receipt of the transfer and assumes responsibility. Further, the receiving team is given the opportunity to ask questions and clarify the proposed care plan in recognition of the fact that communication is more than simply the transfer of information. Rather, such communication involves the need to ensure comprehension and provide an opportunity to have a 2‐way dialog. These standards distinguish between the transmission of information and true communication.

The timing of the release of these standards is ideal. As physicians concentrate their practice within particular settings we can no longer rely on casual random interchanges in hospital parking lots or the hospital's physician lounge. Rather, we need to take a more active and reliable approach to ensuring timely and accurate exchanges. These standards cut to the essence of how we communicate with our physician and nonphysician colleagues alike, and in so doing move us away from nonproductive blame and finger‐pointing.

Although the implications for these standards are far reaching in terms of raising the quality bar, they could reach even further with respect to the types of settings they address. These standards need to extend beyond hospitals and the outpatient arena to include nursing homes, rehabilitation facilities, home care agencies, adult day health centers, and other settings where chronic care services are delivered.

Further, the standards devote considerable focus to the transfer of health information. Even with advances in health information exchange technologies, we must recognize that information is necessary but not sufficient for ensuring safe and high‐quality transfers. Implementing these standards will undoubtedly require that we reconfigure our daily workflows.13 The article in this issue by Graumlich et al.14 emphasizes the challenges of how to introduce technology into our daily clinical routines. The standards also open the door for how we can best ensure not just the transmission of information, but also the comprehension of transfer instructions to our patients with attention to health literacy, cognitive ability, and the patient's level of activation.15 Best and Young16 provide valuable action steps for how to address the needs of diverse and underserved populations.

These standards may serve to uncover the fact that most physicians have not received formal training in executing high‐quality care transitions in the role of either the sender or the receiver. Further, few physicians have a mechanism in place to evaluate their performance. The American Board of Internal Medicine and the American Board of Family Practice has developed Maintenance of Certification Practice Improvement Modules (PIM) on care coordination that provide an excellent opportunity to sharpen our skills. The HMO Care Management Workgroup has also attempted to summarize the essential skills necessary to care for patients during transitions.17

Perhaps the greatest value of these standards is that they lay the framework for actionable improvement. Local, state, and national quality collaboratives can immediately incorporate these recommendations into their overall strategy. These standards will likely influence the design and implementation of the Medical Home.18 As national attention focuses on how to operationalize bundled payment approaches and Accountable Care Organizations,19 these standards provide a clear consensus on communication, accountability, and ensuring patient‐centeredness. The standards are an excellent start and provide a framework for further innovation.

One area in particular may be the opportunity to reinvent the format, content, and medium by which essential information is transferred. For example, one might envision the value of producing a scaled down version of the discharge summary with a limited core set of data elements that could be quickly completed and communicated to the next care team via fax, e‐mail, or text messaging.

Complementing new strategies to improve the exchange of health information are opportunities to reconsider the culture within which this communication occurs. Our profession has a long‐standing tradition of not providing directives to our colleagues on the details of clinical management. Hospitalists develop important insights during a patient's hospital stay and are in an ideal position to anticipate potential developments in the subsequent course after discharge. Contrast this with the 5 to 10 minutes that a primary care physician or specialist may have to come up to speed on the hospital and posthospital events in order to manage the patient in the ambulatory arena. Thus, rather than the traditional historical orientation to a discharge summary, one could envision a more future‐orientated document characterized by a series of if‐then statements that outline a series of possible clinical scenarios that may play out over the weeks after discharge along with recommendations for adjustments to the treatment plan.

At a broader level, the release of these standards demonstrate to our communities and to our nation that physicians can join forces to address a particularly complex and challenging aspect of healthcare. Change can indeed come from within our profession rather than being imposed by outside influences such as government administrators, regulatory bodies, or malpractice attorneys. I applaud such efforts and believe that hospitalists will continue to play a central role in national efforts to improve transitions of care.

Severe sepsis and septic shock account for more than 750,000 hospital admissions and 215,000 deaths per year.1 Early fluid resuscitation is the cornerstone of treatment, and early goal‐directed therapy (EGDT), which includes a target central venous pressure (CVP) of 8 to 12 mm Hg, has been shown to improve outcomes, including mortality and length of stay.2 This goal allows appropriate initial resuscitation and may decrease the risk of excess fluid administration, which is related to adverse outcomes in critically ill patients.3 However, nonintensivists may not start early aggressive fluid resuscitation because of inability to accurately assess intravascular volume, concerns for inadvertent volume overload, or the difficulty of recognizing insidious illness. Assessment of volume status, primarily from inspection of the internal jugular vein to estimate CVP, is difficult to perform by clinical examination alone, especially if CVP is very low.4 Inspection of the external jugular vein is perhaps easier than inspecting the internal jugular vein and appears to accurately estimate CVP,5 but it does not allow the degree of precision necessary for EGDT. Echocardiography can estimate CVP based on respirophasic variation or collapsibility index, but this technique requires expensive equipment and sonographic expertise. The current gold standard technique for measuring CVP requires an invasive central venous catheter, which can delay timely resuscitation and is associated with complications.6

An alternative technique to guide resuscitation efforts should be accurate, safe, rapid, and easy to perform at the bedside, while providing real‐time measurement results. We hypothesized that CVP can be accurately assessed using noninvasive ultrasound imaging of the internal jugular vein, since jugular venous pressure is essentially equal to CVP.7 Specifically, our study estimated the diagnostic accuracy of ultrasound measurement of the aspect ratio (height/width) of the internal jugular vein compared with the invasively measured CVP target for EGDT. We expected that a lower aspect ratio would correlate with a lower CVP and a higher aspect ratio would correlate with a higher CVP.

Methods

Volunteers were enrolled at Saint Mary's Hospital (Mayo Clinic) in Rochester, MN, from January to March 2006, and patients were enrolled at Saint Mary's Hospital and at Abbott Northwestern Hospital (Allina Hospitals and Clinics) in Minneapolis, MN, from May 2006 to October 2007. The study was approved by the Institutional Review Boards of Mayo Clinic and Allina and had 2 phases. The first phase comprised ultrasound measurements of internal jugular vein aspect ratio and determination of intraobserver and interobserver agreement in healthy volunteers. The second phase involved measurement of internal jugular vein aspect ratio and invasive CVP in a convenience sample of 44 spontaneously breathing patients admitted to medical intensive care units: 9 patients at Saint Marys Hospital and 35 patients at Abbott Northwestern Hospital. Patients were enrolled only when study members were on duty in the intensive care unit and able to perform study measurements. As a result, a high proportion of patients who may have been eligible were not asked to participate.

Each volunteer was deemed euvolemic on the basis of normal orthostatic measurements and normal oral intake with no vomiting or diarrhea in the previous 5 days. Measurements of 19 volunteers were made by 1 author (A.S.K.), with subsequent measurements of 15 of the volunteers made by another author (O.G.) to determine interobserver variability; 4 participants did not undergo a second measurement because of scheduling conflicts.

Inclusion and exclusion criteria for the critically ill patients are provided in Table 1. Recruitment was based on presenting symptoms and test results that led the intensive care unit physicians to decide to place a CVP monitor. All the enrolled patients had invasive CVP measurement performed approximately 30 to 40 minutes after ultrasound measurement of the internal jugular vein; this delay was the time required to place the central line and obtain the measurement. All patients who were invited to participate in the study were included. No patients were excluded on the basis of the exclusion criteria or because of inability to place a central line. No complications related to central line placement occurred.

We followed a prescribed measurement technique (Table 2) to determine the internal jugular vein aspect ratio in all volunteers and patients. Measurements of the volunteers were made with a Site‐Rite 3 Ultrasound System (Bard Access Systems, Inc., Salt Lake City, UT) using a 9.0‐MHz transducer. Measurements of the critically ill patients were made with a SonoSite MicroMaxx ultrasound system (SonoSite, Inc., Bothell, WA) using a 10.5‐MHz transducer. Study team physicians initially were blinded to actual measured CVP. Internal jugular vein aspect ratio and CVP were measured at tidal volume end‐expiration for all patients. One measurement was obtained for each patient, with measurements being made by 1 of 4 physicians (2 intensivists, 1 critical care fellow, and 1 chief medicine resident). With no specific ultrasound training and with only minimal practice, the physicians could obtain the optimal aspect ratio within a few seconds (Figure 1).

Figure 1

This was an exploratory prospective study, and all methods of data collection were designed before patient enrollment. However, the ultrasound‐derived aspect ratio of 0.83 (which defined a CVP of 8 mm Hg) was determined post hoc to maximize sensitivity and specificity and was based on the aspect ratio of the euvolemic volunteers and the inflection point of the CVP vs aspect ratio curve for the critically ill patients.

Results

We first evaluated 19 white volunteers: 12 women and 7 men. Mean (SD) age was 42 (11) years and mean body mass index was 26.6 (4.5) kg/m². Mean arterial pressure was 89 (13) mm Hg and mean heart rate was 71 (15) beats/minute. Mean aspect ratio of the right and left internal jugular vein for all volunteers was 0.82 (0.07). There was no difference in aspect ratio between the right (0.83 [0.10]) and left (0.81 [0.13]) vein (P > 0.10). Also, no difference in the aspect ratio was seen between men (0.81 [0.08]) and women (0.83 [0.07]) (P = 0.77). Bland‐Altman analysis indicated moderate intraobserver and interobserver agreement for the aspect ratio measurements (Figure 2).

Figure 2

We then compared the aspect ratio measured using ultrasound and CVP measured with an invasive monitor for 44 spontaneously breathing critically ill patients (22 women and 22 men; 38 were white). Mean (SD) age was 66 (14) years and mean body mass index was 28.8 (9.1) kg/m². Mean arterial pressure (n = 36) was 67 (12) mm Hg and mean heart rate (n = 34) was 92 (22) beats/minute. Systemic inflammatory response syndrome (SIRS) criteria were present in 23 of 40 patients; complete data were unavailable for the other 4 patients. Of these 40 patients, 20 had sepsis, 15 had severe sepsis, and 5 had septic shock. The most common diagnoses were gastrointestinal tract bleeding in 6 patients and congestive heart failure in 4 patients. Acute Physiology and Chronic Health Evaluation (APACHE III) score, available for 8 of the 9 patients at Saint Marys Hospital, was 63 (10).

Figure 3 shows measured aspect ratios vs. invasively measured CVP for the critically ill patients. The curvilinear result is consistent with venous and right ventricular compliance ( volume/ pressure) characteristics. Note that the inflection point (beginning of the increased slope) of the curve corresponds to a CVP of about 8 mm Hg. Furthermore, the aspect ratio (0.8) at this point is the same as that seen in the euvolemic volunteers. These findings suggest that, in spontaneously breathing patients, a CVP of about 8 mm Hg and an aspect ratio of about 0.8 each defines the beginning of the plateau on the cardiac Frank‐Starling curve.

Figure 3

Ultrasound imaging of the internal jugular vein aspect ratio accurately estimated the CVP target of 8 mm Hg based on the area under the receiver operating characteristics curve of 0.84 (95% confidence interval [CI], 0.72‐0.96) (Figure 4). For an invasively measured CVP of less than 8 mm Hg, the likelihood ratio for a positive ultrasound test result (aspect ratio < 0.83) was 3.5 (95% CI, 1.4‐8.4) and for a negative test result (aspect ratio 0.83) was 0.30 (95% CI, 0.14‐0.62). Clinically, this means that patients with a measured aspect ratio of less than 0.83 require further fluid resuscitation, whereas patients with a measured aspect ratio of 0.83 or greater are less likely to benefit from fluid resuscitation.

Figure 4

Discussion

This study demonstrated that the EGDT CVP target of 8 to 12 mm Hg can be accurately estimated (referenced to invasive CVP monitoring) using noninvasive ultrasound measurement of the internal jugular vein in spontaneously breathing critically ill patients. The measurement process is simple to perform at the bedside and moderately reliable when performed by different observers; also, the results appear to be equivalent for both sides and for males or females. Images can be stored electronically for serial comparisons and for viewing by other caregivers. Because the aspect ratio is essentially constant over the length of the internal jugular vein, unlike diameter, measurements can be performed anywhere along the vein. Also, ultrasound imaging allows visualization of the internal jugular vein despite anatomic variation.9

Previous attempts at noninvasive hemodynamic monitoring using plethysmography, thoracic electrical bioimpedance, and external Doppler probes have shown these methods to be cumbersome or inaccurate.1013 Other investigators have used echocardiography14, 15 and handheld ultrasound16 to image the diameter of the inferior vena cava in order to assess intravascular volume status, but these techniques require expertise in sonographic imaging. An alternative technique is to measure peripheral venous pressure, which correlates with CVP.17 This method, however, requires technical expertise to zero the monitor and is not yet widely used for critically ill patients. A literature search found 1 letter to the editor suggesting that real‐time ultrasound imaging of the internal jugular vein could be used to qualitatively determine jugular venous pressure18 and 3 studies using ultrasound in conjunction with a pressure transducer or manometer to determine the pressure needed to collapse the vein (either the internal jugular or a peripheral vein), with subsequent correlation to CVP.1921 These latter techniques appear to be cumbersome and require custom equipment that is not readily available in most hospitals.

Any measurement of CVP, including our technique, assumes correlation with volume responsiveness as a surrogate for intravascular volume. However, CVP is governed by multiple physiologic and pathologic factors, including intravascular volume, vascular and ventricular compliance, ventricular function, tricuspid stenosis and regurgitation, cardiac tamponade, and atrioventricular dissociation.22, 23 Therefore, CVP alone may not be an accurate measure of volume responsiveness (intravascular volume). CVP may also have spontaneous variation similar to pulmonary capillary wedge pressure, which can be as high as 7 mm Hg in any given patient.24 Furthermore, invasive CVP monitors also have limitations, and the overall accuracy of the Philips system used at Saint Marys Hospital is 4% of the reading or 4 mm Hg, whichever is greater.25 Nonetheless, the EGDT algorithm that incorporates CVP measurement with a target of 8 to 12 mm Hg in spontaneously breathing patients and 12 mm Hg in mechanically ventilated patients has resulted in decreased mortality among patients with severe sepsis and is recommended by the Surviving Sepsis Campaign guidelines26 and the Institute for Healthcare Improvement.27

These study results are important because nonintensivists such as hospitalists and emergency department physicians can use this technique to provide rapid fluid resuscitation early in the course of severe sepsis and septic shock, when aggressive fluid resuscitation is most effective. Ultrasound imaging of the internal jugular vein is easy to perform without formal training, and the equipment is readily available in most hospitals. Future studies will evaluate outcomes in spontaneously breathing and ventilated patients to determine the accuracy of this measurement technique in volume‐depleted and volume‐overloaded states. If validated in different patient populations, ultrasound measurement of the internal jugular vein could substitute for the EGDT CVP target in critically ill patients and allow early aggressive fluid resuscitation before a central venous catheter is placed.

Severe sepsis and septic shock account for more than 750,000 hospital admissions and 215,000 deaths per year.1 Early fluid resuscitation is the cornerstone of treatment, and early goal‐directed therapy (EGDT), which includes a target central venous pressure (CVP) of 8 to 12 mm Hg, has been shown to improve outcomes, including mortality and length of stay.2 This goal allows appropriate initial resuscitation and may decrease the risk of excess fluid administration, which is related to adverse outcomes in critically ill patients.3 However, nonintensivists may not start early aggressive fluid resuscitation because of inability to accurately assess intravascular volume, concerns for inadvertent volume overload, or the difficulty of recognizing insidious illness. Assessment of volume status, primarily from inspection of the internal jugular vein to estimate CVP, is difficult to perform by clinical examination alone, especially if CVP is very low.4 Inspection of the external jugular vein is perhaps easier than inspecting the internal jugular vein and appears to accurately estimate CVP,5 but it does not allow the degree of precision necessary for EGDT. Echocardiography can estimate CVP based on respirophasic variation or collapsibility index, but this technique requires expensive equipment and sonographic expertise. The current gold standard technique for measuring CVP requires an invasive central venous catheter, which can delay timely resuscitation and is associated with complications.6

An alternative technique to guide resuscitation efforts should be accurate, safe, rapid, and easy to perform at the bedside, while providing real‐time measurement results. We hypothesized that CVP can be accurately assessed using noninvasive ultrasound imaging of the internal jugular vein, since jugular venous pressure is essentially equal to CVP.7 Specifically, our study estimated the diagnostic accuracy of ultrasound measurement of the aspect ratio (height/width) of the internal jugular vein compared with the invasively measured CVP target for EGDT. We expected that a lower aspect ratio would correlate with a lower CVP and a higher aspect ratio would correlate with a higher CVP.

Methods

Volunteers were enrolled at Saint Mary's Hospital (Mayo Clinic) in Rochester, MN, from January to March 2006, and patients were enrolled at Saint Mary's Hospital and at Abbott Northwestern Hospital (Allina Hospitals and Clinics) in Minneapolis, MN, from May 2006 to October 2007. The study was approved by the Institutional Review Boards of Mayo Clinic and Allina and had 2 phases. The first phase comprised ultrasound measurements of internal jugular vein aspect ratio and determination of intraobserver and interobserver agreement in healthy volunteers. The second phase involved measurement of internal jugular vein aspect ratio and invasive CVP in a convenience sample of 44 spontaneously breathing patients admitted to medical intensive care units: 9 patients at Saint Marys Hospital and 35 patients at Abbott Northwestern Hospital. Patients were enrolled only when study members were on duty in the intensive care unit and able to perform study measurements. As a result, a high proportion of patients who may have been eligible were not asked to participate.

Each volunteer was deemed euvolemic on the basis of normal orthostatic measurements and normal oral intake with no vomiting or diarrhea in the previous 5 days. Measurements of 19 volunteers were made by 1 author (A.S.K.), with subsequent measurements of 15 of the volunteers made by another author (O.G.) to determine interobserver variability; 4 participants did not undergo a second measurement because of scheduling conflicts.

Inclusion and exclusion criteria for the critically ill patients are provided in Table 1. Recruitment was based on presenting symptoms and test results that led the intensive care unit physicians to decide to place a CVP monitor. All the enrolled patients had invasive CVP measurement performed approximately 30 to 40 minutes after ultrasound measurement of the internal jugular vein; this delay was the time required to place the central line and obtain the measurement. All patients who were invited to participate in the study were included. No patients were excluded on the basis of the exclusion criteria or because of inability to place a central line. No complications related to central line placement occurred.

We followed a prescribed measurement technique (Table 2) to determine the internal jugular vein aspect ratio in all volunteers and patients. Measurements of the volunteers were made with a Site‐Rite 3 Ultrasound System (Bard Access Systems, Inc., Salt Lake City, UT) using a 9.0‐MHz transducer. Measurements of the critically ill patients were made with a SonoSite MicroMaxx ultrasound system (SonoSite, Inc., Bothell, WA) using a 10.5‐MHz transducer. Study team physicians initially were blinded to actual measured CVP. Internal jugular vein aspect ratio and CVP were measured at tidal volume end‐expiration for all patients. One measurement was obtained for each patient, with measurements being made by 1 of 4 physicians (2 intensivists, 1 critical care fellow, and 1 chief medicine resident). With no specific ultrasound training and with only minimal practice, the physicians could obtain the optimal aspect ratio within a few seconds (Figure 1).

Figure 1

This was an exploratory prospective study, and all methods of data collection were designed before patient enrollment. However, the ultrasound‐derived aspect ratio of 0.83 (which defined a CVP of 8 mm Hg) was determined post hoc to maximize sensitivity and specificity and was based on the aspect ratio of the euvolemic volunteers and the inflection point of the CVP vs aspect ratio curve for the critically ill patients.

Results

We first evaluated 19 white volunteers: 12 women and 7 men. Mean (SD) age was 42 (11) years and mean body mass index was 26.6 (4.5) kg/m². Mean arterial pressure was 89 (13) mm Hg and mean heart rate was 71 (15) beats/minute. Mean aspect ratio of the right and left internal jugular vein for all volunteers was 0.82 (0.07). There was no difference in aspect ratio between the right (0.83 [0.10]) and left (0.81 [0.13]) vein (P > 0.10). Also, no difference in the aspect ratio was seen between men (0.81 [0.08]) and women (0.83 [0.07]) (P = 0.77). Bland‐Altman analysis indicated moderate intraobserver and interobserver agreement for the aspect ratio measurements (Figure 2).

Figure 2

We then compared the aspect ratio measured using ultrasound and CVP measured with an invasive monitor for 44 spontaneously breathing critically ill patients (22 women and 22 men; 38 were white). Mean (SD) age was 66 (14) years and mean body mass index was 28.8 (9.1) kg/m². Mean arterial pressure (n = 36) was 67 (12) mm Hg and mean heart rate (n = 34) was 92 (22) beats/minute. Systemic inflammatory response syndrome (SIRS) criteria were present in 23 of 40 patients; complete data were unavailable for the other 4 patients. Of these 40 patients, 20 had sepsis, 15 had severe sepsis, and 5 had septic shock. The most common diagnoses were gastrointestinal tract bleeding in 6 patients and congestive heart failure in 4 patients. Acute Physiology and Chronic Health Evaluation (APACHE III) score, available for 8 of the 9 patients at Saint Marys Hospital, was 63 (10).

Figure 3 shows measured aspect ratios vs. invasively measured CVP for the critically ill patients. The curvilinear result is consistent with venous and right ventricular compliance ( volume/ pressure) characteristics. Note that the inflection point (beginning of the increased slope) of the curve corresponds to a CVP of about 8 mm Hg. Furthermore, the aspect ratio (0.8) at this point is the same as that seen in the euvolemic volunteers. These findings suggest that, in spontaneously breathing patients, a CVP of about 8 mm Hg and an aspect ratio of about 0.8 each defines the beginning of the plateau on the cardiac Frank‐Starling curve.

Figure 3

Ultrasound imaging of the internal jugular vein aspect ratio accurately estimated the CVP target of 8 mm Hg based on the area under the receiver operating characteristics curve of 0.84 (95% confidence interval [CI], 0.72‐0.96) (Figure 4). For an invasively measured CVP of less than 8 mm Hg, the likelihood ratio for a positive ultrasound test result (aspect ratio < 0.83) was 3.5 (95% CI, 1.4‐8.4) and for a negative test result (aspect ratio 0.83) was 0.30 (95% CI, 0.14‐0.62). Clinically, this means that patients with a measured aspect ratio of less than 0.83 require further fluid resuscitation, whereas patients with a measured aspect ratio of 0.83 or greater are less likely to benefit from fluid resuscitation.

Figure 4

Discussion

This study demonstrated that the EGDT CVP target of 8 to 12 mm Hg can be accurately estimated (referenced to invasive CVP monitoring) using noninvasive ultrasound measurement of the internal jugular vein in spontaneously breathing critically ill patients. The measurement process is simple to perform at the bedside and moderately reliable when performed by different observers; also, the results appear to be equivalent for both sides and for males or females. Images can be stored electronically for serial comparisons and for viewing by other caregivers. Because the aspect ratio is essentially constant over the length of the internal jugular vein, unlike diameter, measurements can be performed anywhere along the vein. Also, ultrasound imaging allows visualization of the internal jugular vein despite anatomic variation.9

Previous attempts at noninvasive hemodynamic monitoring using plethysmography, thoracic electrical bioimpedance, and external Doppler probes have shown these methods to be cumbersome or inaccurate.1013 Other investigators have used echocardiography14, 15 and handheld ultrasound16 to image the diameter of the inferior vena cava in order to assess intravascular volume status, but these techniques require expertise in sonographic imaging. An alternative technique is to measure peripheral venous pressure, which correlates with CVP.17 This method, however, requires technical expertise to zero the monitor and is not yet widely used for critically ill patients. A literature search found 1 letter to the editor suggesting that real‐time ultrasound imaging of the internal jugular vein could be used to qualitatively determine jugular venous pressure18 and 3 studies using ultrasound in conjunction with a pressure transducer or manometer to determine the pressure needed to collapse the vein (either the internal jugular or a peripheral vein), with subsequent correlation to CVP.1921 These latter techniques appear to be cumbersome and require custom equipment that is not readily available in most hospitals.

Any measurement of CVP, including our technique, assumes correlation with volume responsiveness as a surrogate for intravascular volume. However, CVP is governed by multiple physiologic and pathologic factors, including intravascular volume, vascular and ventricular compliance, ventricular function, tricuspid stenosis and regurgitation, cardiac tamponade, and atrioventricular dissociation.22, 23 Therefore, CVP alone may not be an accurate measure of volume responsiveness (intravascular volume). CVP may also have spontaneous variation similar to pulmonary capillary wedge pressure, which can be as high as 7 mm Hg in any given patient.24 Furthermore, invasive CVP monitors also have limitations, and the overall accuracy of the Philips system used at Saint Marys Hospital is 4% of the reading or 4 mm Hg, whichever is greater.25 Nonetheless, the EGDT algorithm that incorporates CVP measurement with a target of 8 to 12 mm Hg in spontaneously breathing patients and 12 mm Hg in mechanically ventilated patients has resulted in decreased mortality among patients with severe sepsis and is recommended by the Surviving Sepsis Campaign guidelines26 and the Institute for Healthcare Improvement.27

These study results are important because nonintensivists such as hospitalists and emergency department physicians can use this technique to provide rapid fluid resuscitation early in the course of severe sepsis and septic shock, when aggressive fluid resuscitation is most effective. Ultrasound imaging of the internal jugular vein is easy to perform without formal training, and the equipment is readily available in most hospitals. Future studies will evaluate outcomes in spontaneously breathing and ventilated patients to determine the accuracy of this measurement technique in volume‐depleted and volume‐overloaded states. If validated in different patient populations, ultrasound measurement of the internal jugular vein could substitute for the EGDT CVP target in critically ill patients and allow early aggressive fluid resuscitation before a central venous catheter is placed.

Severe sepsis and septic shock account for more than 750,000 hospital admissions and 215,000 deaths per year.1 Early fluid resuscitation is the cornerstone of treatment, and early goal‐directed therapy (EGDT), which includes a target central venous pressure (CVP) of 8 to 12 mm Hg, has been shown to improve outcomes, including mortality and length of stay.2 This goal allows appropriate initial resuscitation and may decrease the risk of excess fluid administration, which is related to adverse outcomes in critically ill patients.3 However, nonintensivists may not start early aggressive fluid resuscitation because of inability to accurately assess intravascular volume, concerns for inadvertent volume overload, or the difficulty of recognizing insidious illness. Assessment of volume status, primarily from inspection of the internal jugular vein to estimate CVP, is difficult to perform by clinical examination alone, especially if CVP is very low.4 Inspection of the external jugular vein is perhaps easier than inspecting the internal jugular vein and appears to accurately estimate CVP,5 but it does not allow the degree of precision necessary for EGDT. Echocardiography can estimate CVP based on respirophasic variation or collapsibility index, but this technique requires expensive equipment and sonographic expertise. The current gold standard technique for measuring CVP requires an invasive central venous catheter, which can delay timely resuscitation and is associated with complications.6

An alternative technique to guide resuscitation efforts should be accurate, safe, rapid, and easy to perform at the bedside, while providing real‐time measurement results. We hypothesized that CVP can be accurately assessed using noninvasive ultrasound imaging of the internal jugular vein, since jugular venous pressure is essentially equal to CVP.7 Specifically, our study estimated the diagnostic accuracy of ultrasound measurement of the aspect ratio (height/width) of the internal jugular vein compared with the invasively measured CVP target for EGDT. We expected that a lower aspect ratio would correlate with a lower CVP and a higher aspect ratio would correlate with a higher CVP.

Methods

Volunteers were enrolled at Saint Mary's Hospital (Mayo Clinic) in Rochester, MN, from January to March 2006, and patients were enrolled at Saint Mary's Hospital and at Abbott Northwestern Hospital (Allina Hospitals and Clinics) in Minneapolis, MN, from May 2006 to October 2007. The study was approved by the Institutional Review Boards of Mayo Clinic and Allina and had 2 phases. The first phase comprised ultrasound measurements of internal jugular vein aspect ratio and determination of intraobserver and interobserver agreement in healthy volunteers. The second phase involved measurement of internal jugular vein aspect ratio and invasive CVP in a convenience sample of 44 spontaneously breathing patients admitted to medical intensive care units: 9 patients at Saint Marys Hospital and 35 patients at Abbott Northwestern Hospital. Patients were enrolled only when study members were on duty in the intensive care unit and able to perform study measurements. As a result, a high proportion of patients who may have been eligible were not asked to participate.

Each volunteer was deemed euvolemic on the basis of normal orthostatic measurements and normal oral intake with no vomiting or diarrhea in the previous 5 days. Measurements of 19 volunteers were made by 1 author (A.S.K.), with subsequent measurements of 15 of the volunteers made by another author (O.G.) to determine interobserver variability; 4 participants did not undergo a second measurement because of scheduling conflicts.

Inclusion and exclusion criteria for the critically ill patients are provided in Table 1. Recruitment was based on presenting symptoms and test results that led the intensive care unit physicians to decide to place a CVP monitor. All the enrolled patients had invasive CVP measurement performed approximately 30 to 40 minutes after ultrasound measurement of the internal jugular vein; this delay was the time required to place the central line and obtain the measurement. All patients who were invited to participate in the study were included. No patients were excluded on the basis of the exclusion criteria or because of inability to place a central line. No complications related to central line placement occurred.

We followed a prescribed measurement technique (Table 2) to determine the internal jugular vein aspect ratio in all volunteers and patients. Measurements of the volunteers were made with a Site‐Rite 3 Ultrasound System (Bard Access Systems, Inc., Salt Lake City, UT) using a 9.0‐MHz transducer. Measurements of the critically ill patients were made with a SonoSite MicroMaxx ultrasound system (SonoSite, Inc., Bothell, WA) using a 10.5‐MHz transducer. Study team physicians initially were blinded to actual measured CVP. Internal jugular vein aspect ratio and CVP were measured at tidal volume end‐expiration for all patients. One measurement was obtained for each patient, with measurements being made by 1 of 4 physicians (2 intensivists, 1 critical care fellow, and 1 chief medicine resident). With no specific ultrasound training and with only minimal practice, the physicians could obtain the optimal aspect ratio within a few seconds (Figure 1).

Figure 1

This was an exploratory prospective study, and all methods of data collection were designed before patient enrollment. However, the ultrasound‐derived aspect ratio of 0.83 (which defined a CVP of 8 mm Hg) was determined post hoc to maximize sensitivity and specificity and was based on the aspect ratio of the euvolemic volunteers and the inflection point of the CVP vs aspect ratio curve for the critically ill patients.

Results

We first evaluated 19 white volunteers: 12 women and 7 men. Mean (SD) age was 42 (11) years and mean body mass index was 26.6 (4.5) kg/m². Mean arterial pressure was 89 (13) mm Hg and mean heart rate was 71 (15) beats/minute. Mean aspect ratio of the right and left internal jugular vein for all volunteers was 0.82 (0.07). There was no difference in aspect ratio between the right (0.83 [0.10]) and left (0.81 [0.13]) vein (P > 0.10). Also, no difference in the aspect ratio was seen between men (0.81 [0.08]) and women (0.83 [0.07]) (P = 0.77). Bland‐Altman analysis indicated moderate intraobserver and interobserver agreement for the aspect ratio measurements (Figure 2).

Figure 2

We then compared the aspect ratio measured using ultrasound and CVP measured with an invasive monitor for 44 spontaneously breathing critically ill patients (22 women and 22 men; 38 were white). Mean (SD) age was 66 (14) years and mean body mass index was 28.8 (9.1) kg/m². Mean arterial pressure (n = 36) was 67 (12) mm Hg and mean heart rate (n = 34) was 92 (22) beats/minute. Systemic inflammatory response syndrome (SIRS) criteria were present in 23 of 40 patients; complete data were unavailable for the other 4 patients. Of these 40 patients, 20 had sepsis, 15 had severe sepsis, and 5 had septic shock. The most common diagnoses were gastrointestinal tract bleeding in 6 patients and congestive heart failure in 4 patients. Acute Physiology and Chronic Health Evaluation (APACHE III) score, available for 8 of the 9 patients at Saint Marys Hospital, was 63 (10).

Figure 3 shows measured aspect ratios vs. invasively measured CVP for the critically ill patients. The curvilinear result is consistent with venous and right ventricular compliance ( volume/ pressure) characteristics. Note that the inflection point (beginning of the increased slope) of the curve corresponds to a CVP of about 8 mm Hg. Furthermore, the aspect ratio (0.8) at this point is the same as that seen in the euvolemic volunteers. These findings suggest that, in spontaneously breathing patients, a CVP of about 8 mm Hg and an aspect ratio of about 0.8 each defines the beginning of the plateau on the cardiac Frank‐Starling curve.

Figure 3

Ultrasound imaging of the internal jugular vein aspect ratio accurately estimated the CVP target of 8 mm Hg based on the area under the receiver operating characteristics curve of 0.84 (95% confidence interval [CI], 0.72‐0.96) (Figure 4). For an invasively measured CVP of less than 8 mm Hg, the likelihood ratio for a positive ultrasound test result (aspect ratio < 0.83) was 3.5 (95% CI, 1.4‐8.4) and for a negative test result (aspect ratio 0.83) was 0.30 (95% CI, 0.14‐0.62). Clinically, this means that patients with a measured aspect ratio of less than 0.83 require further fluid resuscitation, whereas patients with a measured aspect ratio of 0.83 or greater are less likely to benefit from fluid resuscitation.

Figure 4

Discussion

This study demonstrated that the EGDT CVP target of 8 to 12 mm Hg can be accurately estimated (referenced to invasive CVP monitoring) using noninvasive ultrasound measurement of the internal jugular vein in spontaneously breathing critically ill patients. The measurement process is simple to perform at the bedside and moderately reliable when performed by different observers; also, the results appear to be equivalent for both sides and for males or females. Images can be stored electronically for serial comparisons and for viewing by other caregivers. Because the aspect ratio is essentially constant over the length of the internal jugular vein, unlike diameter, measurements can be performed anywhere along the vein. Also, ultrasound imaging allows visualization of the internal jugular vein despite anatomic variation.9

Previous attempts at noninvasive hemodynamic monitoring using plethysmography, thoracic electrical bioimpedance, and external Doppler probes have shown these methods to be cumbersome or inaccurate.1013 Other investigators have used echocardiography14, 15 and handheld ultrasound16 to image the diameter of the inferior vena cava in order to assess intravascular volume status, but these techniques require expertise in sonographic imaging. An alternative technique is to measure peripheral venous pressure, which correlates with CVP.17 This method, however, requires technical expertise to zero the monitor and is not yet widely used for critically ill patients. A literature search found 1 letter to the editor suggesting that real‐time ultrasound imaging of the internal jugular vein could be used to qualitatively determine jugular venous pressure18 and 3 studies using ultrasound in conjunction with a pressure transducer or manometer to determine the pressure needed to collapse the vein (either the internal jugular or a peripheral vein), with subsequent correlation to CVP.1921 These latter techniques appear to be cumbersome and require custom equipment that is not readily available in most hospitals.

Any measurement of CVP, including our technique, assumes correlation with volume responsiveness as a surrogate for intravascular volume. However, CVP is governed by multiple physiologic and pathologic factors, including intravascular volume, vascular and ventricular compliance, ventricular function, tricuspid stenosis and regurgitation, cardiac tamponade, and atrioventricular dissociation.22, 23 Therefore, CVP alone may not be an accurate measure of volume responsiveness (intravascular volume). CVP may also have spontaneous variation similar to pulmonary capillary wedge pressure, which can be as high as 7 mm Hg in any given patient.24 Furthermore, invasive CVP monitors also have limitations, and the overall accuracy of the Philips system used at Saint Marys Hospital is 4% of the reading or 4 mm Hg, whichever is greater.25 Nonetheless, the EGDT algorithm that incorporates CVP measurement with a target of 8 to 12 mm Hg in spontaneously breathing patients and 12 mm Hg in mechanically ventilated patients has resulted in decreased mortality among patients with severe sepsis and is recommended by the Surviving Sepsis Campaign guidelines26 and the Institute for Healthcare Improvement.27

These study results are important because nonintensivists such as hospitalists and emergency department physicians can use this technique to provide rapid fluid resuscitation early in the course of severe sepsis and septic shock, when aggressive fluid resuscitation is most effective. Ultrasound imaging of the internal jugular vein is easy to perform without formal training, and the equipment is readily available in most hospitals. Future studies will evaluate outcomes in spontaneously breathing and ventilated patients to determine the accuracy of this measurement technique in volume‐depleted and volume‐overloaded states. If validated in different patient populations, ultrasound measurement of the internal jugular vein could substitute for the EGDT CVP target in critically ill patients and allow early aggressive fluid resuscitation before a central venous catheter is placed.

A 73‐year‐old male presented with acute congestive heart failure and non‐ST elevation myocardial infarction. His initial chest x‐ray and computed tomography (CT) demonstrated pulmonary vascular congestion and alveolar infiltrates, and he promptly underwent cardiac catheterization with placement of a coronary stent. Subsequently, his respiratory status deteriorated, and repeat films and chest CT demonstrated extensive pneumomediastinum and pneumopericardium (Figures 13). The patient was intubated, and bronchoscopy and upper gastrointestinal (GI) endoscopy were performed, but demonstrated no evidence of perforation that could cause such an air leak. There was no evidence of tamponade, clinically or on echocardiogram. His condition worsened abruptly, and he expired following a cardiac arrest. Postmortem, the team considered that the extensive air leak could have been caused by catheterization, stent placement, central line placement, or mediastinitis or pericarditis causing microscopic fistulae. The patient's tracheal aspirate and biopsy grew Candida albicans but no evidence of invasive candidiasis was found on autopsy. No definitive etiology was found.

Figure 1

Figure 2

Figure 3

In contrast to pneumomediastinum, pneumopericardium is a rare condition and its pathophysiology is not well understood. Most cases have been reported in newborns receiving mechanical ventilation. In adults, the condition occurs due to chest trauma, or can be iatrogenic secondary to laparoscopy, bronchoscopy, or endotracheal intubation. There have been case reports of pneumopericardium after cardiac catheterization and central line placement.1, 2 Other causes include lung transplant, esophageal perforation, severe asthma, positive pressure ventilation, and pericarditis (eg, histoplasmosis and tuberculosis).3, 4 Clinical findings include distant heart sounds, shifting precordial tympany, and a succussion splash with metallic tinkling (known as mill wheel murmur) in hydropneumopericardium.5 Chest CT can distinguish pneumopericardium from pneumomediastinum: with the former, the air changes position when the patient adopts a supine position.6 Cardiac tamponade can occur in up to 37% of cases, and pericardiocentesis or pericardial tube drainage in these cases can be lifesaving.7

A 73‐year‐old male presented with acute congestive heart failure and non‐ST elevation myocardial infarction. His initial chest x‐ray and computed tomography (CT) demonstrated pulmonary vascular congestion and alveolar infiltrates, and he promptly underwent cardiac catheterization with placement of a coronary stent. Subsequently, his respiratory status deteriorated, and repeat films and chest CT demonstrated extensive pneumomediastinum and pneumopericardium (Figures 13). The patient was intubated, and bronchoscopy and upper gastrointestinal (GI) endoscopy were performed, but demonstrated no evidence of perforation that could cause such an air leak. There was no evidence of tamponade, clinically or on echocardiogram. His condition worsened abruptly, and he expired following a cardiac arrest. Postmortem, the team considered that the extensive air leak could have been caused by catheterization, stent placement, central line placement, or mediastinitis or pericarditis causing microscopic fistulae. The patient's tracheal aspirate and biopsy grew Candida albicans but no evidence of invasive candidiasis was found on autopsy. No definitive etiology was found.

Figure 1

Figure 2

Figure 3

In contrast to pneumomediastinum, pneumopericardium is a rare condition and its pathophysiology is not well understood. Most cases have been reported in newborns receiving mechanical ventilation. In adults, the condition occurs due to chest trauma, or can be iatrogenic secondary to laparoscopy, bronchoscopy, or endotracheal intubation. There have been case reports of pneumopericardium after cardiac catheterization and central line placement.1, 2 Other causes include lung transplant, esophageal perforation, severe asthma, positive pressure ventilation, and pericarditis (eg, histoplasmosis and tuberculosis).3, 4 Clinical findings include distant heart sounds, shifting precordial tympany, and a succussion splash with metallic tinkling (known as mill wheel murmur) in hydropneumopericardium.5 Chest CT can distinguish pneumopericardium from pneumomediastinum: with the former, the air changes position when the patient adopts a supine position.6 Cardiac tamponade can occur in up to 37% of cases, and pericardiocentesis or pericardial tube drainage in these cases can be lifesaving.7

A 73‐year‐old male presented with acute congestive heart failure and non‐ST elevation myocardial infarction. His initial chest x‐ray and computed tomography (CT) demonstrated pulmonary vascular congestion and alveolar infiltrates, and he promptly underwent cardiac catheterization with placement of a coronary stent. Subsequently, his respiratory status deteriorated, and repeat films and chest CT demonstrated extensive pneumomediastinum and pneumopericardium (Figures 13). The patient was intubated, and bronchoscopy and upper gastrointestinal (GI) endoscopy were performed, but demonstrated no evidence of perforation that could cause such an air leak. There was no evidence of tamponade, clinically or on echocardiogram. His condition worsened abruptly, and he expired following a cardiac arrest. Postmortem, the team considered that the extensive air leak could have been caused by catheterization, stent placement, central line placement, or mediastinitis or pericarditis causing microscopic fistulae. The patient's tracheal aspirate and biopsy grew Candida albicans but no evidence of invasive candidiasis was found on autopsy. No definitive etiology was found.

Figure 1

Figure 2

Figure 3

In contrast to pneumomediastinum, pneumopericardium is a rare condition and its pathophysiology is not well understood. Most cases have been reported in newborns receiving mechanical ventilation. In adults, the condition occurs due to chest trauma, or can be iatrogenic secondary to laparoscopy, bronchoscopy, or endotracheal intubation. There have been case reports of pneumopericardium after cardiac catheterization and central line placement.1, 2 Other causes include lung transplant, esophageal perforation, severe asthma, positive pressure ventilation, and pericarditis (eg, histoplasmosis and tuberculosis).3, 4 Clinical findings include distant heart sounds, shifting precordial tympany, and a succussion splash with metallic tinkling (known as mill wheel murmur) in hydropneumopericardium.5 Chest CT can distinguish pneumopericardium from pneumomediastinum: with the former, the air changes position when the patient adopts a supine position.6 Cardiac tamponade can occur in up to 37% of cases, and pericardiocentesis or pericardial tube drainage in these cases can be lifesaving.7

Hand‐carried ultrasound echocardiography (HCUE) can help noncardiologists answer well‐defined questions at patients' bedsides in less than 10 minutes.1, 2 Indeed, intensivists3 and emergency department physicians4 already use HCUE to make rapid, point‐of‐care assessments. Since cardiovascular diagnoses are common among general medicine inpatients, HCUE may become an important skill for hospitalists to learn.5

However, uncertainty exists about the duration of HCUE training for hospitalists. In 2002, experts from the American Society of Echocardiography (ASE) published recommendations on training requirements for HCUE.6 With limited data on the safety or performance of HCUE training programs, which had just begun to emerge, the ASE borrowed from the proven training recommendations for standard echocardiography (SE). They recommended that all HCUE trainees, cardiologist and noncardiologist alike, complete level 1 SE training: 75 personally‐performed and 150 personally‐interpreted echocardiographic examinations. Since then, however, several HCUE training programs designed for noncardiologists have emerged.2, 5, 710 These alternative programs suggest that the ASE's recommended duration of training may be too long, particularly for focused HCUE that is limited to a few relatively simple assessments. It is important not to overshoot the requirements of HCUE training, because doing so may discourage groups of noncardiologists, like hospitalists, who may derive great benefits from HCUE.11

To address this uncertainty for hospitalists, we first developed a brief HCUE training program to assess 6 important cardiac abnormalities. We then studied the diagnostic accuracy of HCUE by hospitalists as a test of these 6 cardiac abnormalities assessed by SE.

Patients and Methods

Setting and Subjects

This prospective cohort study was performed at Stroger Hospital of Cook County, a 500‐bed public teaching hospital in Chicago, IL, from March through May of 2007. The cohort was adult inpatients who were referred for SE on weekdays from 3 distinct patient care units (Figure 1). We used 2 sampling modes to balance practical constraints (short‐stay unit [SSU] patients were more localized and, therefore, easier to study) with clinical diversity. We consecutively sampled patients from our SSU, where adults with provisional cardiovascular diagnoses are admitted if they might be eligible for discharge with in 3 days.12 But we used random number tables with a daily unique starting point to randomly sample patients from the general medical wards and the coronary care unit (CCU). Patients were excluded if repositioning them for HCUE was potentially harmful. The study was approved by our hospital's institutional review board, and we obtained written informed consent from all enrolled patients.

Figure 1

Results

During the 3 month study period, 654 patients were referred for SE from the 3 participating patient care units (Figure 1). Among these, 65 patients were ineligible because their SE was performed on the weekend and 178 other patients were not randomized from the general medical wards and CCU. From the remaining eligible patients, 322 underwent HCUE and 314 (98% of 322) underwent both SE and HCUE. Individual SE assessments were not interpretable (and therefore excluded) due to poor image quality for LA enlargement in 1 patient and IVC dilatation in 30 patients. Eighty‐three percent of patients who underwent SE (260/314) were referred to assess LV function (Table 3). The prevalence of the 6 clinically pertinent cardiac abnormalities under study ranged from 1% for moderate or large pericardial effusion to 25% for LV systolic dysfunction. Overall, 40% of patients had at least 1 out of 6 cardiac abnormalities.

Each hospitalist performed a similar total number of HCUE examinations (range, 3447). The median time difference between performance of SE and HCUE was 2.8 hours (25th75th percentiles, 1.45.1). Despite the high prevalence of chronic obstructive pulmonary disease and obesity, hospitalists considered HCUE assessments indeterminate in only 2% to 6% of the 6 assessments made for each patient (Table 4). Among the 38 patients (12% of 322) with any indeterminate HCUE assessment, 24 patients had only 1 out of 6 possible. Hospitalists completed HCUE in a median time of 28 minutes (25th‐75th percentiles, 2035), which included the time to record 7 best‐quality moving images and to fill out the research data collection form.

When HCUE results were analyzed as dichotomous values, positive likelihood ratios ranged from 2.5 to 21, and negative likelihood ratios ranged from 0 to 0.4 (Table 5). Positive and negative likelihood ratios were both sufficiency high and low to respectively increase and decrease by 5‐fold the prior odds of 3 out of 6 cardiac abnormalities: LV systolic dysfunction, moderate or severe MR regurgitation, and moderate or large pericardial effusion. Considering HCUE results as ordinal values for ROC analysis yielded additional diagnostic information (Figure 2). For example, the likelihood ratio of 1.0 (95% CI, 0.42.0) for borderline positive moderate or severe LA enlargement increased to 29 (range, 1362) for extreme positive results. Areas under the ROC curves were 0.9 for 4 out of 6 cardiac abnormalities.

Figure 2

LV systolic dysfunction and IVC dilatation were both prevalent enough to meet our criterion to examine interobserver variability; the mean number of abnormal patients per hospitalist was 10 patients for LV systolic dysfunction and 6 patients for IVC dilatation. For LV systolic dysfunction, SDs around mean sensitivity (84%) and specificity (87%) were 12% and 6%, respectively. For IVC dilatation, SDs around mean sensitivity (58%) and specificity (86%) were 24% and 7%, respectively.

Discussion

We found that, after a 27‐hour training program, hospitalists performed HCUE with moderate to excellent diagnostic accuracy for 6 important cardiac abnormalities. For example, hospitalists' assessments of LV systolic function yielded positive and negative likelihood ratios of 6.9 (95% CI, 4.99.8) and 0.2 (95% CI, 0.10.3), respectively. At the bedsides of patients with acute heart failure, therefore, hospitalists could use HCUE to lower or raise the 50:50 chance of LV systolic dysfunction30 to 15% or 85%, respectively. Whether or not these posttest likelihoods are extreme enough to cross important thresholds will depend on the clinical context. Yet these findings demonstrate how HCUE has the potential to provide hospitalists with valuable point‐of‐care data that are otherwise unavailableeither because routine clinical assessments are unreliable31 or because echocardiographic services are not immediately accessible.1

In fact, recent data from the Joint Commission on Accreditation of Healthcare Organizations shows how inaccessible SE may be. Approximately one‐quarter of hospitals in the United States send home about 10% of patients with acute heart failure without echocardiographic assessment of LV systolic function before, during, or immediately after hospitalization.32 In doing so, these hospitals leave unmet the 2002 National Quality Improvement Goal of universal assessment of LV systolic function for all heart failure patients. Hospitalists could close this quality gap with routine, 10‐minute HCUE assessments in all patients admitted with acute heart failure. (Our research HCUE protocol required a median time of 28 minutes, but this included time to assess 5 other cardiac abnormalities and collect data for research purposes). Until the clinical consequences of introducing hospitalist‐performed HCUE are studied, potential benefits like this are tentative. But our findings suggest that training hospitalists to accurately perform HCUE can be successfully accomplished in just 27 hours.

Other studies of HCUE training programs for noncardiologists have also challenged the opinion that learning to perform HCUE requires more than 100 hours of training.2, 711 Yet only 1 prior study has examined an HCUE training program for hospitalists.5 In this study by Martin et al.,5 hospitalists completed 5 supervised HCUE examinations and 6 hours of interpretation training before investigators scored their image acquisition and interpretation skills from 30 unsupervised HCUE examinations. To estimate their final skill levels at the completion of all 35 examinations by accounting for an initially steep learning curve, investigators then adjusted these scores with regression models. Despite these upward adjustments, hospitalists' image acquisition and interpretation scores were low in comparison to echocardiographic technicians and cardiology fellows. Besides these adjusted measurements of hospitalists' skills, however, Martin et al.5 unfortunately did not also report standard measures of diagnostic accuracy, like those proposed by the Standards for Reporting of Diagnostic Accuracy (STARD) initiative.33 Therefore, direct comparisons to the present study are difficult. Nevertheless, their findings suggest that a training program limited to 5 supervised HCUE examinations may be inadequate for hospitalists. In fact, the same group's earlier study of medical trainees suggested a minimum of 30 supervised HCUE examinations.9 We chose to design our hospitalist training program based on this minimum, though they surprisingly did not.5 As others continue to refine the components of hospitalist HCUE training programs, such as the optimal number of supervised examinations, our program could serve as a reasonable comparative example: more rigorous than the program designed by Martin et al.5 but more feasible than ASE level 1 training.

The number and complexity of assessments taught in HCUE training programs will determine their duration. With ongoing advancements in HCUE technology, there is a growing list of potential assessments to choose from. Although HCUE training programs ought to include assessments with proven clinical applications, there are no trials of HCUE‐directed care to inform such decisions. In their absence, therefore, we chose 6 assessments based on the following 3 criteria. First, our assessments were otherwise not reliably available from routine clinical data, such as the physical examination. Second, our assessments were straightforward: easy to learn and simple to perform. Here, we based our reasoning on an expectation that the value of HCUE lies not in highly complex, state‐of‐the‐art assessmentswhich are best left to echocardiographers equipped with SEbut in simple, routine assessments made with highly portable machines that grant noncardiologists newfound access to point‐of‐care data.34 Third, our assessments were clinically pertinent and, where appropriate, defined by cut‐points at levels of severity that often lead to changes in management. We suspect that setting high cut‐points has the salutary effects of making assessments easier to learn and more accurate, because distinguishing mild abnormalities is likely the most challenging aspect of echocardiographic interpretation.35 Whether or not our choices of assessments, and their cut‐points, are optimal has yet to be determined by future research designed to study how they affect patient outcomes. Given our hospitalists' performance in the present study, these assessments seem worthy of such future research.

Our study had several limitations. We studied physicians and patients from only 1 hospital; similar studies performed in different settings, particularly among patients with different proportions and manifestations of disease, may find different results. Nevertheless, our sampling method of prospectively enrolling consecutive patients strengthens our findings. Some echocardiographic measurement methods used by our hospitalists differed in subtle ways from echocardiography guideline recommendations.35 We chose our methods (Table 2) for 2 reasons. First, whenever possible, we chose methods of interpretation that coincided with our local cardiologists'. Second, we chose simplicity over precision. For example, the biplane method of disks, or modified Simpson's rule, is the preferred volumetric method of calculating LA size.35 This method requires tracing the contours of the LA in 2 planes and then dividing the LA volume into stacked oval disks for calculation. We chose instead to train our hospitalists in a simpler method based on 2 linear measurements. Any loss of precision, however, was balanced by a large gain in simplicity. Regardless, minor variations in LA size are not likely to affect hospitalists' bedside evaluations. Finally, we did not validate the results of our reference standard (SE) by documenting interobserver reliability. Yet, because SE is generally accurate for the 6 cardiac abnormalities under study, the effect of this bias should be small.

These limitations can be addressed best by controlled trials of HCUE‐directed care. These trials will determine the clinical impact of hospitalist‐performed HCUE and, in turn, inform our design of HCUE training programs. As the current study shows, training hospitalists to participate in such trials is feasible: like other groups of noncardiologists, hospitalists can accurately perform HCUE after a brief training program. Whether or not hospitalists should perform HCUE requires further study.

Hand‐carried ultrasound echocardiography (HCUE) can help noncardiologists answer well‐defined questions at patients' bedsides in less than 10 minutes.1, 2 Indeed, intensivists3 and emergency department physicians4 already use HCUE to make rapid, point‐of‐care assessments. Since cardiovascular diagnoses are common among general medicine inpatients, HCUE may become an important skill for hospitalists to learn.5

However, uncertainty exists about the duration of HCUE training for hospitalists. In 2002, experts from the American Society of Echocardiography (ASE) published recommendations on training requirements for HCUE.6 With limited data on the safety or performance of HCUE training programs, which had just begun to emerge, the ASE borrowed from the proven training recommendations for standard echocardiography (SE). They recommended that all HCUE trainees, cardiologist and noncardiologist alike, complete level 1 SE training: 75 personally‐performed and 150 personally‐interpreted echocardiographic examinations. Since then, however, several HCUE training programs designed for noncardiologists have emerged.2, 5, 710 These alternative programs suggest that the ASE's recommended duration of training may be too long, particularly for focused HCUE that is limited to a few relatively simple assessments. It is important not to overshoot the requirements of HCUE training, because doing so may discourage groups of noncardiologists, like hospitalists, who may derive great benefits from HCUE.11

To address this uncertainty for hospitalists, we first developed a brief HCUE training program to assess 6 important cardiac abnormalities. We then studied the diagnostic accuracy of HCUE by hospitalists as a test of these 6 cardiac abnormalities assessed by SE.

Patients and Methods

Setting and Subjects

This prospective cohort study was performed at Stroger Hospital of Cook County, a 500‐bed public teaching hospital in Chicago, IL, from March through May of 2007. The cohort was adult inpatients who were referred for SE on weekdays from 3 distinct patient care units (Figure 1). We used 2 sampling modes to balance practical constraints (short‐stay unit [SSU] patients were more localized and, therefore, easier to study) with clinical diversity. We consecutively sampled patients from our SSU, where adults with provisional cardiovascular diagnoses are admitted if they might be eligible for discharge with in 3 days.12 But we used random number tables with a daily unique starting point to randomly sample patients from the general medical wards and the coronary care unit (CCU). Patients were excluded if repositioning them for HCUE was potentially harmful. The study was approved by our hospital's institutional review board, and we obtained written informed consent from all enrolled patients.

Figure 1

Results

During the 3 month study period, 654 patients were referred for SE from the 3 participating patient care units (Figure 1). Among these, 65 patients were ineligible because their SE was performed on the weekend and 178 other patients were not randomized from the general medical wards and CCU. From the remaining eligible patients, 322 underwent HCUE and 314 (98% of 322) underwent both SE and HCUE. Individual SE assessments were not interpretable (and therefore excluded) due to poor image quality for LA enlargement in 1 patient and IVC dilatation in 30 patients. Eighty‐three percent of patients who underwent SE (260/314) were referred to assess LV function (Table 3). The prevalence of the 6 clinically pertinent cardiac abnormalities under study ranged from 1% for moderate or large pericardial effusion to 25% for LV systolic dysfunction. Overall, 40% of patients had at least 1 out of 6 cardiac abnormalities.

Each hospitalist performed a similar total number of HCUE examinations (range, 3447). The median time difference between performance of SE and HCUE was 2.8 hours (25th75th percentiles, 1.45.1). Despite the high prevalence of chronic obstructive pulmonary disease and obesity, hospitalists considered HCUE assessments indeterminate in only 2% to 6% of the 6 assessments made for each patient (Table 4). Among the 38 patients (12% of 322) with any indeterminate HCUE assessment, 24 patients had only 1 out of 6 possible. Hospitalists completed HCUE in a median time of 28 minutes (25th‐75th percentiles, 2035), which included the time to record 7 best‐quality moving images and to fill out the research data collection form.

When HCUE results were analyzed as dichotomous values, positive likelihood ratios ranged from 2.5 to 21, and negative likelihood ratios ranged from 0 to 0.4 (Table 5). Positive and negative likelihood ratios were both sufficiency high and low to respectively increase and decrease by 5‐fold the prior odds of 3 out of 6 cardiac abnormalities: LV systolic dysfunction, moderate or severe MR regurgitation, and moderate or large pericardial effusion. Considering HCUE results as ordinal values for ROC analysis yielded additional diagnostic information (Figure 2). For example, the likelihood ratio of 1.0 (95% CI, 0.42.0) for borderline positive moderate or severe LA enlargement increased to 29 (range, 1362) for extreme positive results. Areas under the ROC curves were 0.9 for 4 out of 6 cardiac abnormalities.

Figure 2

LV systolic dysfunction and IVC dilatation were both prevalent enough to meet our criterion to examine interobserver variability; the mean number of abnormal patients per hospitalist was 10 patients for LV systolic dysfunction and 6 patients for IVC dilatation. For LV systolic dysfunction, SDs around mean sensitivity (84%) and specificity (87%) were 12% and 6%, respectively. For IVC dilatation, SDs around mean sensitivity (58%) and specificity (86%) were 24% and 7%, respectively.

Discussion

We found that, after a 27‐hour training program, hospitalists performed HCUE with moderate to excellent diagnostic accuracy for 6 important cardiac abnormalities. For example, hospitalists' assessments of LV systolic function yielded positive and negative likelihood ratios of 6.9 (95% CI, 4.99.8) and 0.2 (95% CI, 0.10.3), respectively. At the bedsides of patients with acute heart failure, therefore, hospitalists could use HCUE to lower or raise the 50:50 chance of LV systolic dysfunction30 to 15% or 85%, respectively. Whether or not these posttest likelihoods are extreme enough to cross important thresholds will depend on the clinical context. Yet these findings demonstrate how HCUE has the potential to provide hospitalists with valuable point‐of‐care data that are otherwise unavailableeither because routine clinical assessments are unreliable31 or because echocardiographic services are not immediately accessible.1

In fact, recent data from the Joint Commission on Accreditation of Healthcare Organizations shows how inaccessible SE may be. Approximately one‐quarter of hospitals in the United States send home about 10% of patients with acute heart failure without echocardiographic assessment of LV systolic function before, during, or immediately after hospitalization.32 In doing so, these hospitals leave unmet the 2002 National Quality Improvement Goal of universal assessment of LV systolic function for all heart failure patients. Hospitalists could close this quality gap with routine, 10‐minute HCUE assessments in all patients admitted with acute heart failure. (Our research HCUE protocol required a median time of 28 minutes, but this included time to assess 5 other cardiac abnormalities and collect data for research purposes). Until the clinical consequences of introducing hospitalist‐performed HCUE are studied, potential benefits like this are tentative. But our findings suggest that training hospitalists to accurately perform HCUE can be successfully accomplished in just 27 hours.

Other studies of HCUE training programs for noncardiologists have also challenged the opinion that learning to perform HCUE requires more than 100 hours of training.2, 711 Yet only 1 prior study has examined an HCUE training program for hospitalists.5 In this study by Martin et al.,5 hospitalists completed 5 supervised HCUE examinations and 6 hours of interpretation training before investigators scored their image acquisition and interpretation skills from 30 unsupervised HCUE examinations. To estimate their final skill levels at the completion of all 35 examinations by accounting for an initially steep learning curve, investigators then adjusted these scores with regression models. Despite these upward adjustments, hospitalists' image acquisition and interpretation scores were low in comparison to echocardiographic technicians and cardiology fellows. Besides these adjusted measurements of hospitalists' skills, however, Martin et al.5 unfortunately did not also report standard measures of diagnostic accuracy, like those proposed by the Standards for Reporting of Diagnostic Accuracy (STARD) initiative.33 Therefore, direct comparisons to the present study are difficult. Nevertheless, their findings suggest that a training program limited to 5 supervised HCUE examinations may be inadequate for hospitalists. In fact, the same group's earlier study of medical trainees suggested a minimum of 30 supervised HCUE examinations.9 We chose to design our hospitalist training program based on this minimum, though they surprisingly did not.5 As others continue to refine the components of hospitalist HCUE training programs, such as the optimal number of supervised examinations, our program could serve as a reasonable comparative example: more rigorous than the program designed by Martin et al.5 but more feasible than ASE level 1 training.

The number and complexity of assessments taught in HCUE training programs will determine their duration. With ongoing advancements in HCUE technology, there is a growing list of potential assessments to choose from. Although HCUE training programs ought to include assessments with proven clinical applications, there are no trials of HCUE‐directed care to inform such decisions. In their absence, therefore, we chose 6 assessments based on the following 3 criteria. First, our assessments were otherwise not reliably available from routine clinical data, such as the physical examination. Second, our assessments were straightforward: easy to learn and simple to perform. Here, we based our reasoning on an expectation that the value of HCUE lies not in highly complex, state‐of‐the‐art assessmentswhich are best left to echocardiographers equipped with SEbut in simple, routine assessments made with highly portable machines that grant noncardiologists newfound access to point‐of‐care data.34 Third, our assessments were clinically pertinent and, where appropriate, defined by cut‐points at levels of severity that often lead to changes in management. We suspect that setting high cut‐points has the salutary effects of making assessments easier to learn and more accurate, because distinguishing mild abnormalities is likely the most challenging aspect of echocardiographic interpretation.35 Whether or not our choices of assessments, and their cut‐points, are optimal has yet to be determined by future research designed to study how they affect patient outcomes. Given our hospitalists' performance in the present study, these assessments seem worthy of such future research.

Our study had several limitations. We studied physicians and patients from only 1 hospital; similar studies performed in different settings, particularly among patients with different proportions and manifestations of disease, may find different results. Nevertheless, our sampling method of prospectively enrolling consecutive patients strengthens our findings. Some echocardiographic measurement methods used by our hospitalists differed in subtle ways from echocardiography guideline recommendations.35 We chose our methods (Table 2) for 2 reasons. First, whenever possible, we chose methods of interpretation that coincided with our local cardiologists'. Second, we chose simplicity over precision. For example, the biplane method of disks, or modified Simpson's rule, is the preferred volumetric method of calculating LA size.35 This method requires tracing the contours of the LA in 2 planes and then dividing the LA volume into stacked oval disks for calculation. We chose instead to train our hospitalists in a simpler method based on 2 linear measurements. Any loss of precision, however, was balanced by a large gain in simplicity. Regardless, minor variations in LA size are not likely to affect hospitalists' bedside evaluations. Finally, we did not validate the results of our reference standard (SE) by documenting interobserver reliability. Yet, because SE is generally accurate for the 6 cardiac abnormalities under study, the effect of this bias should be small.

These limitations can be addressed best by controlled trials of HCUE‐directed care. These trials will determine the clinical impact of hospitalist‐performed HCUE and, in turn, inform our design of HCUE training programs. As the current study shows, training hospitalists to participate in such trials is feasible: like other groups of noncardiologists, hospitalists can accurately perform HCUE after a brief training program. Whether or not hospitalists should perform HCUE requires further study.

Hand‐carried ultrasound echocardiography (HCUE) can help noncardiologists answer well‐defined questions at patients' bedsides in less than 10 minutes.1, 2 Indeed, intensivists3 and emergency department physicians4 already use HCUE to make rapid, point‐of‐care assessments. Since cardiovascular diagnoses are common among general medicine inpatients, HCUE may become an important skill for hospitalists to learn.5

However, uncertainty exists about the duration of HCUE training for hospitalists. In 2002, experts from the American Society of Echocardiography (ASE) published recommendations on training requirements for HCUE.6 With limited data on the safety or performance of HCUE training programs, which had just begun to emerge, the ASE borrowed from the proven training recommendations for standard echocardiography (SE). They recommended that all HCUE trainees, cardiologist and noncardiologist alike, complete level 1 SE training: 75 personally‐performed and 150 personally‐interpreted echocardiographic examinations. Since then, however, several HCUE training programs designed for noncardiologists have emerged.2, 5, 710 These alternative programs suggest that the ASE's recommended duration of training may be too long, particularly for focused HCUE that is limited to a few relatively simple assessments. It is important not to overshoot the requirements of HCUE training, because doing so may discourage groups of noncardiologists, like hospitalists, who may derive great benefits from HCUE.11

To address this uncertainty for hospitalists, we first developed a brief HCUE training program to assess 6 important cardiac abnormalities. We then studied the diagnostic accuracy of HCUE by hospitalists as a test of these 6 cardiac abnormalities assessed by SE.

Patients and Methods

Setting and Subjects

This prospective cohort study was performed at Stroger Hospital of Cook County, a 500‐bed public teaching hospital in Chicago, IL, from March through May of 2007. The cohort was adult inpatients who were referred for SE on weekdays from 3 distinct patient care units (Figure 1). We used 2 sampling modes to balance practical constraints (short‐stay unit [SSU] patients were more localized and, therefore, easier to study) with clinical diversity. We consecutively sampled patients from our SSU, where adults with provisional cardiovascular diagnoses are admitted if they might be eligible for discharge with in 3 days.12 But we used random number tables with a daily unique starting point to randomly sample patients from the general medical wards and the coronary care unit (CCU). Patients were excluded if repositioning them for HCUE was potentially harmful. The study was approved by our hospital's institutional review board, and we obtained written informed consent from all enrolled patients.

Figure 1

Results

During the 3 month study period, 654 patients were referred for SE from the 3 participating patient care units (Figure 1). Among these, 65 patients were ineligible because their SE was performed on the weekend and 178 other patients were not randomized from the general medical wards and CCU. From the remaining eligible patients, 322 underwent HCUE and 314 (98% of 322) underwent both SE and HCUE. Individual SE assessments were not interpretable (and therefore excluded) due to poor image quality for LA enlargement in 1 patient and IVC dilatation in 30 patients. Eighty‐three percent of patients who underwent SE (260/314) were referred to assess LV function (Table 3). The prevalence of the 6 clinically pertinent cardiac abnormalities under study ranged from 1% for moderate or large pericardial effusion to 25% for LV systolic dysfunction. Overall, 40% of patients had at least 1 out of 6 cardiac abnormalities.

Each hospitalist performed a similar total number of HCUE examinations (range, 3447). The median time difference between performance of SE and HCUE was 2.8 hours (25th75th percentiles, 1.45.1). Despite the high prevalence of chronic obstructive pulmonary disease and obesity, hospitalists considered HCUE assessments indeterminate in only 2% to 6% of the 6 assessments made for each patient (Table 4). Among the 38 patients (12% of 322) with any indeterminate HCUE assessment, 24 patients had only 1 out of 6 possible. Hospitalists completed HCUE in a median time of 28 minutes (25th‐75th percentiles, 2035), which included the time to record 7 best‐quality moving images and to fill out the research data collection form.

When HCUE results were analyzed as dichotomous values, positive likelihood ratios ranged from 2.5 to 21, and negative likelihood ratios ranged from 0 to 0.4 (Table 5). Positive and negative likelihood ratios were both sufficiency high and low to respectively increase and decrease by 5‐fold the prior odds of 3 out of 6 cardiac abnormalities: LV systolic dysfunction, moderate or severe MR regurgitation, and moderate or large pericardial effusion. Considering HCUE results as ordinal values for ROC analysis yielded additional diagnostic information (Figure 2). For example, the likelihood ratio of 1.0 (95% CI, 0.42.0) for borderline positive moderate or severe LA enlargement increased to 29 (range, 1362) for extreme positive results. Areas under the ROC curves were 0.9 for 4 out of 6 cardiac abnormalities.

Figure 2

LV systolic dysfunction and IVC dilatation were both prevalent enough to meet our criterion to examine interobserver variability; the mean number of abnormal patients per hospitalist was 10 patients for LV systolic dysfunction and 6 patients for IVC dilatation. For LV systolic dysfunction, SDs around mean sensitivity (84%) and specificity (87%) were 12% and 6%, respectively. For IVC dilatation, SDs around mean sensitivity (58%) and specificity (86%) were 24% and 7%, respectively.

Discussion

We found that, after a 27‐hour training program, hospitalists performed HCUE with moderate to excellent diagnostic accuracy for 6 important cardiac abnormalities. For example, hospitalists' assessments of LV systolic function yielded positive and negative likelihood ratios of 6.9 (95% CI, 4.99.8) and 0.2 (95% CI, 0.10.3), respectively. At the bedsides of patients with acute heart failure, therefore, hospitalists could use HCUE to lower or raise the 50:50 chance of LV systolic dysfunction30 to 15% or 85%, respectively. Whether or not these posttest likelihoods are extreme enough to cross important thresholds will depend on the clinical context. Yet these findings demonstrate how HCUE has the potential to provide hospitalists with valuable point‐of‐care data that are otherwise unavailableeither because routine clinical assessments are unreliable31 or because echocardiographic services are not immediately accessible.1

In fact, recent data from the Joint Commission on Accreditation of Healthcare Organizations shows how inaccessible SE may be. Approximately one‐quarter of hospitals in the United States send home about 10% of patients with acute heart failure without echocardiographic assessment of LV systolic function before, during, or immediately after hospitalization.32 In doing so, these hospitals leave unmet the 2002 National Quality Improvement Goal of universal assessment of LV systolic function for all heart failure patients. Hospitalists could close this quality gap with routine, 10‐minute HCUE assessments in all patients admitted with acute heart failure. (Our research HCUE protocol required a median time of 28 minutes, but this included time to assess 5 other cardiac abnormalities and collect data for research purposes). Until the clinical consequences of introducing hospitalist‐performed HCUE are studied, potential benefits like this are tentative. But our findings suggest that training hospitalists to accurately perform HCUE can be successfully accomplished in just 27 hours.

Other studies of HCUE training programs for noncardiologists have also challenged the opinion that learning to perform HCUE requires more than 100 hours of training.2, 711 Yet only 1 prior study has examined an HCUE training program for hospitalists.5 In this study by Martin et al.,5 hospitalists completed 5 supervised HCUE examinations and 6 hours of interpretation training before investigators scored their image acquisition and interpretation skills from 30 unsupervised HCUE examinations. To estimate their final skill levels at the completion of all 35 examinations by accounting for an initially steep learning curve, investigators then adjusted these scores with regression models. Despite these upward adjustments, hospitalists' image acquisition and interpretation scores were low in comparison to echocardiographic technicians and cardiology fellows. Besides these adjusted measurements of hospitalists' skills, however, Martin et al.5 unfortunately did not also report standard measures of diagnostic accuracy, like those proposed by the Standards for Reporting of Diagnostic Accuracy (STARD) initiative.33 Therefore, direct comparisons to the present study are difficult. Nevertheless, their findings suggest that a training program limited to 5 supervised HCUE examinations may be inadequate for hospitalists. In fact, the same group's earlier study of medical trainees suggested a minimum of 30 supervised HCUE examinations.9 We chose to design our hospitalist training program based on this minimum, though they surprisingly did not.5 As others continue to refine the components of hospitalist HCUE training programs, such as the optimal number of supervised examinations, our program could serve as a reasonable comparative example: more rigorous than the program designed by Martin et al.5 but more feasible than ASE level 1 training.

The number and complexity of assessments taught in HCUE training programs will determine their duration. With ongoing advancements in HCUE technology, there is a growing list of potential assessments to choose from. Although HCUE training programs ought to include assessments with proven clinical applications, there are no trials of HCUE‐directed care to inform such decisions. In their absence, therefore, we chose 6 assessments based on the following 3 criteria. First, our assessments were otherwise not reliably available from routine clinical data, such as the physical examination. Second, our assessments were straightforward: easy to learn and simple to perform. Here, we based our reasoning on an expectation that the value of HCUE lies not in highly complex, state‐of‐the‐art assessmentswhich are best left to echocardiographers equipped with SEbut in simple, routine assessments made with highly portable machines that grant noncardiologists newfound access to point‐of‐care data.34 Third, our assessments were clinically pertinent and, where appropriate, defined by cut‐points at levels of severity that often lead to changes in management. We suspect that setting high cut‐points has the salutary effects of making assessments easier to learn and more accurate, because distinguishing mild abnormalities is likely the most challenging aspect of echocardiographic interpretation.35 Whether or not our choices of assessments, and their cut‐points, are optimal has yet to be determined by future research designed to study how they affect patient outcomes. Given our hospitalists' performance in the present study, these assessments seem worthy of such future research.

Our study had several limitations. We studied physicians and patients from only 1 hospital; similar studies performed in different settings, particularly among patients with different proportions and manifestations of disease, may find different results. Nevertheless, our sampling method of prospectively enrolling consecutive patients strengthens our findings. Some echocardiographic measurement methods used by our hospitalists differed in subtle ways from echocardiography guideline recommendations.35 We chose our methods (Table 2) for 2 reasons. First, whenever possible, we chose methods of interpretation that coincided with our local cardiologists'. Second, we chose simplicity over precision. For example, the biplane method of disks, or modified Simpson's rule, is the preferred volumetric method of calculating LA size.35 This method requires tracing the contours of the LA in 2 planes and then dividing the LA volume into stacked oval disks for calculation. We chose instead to train our hospitalists in a simpler method based on 2 linear measurements. Any loss of precision, however, was balanced by a large gain in simplicity. Regardless, minor variations in LA size are not likely to affect hospitalists' bedside evaluations. Finally, we did not validate the results of our reference standard (SE) by documenting interobserver reliability. Yet, because SE is generally accurate for the 6 cardiac abnormalities under study, the effect of this bias should be small.

These limitations can be addressed best by controlled trials of HCUE‐directed care. These trials will determine the clinical impact of hospitalist‐performed HCUE and, in turn, inform our design of HCUE training programs. As the current study shows, training hospitalists to participate in such trials is feasible: like other groups of noncardiologists, hospitalists can accurately perform HCUE after a brief training program. Whether or not hospitalists should perform HCUE requires further study.

Myocardial calcification is very rare and has been associated with metastatic calcium deposition. A 57‐year‐old woman with end‐stage renal disease (ESRD) due to hypertension on peritoneal dialysis, coronary artery disease, mechanical valve from mitral stenosis without history of rheumatic disease, atrial fibrillation, and a positive tuberculin skin test presented with tuberculous peritonitis (culture confirmed) and calcifications of her heart. Her chest film showed a retrocardiac calcified lesion (Figure 1). Chest computed tomography (CT) showed cardiac hypertrophy with calcification of the left atrium and ventricle (Figure 2). She began antituberculosis medications but she died 1 month later. At autopsy, the cardiac tissue confirmed endocardial and myocardial calcifications without tuberculum bacilli (Figure 3).

Figure 1

Figure 2

Figure 3

Her ESRD led to an elevated calcium‐phosphate product, which more commonly causes vascular calcifications (calciphylaxis), but can lead to calcification of the cardiac tissue.1 Some other possible causes include myocardial infarction, myocardial fibrosis, rheumatic carditis, and caseous necrosis from tuberculosis.2 Treatment for massive cardiac calcification includes endoatriectomy and replacement of the mitral valve.

Myocardial calcification is very rare and has been associated with metastatic calcium deposition. A 57‐year‐old woman with end‐stage renal disease (ESRD) due to hypertension on peritoneal dialysis, coronary artery disease, mechanical valve from mitral stenosis without history of rheumatic disease, atrial fibrillation, and a positive tuberculin skin test presented with tuberculous peritonitis (culture confirmed) and calcifications of her heart. Her chest film showed a retrocardiac calcified lesion (Figure 1). Chest computed tomography (CT) showed cardiac hypertrophy with calcification of the left atrium and ventricle (Figure 2). She began antituberculosis medications but she died 1 month later. At autopsy, the cardiac tissue confirmed endocardial and myocardial calcifications without tuberculum bacilli (Figure 3).

Figure 1

Figure 2

Figure 3

Her ESRD led to an elevated calcium‐phosphate product, which more commonly causes vascular calcifications (calciphylaxis), but can lead to calcification of the cardiac tissue.1 Some other possible causes include myocardial infarction, myocardial fibrosis, rheumatic carditis, and caseous necrosis from tuberculosis.2 Treatment for massive cardiac calcification includes endoatriectomy and replacement of the mitral valve.

Myocardial calcification is very rare and has been associated with metastatic calcium deposition. A 57‐year‐old woman with end‐stage renal disease (ESRD) due to hypertension on peritoneal dialysis, coronary artery disease, mechanical valve from mitral stenosis without history of rheumatic disease, atrial fibrillation, and a positive tuberculin skin test presented with tuberculous peritonitis (culture confirmed) and calcifications of her heart. Her chest film showed a retrocardiac calcified lesion (Figure 1). Chest computed tomography (CT) showed cardiac hypertrophy with calcification of the left atrium and ventricle (Figure 2). She began antituberculosis medications but she died 1 month later. At autopsy, the cardiac tissue confirmed endocardial and myocardial calcifications without tuberculum bacilli (Figure 3).

Figure 1

Figure 2

Figure 3

Her ESRD led to an elevated calcium‐phosphate product, which more commonly causes vascular calcifications (calciphylaxis), but can lead to calcification of the cardiac tissue.1 Some other possible causes include myocardial infarction, myocardial fibrosis, rheumatic carditis, and caseous necrosis from tuberculosis.2 Treatment for massive cardiac calcification includes endoatriectomy and replacement of the mitral valve.

Case Report

A 66‐year‐old woman with a history of breast cancer treated with lumpectomy, chemotherapy, and radiation presented to the emergency department with a 1‐week history of left eye pain, progressive fatigue, and numbness and tingling on the left upper face. One week prior to presentation, she experienced dull pain in her left eye, anorexia, vomiting, and numbness and tingling in her upper left face. She was diagnosed with sinusitis by a local physician and prescribed a nasal spray and an unknown antibiotic. She became progressively weaker and fatigued and then 2 days prior to admission she noticed red papules on her forehead. She presented to the emergency department 1 day prior to admission. In the emergency department, she was diagnosed with herpes zoster ophthalmicus, placed on acyclovir, acetaminophen/hydrocodone, ondansetron, and trifluridine eye drops, and discharged. Her symptoms worsened throughout the night and she became progressively more somnolent. She was brought to the emergency department again the following day and was found to be extremely somnolent and oriented only to person. The patient's past medical history was significant for lobular carcinoma in situ of the breast, which was diagnosed 22 years ago and treated with a lumpectomy. She had a recurrence of ductal and lobular carcinoma in‐situ 20 years after her initial diagnosis and was treated with 3 months of chemotherapy, completed 13 months prior to admission, and 6 months of radiation therapy, completed 6 months prior to admission. Her physical examination was remarkable for an erythematous maculopapular rash in the distribution of the ophthalmic division of the trigeminal nerve, swelling of the left orbit such that she could not open her eye without assistance, and white mucus‐like drainage from the left eye. The area around the eyelid was tender and the left sclera was pink. Extraocular movements were intact and the pupils were equal, round, and reactive to light and accommodation. Cranial nerves III to XII were intact bilaterally; cerebellar function, sensation, proprioception, and deep tendon reflexes were also intact. The patient did not have any meningismus.

On lumbar puncture in the emergency department (ED), the cerebrospinal fluid (CSF) from tube 4 was found to have a glucose concentration of 52 mg/dL (blood glucose of 111 mg/dL), a protein concentration of 90 mg/dL, a red blood cell (RBC) count of 70 cells/mL, and 16 nucleated cells/mL with 67% lymphocytes and 20% monocytes. Viral cultures and polymerase chain reaction (PCR) for herpes simplex virus (HSV)‐1, HSV‐2, and varicella zoster virus (VZV) were sent to the laboratory. Therapy with acyclovir, vancomycin, and cefotaxime was initiated. Magnetic resonance imaging (MRI) revealed leptomeningeal and dural enhancement involving the posterior fossa, which was read to be consistent with infectious meningitis; temporal lobe involvement was not seen (Figure 1).

Figure 1

Additional results from the lumbar puncture were received the following day. PCR for HSV‐1 and HSV‐2 was found to be negative, while PCR for VZV was found to be positive. Treatment with intravenous (IV) acyclovir was continued. The patient's clinical condition improved significantly by the morning after admission and she was found to be less somnolent and alert and oriented to person, place, and time. Her condition continued to improve and she was discharged 4 days after admission after her mental status returned to baseline; the patient subsequently completed a 21‐day course of 540 mg twice a day IV acyclovir.

In the 9 months following her initial hospitalization, the patient was admitted multiple times to an outside hospital for varicella zoster meningitis and herpes zoster ophthalmicus, with complete resolution of her symptoms after each hospitalization. However, 10 months after her initial hospitalization, the patient presented to our hospital with lethargy and was found to have a recurrence of her breast cancer with metastatic disease. She was subsequently diagnosed with carcinomatous meningitis and passed away shortly after this diagnosis.

Discussion

The development of clinically significant varicella zosterassociated meningoencephalitis after herpes zoster ophthalmicus is rare. Cerebrospinal fluid PCR has been shown to have a sensitivity and specificity >95% for diagnosing VZV encephalitis.3 The interpretation of the MRI was consistent with several case reports in the literature that also described enhancing meningeal lesions on MRI in patients with varicella encephalitis.3

While subclinical invasion of VZV into the central nervous system (CNS) is relatively common, with approximately one‐third of asymptomatic immunocompetent patients having a CSF PCR positive for VZV and 46% of patients demonstrating CSF leukocytosis, it is rare for patients to present with the serious clinical manifestations seen in this case.4 It is hypothesized that herpes zosterassociated meningoencephalitis most likely occurs when the zoster involves the ophthalmic branch of the trigeminal nerve, allowing for the spread of the virus to the tentorium through the recurrent nerve of Arnold, which branches off the ophthalmic division of the trigeminal nerve.5 On review of the literature, there are very few studies and no controlled trials on the optimal treatment of this complication, although an empirical treatment of 15 to 30 mg of acyclovir per kilogram of body weight for 10 days has been suggested.3 There have been several reports of rapid responses to IV acyclovir but, due to the rarity of this complication, to our knowledge, no studies have been conducted to determine the optimal treatment of herpes zosterassociated meningoencephalitis.3, 6 A similar case of meningoencephalitis has been described in a 5‐year‐old boy whose presentation was similar to that of our patient, with periorbital vesicular lesions and mental status changes including somnolence. This child was treated with acyclovir and made a full recovery.7

Several other CNS‐related manifestations of CN zoster have been reported, including development of the syndrome of inappropriate antidiuretic hormone, development of contralateral hemiparesis, and the coexistence of Ramsay‐Hunt syndrome and zoster encephalitis (Table 1). It is hypothesized that stimulation of the ophthalmic division of the trigeminal nerve by the zoster virus leads to excess antidiuretic hormone (ADH) secretion from the posterior pituitary, which results in the development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). To date, 2 cases of SIADH following a herpes zoster ophthalmicus infection have been reported.8, 9 Several cases of coexisting varicella zoster encephalitis and Ramsay‐Hunt syndrome have been reported. Ramsay‐Hunt syndrome, which is characterized by zoster oticus and peripheral facial nerve involvement, is a known complication of varicella zoster infection; however, coexistence of Ramsay‐Hunt syndrome and varicella encephalitis is rare and has only been reported in 9 patients.3, 10 To our knowledge, the coexistence of these 2 complications has not been reported in a patient with herpes zoster ophthalmicus. Contralateral hemiparesis following herpes zoster infection has been reported in 2 patients, both of whom were treated with acyclovir, resulting in partial recovery. Other CNS complications of herpes zoster include myelitis, large‐vessel encephalitis, and small‐vessel encephalitis.3

It has also been shown that patients with compromised immune systems are at a greater risk for recurrence of the herpes zoster infection and for development of zoster encephalitis. It is estimated that mortality rates from zoster encephalitis are as high as 25%, with an average rate of 10%, and are determined by the patient's immune status.3, 4 Our particular patient was immunosuppressed, given that she had been treated for breast cancer with radiation 6 months prior to admission and chemotherapy 13 months prior to admission, putting her at an increased risk of developing encephalitis. There have been reports of herpes‐associated meningoencephalitis in patients with systemic cancers, including adenocarcinoma of the lung, prostate cancer, chronic lymphocytic leukemia, and lymphoma; the response to treatment with acyclovir was favorable in these cases.11 It has also been established that patients with human immunodeficiency virus (HIV) are at increased risk for developing meningoencephalitis after herpes zoster infection as a result of their compromised immune systems.12 In addition to having a higher mortality rate, patients with compromised immune systems are at a greater risk for recurrence of herpes zoster, which leads to an additional increase in mortality, as was seen in the case of this particular patient.

Case Report

A 66‐year‐old woman with a history of breast cancer treated with lumpectomy, chemotherapy, and radiation presented to the emergency department with a 1‐week history of left eye pain, progressive fatigue, and numbness and tingling on the left upper face. One week prior to presentation, she experienced dull pain in her left eye, anorexia, vomiting, and numbness and tingling in her upper left face. She was diagnosed with sinusitis by a local physician and prescribed a nasal spray and an unknown antibiotic. She became progressively weaker and fatigued and then 2 days prior to admission she noticed red papules on her forehead. She presented to the emergency department 1 day prior to admission. In the emergency department, she was diagnosed with herpes zoster ophthalmicus, placed on acyclovir, acetaminophen/hydrocodone, ondansetron, and trifluridine eye drops, and discharged. Her symptoms worsened throughout the night and she became progressively more somnolent. She was brought to the emergency department again the following day and was found to be extremely somnolent and oriented only to person. The patient's past medical history was significant for lobular carcinoma in situ of the breast, which was diagnosed 22 years ago and treated with a lumpectomy. She had a recurrence of ductal and lobular carcinoma in‐situ 20 years after her initial diagnosis and was treated with 3 months of chemotherapy, completed 13 months prior to admission, and 6 months of radiation therapy, completed 6 months prior to admission. Her physical examination was remarkable for an erythematous maculopapular rash in the distribution of the ophthalmic division of the trigeminal nerve, swelling of the left orbit such that she could not open her eye without assistance, and white mucus‐like drainage from the left eye. The area around the eyelid was tender and the left sclera was pink. Extraocular movements were intact and the pupils were equal, round, and reactive to light and accommodation. Cranial nerves III to XII were intact bilaterally; cerebellar function, sensation, proprioception, and deep tendon reflexes were also intact. The patient did not have any meningismus.

On lumbar puncture in the emergency department (ED), the cerebrospinal fluid (CSF) from tube 4 was found to have a glucose concentration of 52 mg/dL (blood glucose of 111 mg/dL), a protein concentration of 90 mg/dL, a red blood cell (RBC) count of 70 cells/mL, and 16 nucleated cells/mL with 67% lymphocytes and 20% monocytes. Viral cultures and polymerase chain reaction (PCR) for herpes simplex virus (HSV)‐1, HSV‐2, and varicella zoster virus (VZV) were sent to the laboratory. Therapy with acyclovir, vancomycin, and cefotaxime was initiated. Magnetic resonance imaging (MRI) revealed leptomeningeal and dural enhancement involving the posterior fossa, which was read to be consistent with infectious meningitis; temporal lobe involvement was not seen (Figure 1).

Figure 1

Additional results from the lumbar puncture were received the following day. PCR for HSV‐1 and HSV‐2 was found to be negative, while PCR for VZV was found to be positive. Treatment with intravenous (IV) acyclovir was continued. The patient's clinical condition improved significantly by the morning after admission and she was found to be less somnolent and alert and oriented to person, place, and time. Her condition continued to improve and she was discharged 4 days after admission after her mental status returned to baseline; the patient subsequently completed a 21‐day course of 540 mg twice a day IV acyclovir.

In the 9 months following her initial hospitalization, the patient was admitted multiple times to an outside hospital for varicella zoster meningitis and herpes zoster ophthalmicus, with complete resolution of her symptoms after each hospitalization. However, 10 months after her initial hospitalization, the patient presented to our hospital with lethargy and was found to have a recurrence of her breast cancer with metastatic disease. She was subsequently diagnosed with carcinomatous meningitis and passed away shortly after this diagnosis.

Discussion

The development of clinically significant varicella zosterassociated meningoencephalitis after herpes zoster ophthalmicus is rare. Cerebrospinal fluid PCR has been shown to have a sensitivity and specificity >95% for diagnosing VZV encephalitis.3 The interpretation of the MRI was consistent with several case reports in the literature that also described enhancing meningeal lesions on MRI in patients with varicella encephalitis.3

While subclinical invasion of VZV into the central nervous system (CNS) is relatively common, with approximately one‐third of asymptomatic immunocompetent patients having a CSF PCR positive for VZV and 46% of patients demonstrating CSF leukocytosis, it is rare for patients to present with the serious clinical manifestations seen in this case.4 It is hypothesized that herpes zosterassociated meningoencephalitis most likely occurs when the zoster involves the ophthalmic branch of the trigeminal nerve, allowing for the spread of the virus to the tentorium through the recurrent nerve of Arnold, which branches off the ophthalmic division of the trigeminal nerve.5 On review of the literature, there are very few studies and no controlled trials on the optimal treatment of this complication, although an empirical treatment of 15 to 30 mg of acyclovir per kilogram of body weight for 10 days has been suggested.3 There have been several reports of rapid responses to IV acyclovir but, due to the rarity of this complication, to our knowledge, no studies have been conducted to determine the optimal treatment of herpes zosterassociated meningoencephalitis.3, 6 A similar case of meningoencephalitis has been described in a 5‐year‐old boy whose presentation was similar to that of our patient, with periorbital vesicular lesions and mental status changes including somnolence. This child was treated with acyclovir and made a full recovery.7

Several other CNS‐related manifestations of CN zoster have been reported, including development of the syndrome of inappropriate antidiuretic hormone, development of contralateral hemiparesis, and the coexistence of Ramsay‐Hunt syndrome and zoster encephalitis (Table 1). It is hypothesized that stimulation of the ophthalmic division of the trigeminal nerve by the zoster virus leads to excess antidiuretic hormone (ADH) secretion from the posterior pituitary, which results in the development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). To date, 2 cases of SIADH following a herpes zoster ophthalmicus infection have been reported.8, 9 Several cases of coexisting varicella zoster encephalitis and Ramsay‐Hunt syndrome have been reported. Ramsay‐Hunt syndrome, which is characterized by zoster oticus and peripheral facial nerve involvement, is a known complication of varicella zoster infection; however, coexistence of Ramsay‐Hunt syndrome and varicella encephalitis is rare and has only been reported in 9 patients.3, 10 To our knowledge, the coexistence of these 2 complications has not been reported in a patient with herpes zoster ophthalmicus. Contralateral hemiparesis following herpes zoster infection has been reported in 2 patients, both of whom were treated with acyclovir, resulting in partial recovery. Other CNS complications of herpes zoster include myelitis, large‐vessel encephalitis, and small‐vessel encephalitis.3

It has also been shown that patients with compromised immune systems are at a greater risk for recurrence of the herpes zoster infection and for development of zoster encephalitis. It is estimated that mortality rates from zoster encephalitis are as high as 25%, with an average rate of 10%, and are determined by the patient's immune status.3, 4 Our particular patient was immunosuppressed, given that she had been treated for breast cancer with radiation 6 months prior to admission and chemotherapy 13 months prior to admission, putting her at an increased risk of developing encephalitis. There have been reports of herpes‐associated meningoencephalitis in patients with systemic cancers, including adenocarcinoma of the lung, prostate cancer, chronic lymphocytic leukemia, and lymphoma; the response to treatment with acyclovir was favorable in these cases.11 It has also been established that patients with human immunodeficiency virus (HIV) are at increased risk for developing meningoencephalitis after herpes zoster infection as a result of their compromised immune systems.12 In addition to having a higher mortality rate, patients with compromised immune systems are at a greater risk for recurrence of herpes zoster, which leads to an additional increase in mortality, as was seen in the case of this particular patient.

Case Report

A 66‐year‐old woman with a history of breast cancer treated with lumpectomy, chemotherapy, and radiation presented to the emergency department with a 1‐week history of left eye pain, progressive fatigue, and numbness and tingling on the left upper face. One week prior to presentation, she experienced dull pain in her left eye, anorexia, vomiting, and numbness and tingling in her upper left face. She was diagnosed with sinusitis by a local physician and prescribed a nasal spray and an unknown antibiotic. She became progressively weaker and fatigued and then 2 days prior to admission she noticed red papules on her forehead. She presented to the emergency department 1 day prior to admission. In the emergency department, she was diagnosed with herpes zoster ophthalmicus, placed on acyclovir, acetaminophen/hydrocodone, ondansetron, and trifluridine eye drops, and discharged. Her symptoms worsened throughout the night and she became progressively more somnolent. She was brought to the emergency department again the following day and was found to be extremely somnolent and oriented only to person. The patient's past medical history was significant for lobular carcinoma in situ of the breast, which was diagnosed 22 years ago and treated with a lumpectomy. She had a recurrence of ductal and lobular carcinoma in‐situ 20 years after her initial diagnosis and was treated with 3 months of chemotherapy, completed 13 months prior to admission, and 6 months of radiation therapy, completed 6 months prior to admission. Her physical examination was remarkable for an erythematous maculopapular rash in the distribution of the ophthalmic division of the trigeminal nerve, swelling of the left orbit such that she could not open her eye without assistance, and white mucus‐like drainage from the left eye. The area around the eyelid was tender and the left sclera was pink. Extraocular movements were intact and the pupils were equal, round, and reactive to light and accommodation. Cranial nerves III to XII were intact bilaterally; cerebellar function, sensation, proprioception, and deep tendon reflexes were also intact. The patient did not have any meningismus.

On lumbar puncture in the emergency department (ED), the cerebrospinal fluid (CSF) from tube 4 was found to have a glucose concentration of 52 mg/dL (blood glucose of 111 mg/dL), a protein concentration of 90 mg/dL, a red blood cell (RBC) count of 70 cells/mL, and 16 nucleated cells/mL with 67% lymphocytes and 20% monocytes. Viral cultures and polymerase chain reaction (PCR) for herpes simplex virus (HSV)‐1, HSV‐2, and varicella zoster virus (VZV) were sent to the laboratory. Therapy with acyclovir, vancomycin, and cefotaxime was initiated. Magnetic resonance imaging (MRI) revealed leptomeningeal and dural enhancement involving the posterior fossa, which was read to be consistent with infectious meningitis; temporal lobe involvement was not seen (Figure 1).

Figure 1

Additional results from the lumbar puncture were received the following day. PCR for HSV‐1 and HSV‐2 was found to be negative, while PCR for VZV was found to be positive. Treatment with intravenous (IV) acyclovir was continued. The patient's clinical condition improved significantly by the morning after admission and she was found to be less somnolent and alert and oriented to person, place, and time. Her condition continued to improve and she was discharged 4 days after admission after her mental status returned to baseline; the patient subsequently completed a 21‐day course of 540 mg twice a day IV acyclovir.

In the 9 months following her initial hospitalization, the patient was admitted multiple times to an outside hospital for varicella zoster meningitis and herpes zoster ophthalmicus, with complete resolution of her symptoms after each hospitalization. However, 10 months after her initial hospitalization, the patient presented to our hospital with lethargy and was found to have a recurrence of her breast cancer with metastatic disease. She was subsequently diagnosed with carcinomatous meningitis and passed away shortly after this diagnosis.

Discussion

The development of clinically significant varicella zosterassociated meningoencephalitis after herpes zoster ophthalmicus is rare. Cerebrospinal fluid PCR has been shown to have a sensitivity and specificity >95% for diagnosing VZV encephalitis.3 The interpretation of the MRI was consistent with several case reports in the literature that also described enhancing meningeal lesions on MRI in patients with varicella encephalitis.3

While subclinical invasion of VZV into the central nervous system (CNS) is relatively common, with approximately one‐third of asymptomatic immunocompetent patients having a CSF PCR positive for VZV and 46% of patients demonstrating CSF leukocytosis, it is rare for patients to present with the serious clinical manifestations seen in this case.4 It is hypothesized that herpes zosterassociated meningoencephalitis most likely occurs when the zoster involves the ophthalmic branch of the trigeminal nerve, allowing for the spread of the virus to the tentorium through the recurrent nerve of Arnold, which branches off the ophthalmic division of the trigeminal nerve.5 On review of the literature, there are very few studies and no controlled trials on the optimal treatment of this complication, although an empirical treatment of 15 to 30 mg of acyclovir per kilogram of body weight for 10 days has been suggested.3 There have been several reports of rapid responses to IV acyclovir but, due to the rarity of this complication, to our knowledge, no studies have been conducted to determine the optimal treatment of herpes zosterassociated meningoencephalitis.3, 6 A similar case of meningoencephalitis has been described in a 5‐year‐old boy whose presentation was similar to that of our patient, with periorbital vesicular lesions and mental status changes including somnolence. This child was treated with acyclovir and made a full recovery.7

Several other CNS‐related manifestations of CN zoster have been reported, including development of the syndrome of inappropriate antidiuretic hormone, development of contralateral hemiparesis, and the coexistence of Ramsay‐Hunt syndrome and zoster encephalitis (Table 1). It is hypothesized that stimulation of the ophthalmic division of the trigeminal nerve by the zoster virus leads to excess antidiuretic hormone (ADH) secretion from the posterior pituitary, which results in the development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). To date, 2 cases of SIADH following a herpes zoster ophthalmicus infection have been reported.8, 9 Several cases of coexisting varicella zoster encephalitis and Ramsay‐Hunt syndrome have been reported. Ramsay‐Hunt syndrome, which is characterized by zoster oticus and peripheral facial nerve involvement, is a known complication of varicella zoster infection; however, coexistence of Ramsay‐Hunt syndrome and varicella encephalitis is rare and has only been reported in 9 patients.3, 10 To our knowledge, the coexistence of these 2 complications has not been reported in a patient with herpes zoster ophthalmicus. Contralateral hemiparesis following herpes zoster infection has been reported in 2 patients, both of whom were treated with acyclovir, resulting in partial recovery. Other CNS complications of herpes zoster include myelitis, large‐vessel encephalitis, and small‐vessel encephalitis.3

It has also been shown that patients with compromised immune systems are at a greater risk for recurrence of the herpes zoster infection and for development of zoster encephalitis. It is estimated that mortality rates from zoster encephalitis are as high as 25%, with an average rate of 10%, and are determined by the patient's immune status.3, 4 Our particular patient was immunosuppressed, given that she had been treated for breast cancer with radiation 6 months prior to admission and chemotherapy 13 months prior to admission, putting her at an increased risk of developing encephalitis. There have been reports of herpes‐associated meningoencephalitis in patients with systemic cancers, including adenocarcinoma of the lung, prostate cancer, chronic lymphocytic leukemia, and lymphoma; the response to treatment with acyclovir was favorable in these cases.11 It has also been established that patients with human immunodeficiency virus (HIV) are at increased risk for developing meningoencephalitis after herpes zoster infection as a result of their compromised immune systems.12 In addition to having a higher mortality rate, patients with compromised immune systems are at a greater risk for recurrence of herpes zoster, which leads to an additional increase in mortality, as was seen in the case of this particular patient.

A 47‐year‐old male presented to a community hospital with 5 weeks of daily fevers, accompanied by headache, myalgias, and malaise. He reported that his symptoms began abruptly 2 days after a weekend of camping in Connecticut.

This patient describes the onset of undifferentiated fever 2 days after a weekend of camping. Few infectious diseases have such short incubation periods, and either the accuracy of the history or the relationship of the camping trip to the present illness is thus questionable. However, more information about the onset and nature of the illness, and details about food, animal, water, mud, cave, wood chopping, and other environmental exposures during his trip is required. The exact dates of the camping trip may be helpful, as there is clear seasonality to vector‐borne diseases such as Lyme disease, babesiosis, ehrlichiosis, and rickettsial infections. Conditions unrelated to his camping trip, such as malignancies, rheumatologic conditions, and other infectious causes of prolonged fever, such as tuberculosis, endocarditis, or osteomyelitis, are more likely, given the duration of fever.

The fevers were accompanied by chills, without rigors, and subjectively worsened over the first 2 days. At that point, the patient began taking his temperature, and noted fevers of 38.5C to 40C occurring once or twice daily, generally in the afternoon or evening. The patient did not recall tick bites but did not carefully examine himself for ticks; he reported numerous mosquito bites during the trip. The patient camped in a tent and grilled meats and other food he had brought in a cooler. No family members or other travelers became ill. He denied spelunking, but had collected wood for camp fires, and acknowledged swimming in a freshwater pond during his trip, which occurred in August.

West Nile fever, St. Louis encephalitis, and eastern equine encephalitis are transmitted by mosquitoes in New England, but are unlikely causes of prolonged fever. Water exposure suggests the possibility of leptospirosis, and wood exposure suggests blastomycosis, but this usually presents with a pulmonary syndrome. Food‐borne illness seems unlikely. While no aspect of the history has pinpointed a specific diagnosis, exploring the progression of symptoms may offer a clue, and if he has undergone any previous evaluation, the results may significantly alter the differential diagnosis. For example, arthritis may develop weeks after fever in adult‐onset Still's disease, negative blood cultures would lower the probability of endocarditis, and common sites of pyrogenic malignancies (eg, liver, kidneys, and especially lymph nodes) may already have been imaged.

During the first 3 weeks of illness, the patient experienced daily fever and a gradual, 10‐pound weight loss. Over the next 10 days, he sought medical attention at 3 emergency departments. At one, a head computed tomography (CT) showed possible sinusitis, and he was prescribed a 7‐day course of clarithromycin, which he took without any improvement. At 2 others, he was told that his laboratory studies, and a CT of the abdomen, were normal, and that he had a viral syndrome. Several days later, and 5 weeks after the onset of symptoms, the development of dull right upper‐quadrant pain and mild nausea without vomiting prompted the current presentation to the community hospital. He reported several years of loose stools, but denied rash, arthritis, diarrhea, neck stiffness, cough, or other complaints.

A detailed past medical, social, and family history is required, with particular attention to ethnicity; immunocompromising conditions such as splenectomy or corticosteroid use; undiagnosed febrile diseases; severe, unusual, or recurrent infections; medication use; diet; sexual history; pet exposures; and any personal or family history of cancer. The development of right upper‐quadrant pain mandates attention to risk factors for viral hepatitis, known biliary pathology, or travel that might predispose the patient to pyogenic or amoebic liver abscess, and hematochezia, which could suggest a malignancy metastatic to the liver. Additionally, chronic diarrhea with new right upper‐quadrant pain may represent inflammatory bowel disease complicated by primary sclerosing cholangitis (PSC).

The patient was a Caucasian male of Mediterranean ancestry with thalassemia minor. He had undergone dilation of a benign esophageal stricture, but no surgical procedures, and he had never experienced unexplained fever or unusual infections. Medication exposure was limited to occasional use of acetaminophen for fever, and he had no known allergies. His diet was unremarkable and included no well water or unpasteurized dairy products. He denied risk factors for tuberculosis. He drank 2 to 10 beers a day, 5 times a week, had last smoked 10 years previously, and had never used illicit drugs. He denied any high‐risk sexual contacts and was monogamous with his wife, with whom he had 2 children. The family owned no pets and no relatives had suffered from malignant, rheumatologic, or febrile illness, with the exception of hand, foot, and mouth infection in an infant son, 1 year previously. The patient had never traveled outside of New England.

The history has uncovered several clues, but their relevance is doubtful. His ethnicity suggests possible familial Mediterranean fever, but recurrent abdominal pain and polyserositis, rather than a single prolonged episode, would be expected with this disease. A transfusion history should be obtained to explore the possibility of viral hepatitis. While iron overload can predispose patients to various infections including liver abscess, thalassemia minor should not require transfusion. Esophageal stricture could conceivably be due to histoplasmosis (complicated by mediastinal fibrosis) or tuberculosis, but is probably unrelated to his present illness. His excessive alcohol intake increases his risk for esophageal cancer and liver disease, but it is unlikely that metastatic disease to the liver would present with fever without preceding dysphagia, or that alcoholic hepatitis could have escaped detection after evaluations by several physicians.

We need to learn the details of the patient's physical examination. Given the development of right upper‐quadrant pain, I would particularly like to know if he had hepatosplenomegaly and if a Murphy's sign was present.

His temperature ranged from 36.9C to 39.8C, his pulse was 76 beats per minute with minimal elevations during fever spikes, and his respirations were 18 per minute. His blood pressure was 105/70 mm Hg. He was a well‐developed, overweight male with scleral icterus. He had good dentition and an oropharynx free of lesions. Cardiac examination demonstrated a regular rhythm with a normal S1 and S2, without murmurs or peripheral stigmata of infectious endocarditis. A smooth, minimally tender liver edge was palpable 2 cm below the costal margin; the spleen was nonpalpable. Murphy's sign was absent. There was no lymphadenopathy or rash. He had multiple, shallow, uninfected lacerations of both hands in various stages of healing. The remainder of his examination was normal.

The patient has obvious liver involvement. The pulse‐temperature dissociation suggests a variety of infections, including salmonellosis, psittacosis, typhoid fever, leptospirosis, tularemia, brucellosis, legionellosis, and mycoplasma pneumoniae infection. The patient should be asked how and when he injured his hands, as fresh water exposure can transmit leptospirosis across broken skin. However, while severe leptospirosis can cause fever and jaundice, the long duration of illness is not typical. The cryptogenic form of tularemiawhich can manifest as a typhoidal illnessshould be considered, given that tularemia is present in the area the patient visited; he should be asked about exposure to rabbits.

At this point, I would like to see a standard biochemical profile, a liver panel, a complete blood count and differential, urinalysis, chest X‐ray, and an electrocardiogram. I would examine thick and thin Wright‐Giemsa‐stained smears for evidence of babesiosis. Blood cultures should be held for at least 2 weeks to recover fastidious organisms like Francisella tularensis and Brucella sp. Bone marrow cultures should be obtained; they are more sensitive for mycobacteria and Brucella, and may also yield fungal pathogens. Serologies for a variety of infectious diseases, such as leptospirosis, typhoid fever, and tularemia, will be required if other diagnostic tests are unrevealing.

His white cell count was 8,100/L, with a normal differential, and his hemoglobin was 10 g/dL (normal range, 1417), with a mean corpuscular hemoglobin of 63 m³ (normal range, 8298). The platelet count was 303,000/L. Serum electrolytes were normal. His aspartate aminotransferase was 58 U/L and his alanine aminotransferase was 60 U/L (normal range for both, 1045). Bilirubin was 2.6 mg/dL (normal, <1.2); direct bilirubin was 0.9 mg/dL. Alkaline phosphatase was 150 U/L. Lactate dehydrogenase was 342 U/L (normal range, 2251). A lipase was 62 U/L. International normalized ratio (INR) was 1.4 with an activated partial thromboplastin time (aPTT) of 52 seconds (normal range, 2533). Erythrocyte sedimentation rate (ESR) was 50 mm/hour (normal range, 015). Iron studies showed a suppressed iron and iron‐binding capacity and elevated haptoglobin and ferritin (1878 ng/L; normal range, 22322). Several blood cultures obtained at admission showed no growth after 48 hours of incubation.

The anemia, low mean cell volume (MCV), and elevated ferritin and ESR are consistent with anemia of chronic disease, superimposed upon thalassemia minor. Transaminase elevations occur in a plethora of infectious processes. The elevated INR and aPTT are concerning, and may indicate a septic or malignant process with disseminated intravascular coagulation (DIC). While there is no mention of clinical DIC, it would be appropriate to obtain D‐dimers, fibrin degradation products, and a fibrinogen level. The platelet count is normal, which is reassuring.

Before initiating any empiric antimicrobials, I would obtain an abdominal ultrasound, and possibly an abdominal CT. Hepatitis (especially B and C), cytomegalovirus, and Epstein‐Barr virus serologies should be obtained. A variety of conditions including leptospirosis, tularemia, and babesiosis are possible; specific laboratory testing is required to guide therapy.

Ultrasound showed a thickened gallbladder; the liver was slightly enlarged with normal echotexture. Magnetic resonance cholangiopancreatography (MRCP) showed diffuse sequential beading and scarring of his extrahepatic biliary ducts.

There is no evidence of biliary stones, intrahepatic tumor, or abscess to explain the fever and hepatitis, although it would be helpful to know what other abdominal structures were imaged. The MRCP finding increases my suspicion of PSC, possibly complicated by infection, although the biliary abnormalities may be incidental, and an unrelated process may be responsible for the clinical presentation.

His physicians considered the possibilities of PSC and cholangiopathy due to as‐yet undiagnosed acquired immunodeficiency syndrome. Ampicillin‐sulbactam, ceftazidime, and gentamicin were administered for possible bacterial cholangitis, and endoscopic retrograde cholangiopancreatography was performed. This procedure showed only slight narrowing of his common bile duct, which was felt to be a normal variant. He felt no better after several days of antibiotic therapy, and was transferred to a tertiary care center for further evaluation. Repeat physical exam and laboratory studies were essentially unchanged. The patient explained that his hand lacerations were sustained during his work as a butcher who worked with lamb, beef, rabbit, and poultry. He rarely wore protective gloves because they induced contact dermatitis.

Tularemia becomes more likely given his history of rabbit butchering. Salmonellosis and leptospirosis also remain possible. Typhoid fever and brucellosis are unlikely unless the patient worked with imported exotic animals. At this point, given the systemic illness, empiric antibacterial therapy is reasonable. Of the chosen antimicrobials, only the gentamicin would reliably treat tularemia. I would stop ampicillin‐sulbactam and ceftazidime and replace gentamicin with ciprofloxacin, an effective and better‐tolerated agent for tularemia. Cultures of blood and bone marrow aspirate should be obtained. Stool should be cultured for Salmonella. Tularemia, leptospirosis, and typhoid serologies should be sent to a reference laboratory. At this point in the patient's illness, high‐titered antibodies should be present. However, it would be ideal to compare titers with those from previous serum sample, if possible.

The patient's antimicrobials were narrowed to doxycycline alone, for suspected zoonotic infection, but his fevers were unchanged after 1 week of treatment. Hepatitis serologies, human immunodeficiency virus (HIV) antibody, and smears for ehrlichiosis and babesiosis were negative. He had a positive immunoglobulin (Ig)G and a negative IgM for Epstein‐Barr virus and cytomegalovirus. Tularemia, ehrlichiosis, leptospirosis, brucellosis, and Query fever (Q fever) serologies were ordered. The elevated aPTT did not correct when his serum was mixed with normal serum. Thrombin was normal; factor VIII, von Willebrand (VW) factor, and VW cofactor were mildly elevated. Lupus anticoagulant was detected. A hepatologist declined to obtain a liver biopsy, citing the elevated aPTT and pending serologies. Given his clinical stability, the patient was discharged on doxycycline to await further results.

My highest suspicion is for tularemia, and I would switch antibiotic treatment to ciprofloxacin, awaiting serological results. Some in vitro studies have suggested that F. tularensis may often be resistant to doxycycline, and recent clinical experience has shown fluoroquinolones are superior to doxycycline in the treatment of tularemia.

His serologic results were as follows: tularemia, 1:32 (positive, 1:128); ehrlichia, 1:128 (granulocytic) and <1:64 (monocytic; normal for both, <1:64); leptospira, agglutinated nonspecifically; Brucella IgG and IgM 1 (negative, <9), Q fever (coxiella) IgG 1 + 2, IgM 1 + 2, all positive at 1:256 (<1:16). A transesophageal echocardiogram showed no evidence of endocarditis. The patient was treated with 10 weeks of doxycycline for Q fever hepatitis. His fever, headache, and laboratory abnormalities resolved, and he remained well after the completion of therapy.

The serologies suggest the patient had Coxiella burnetii hepatitis, and illustrate the value of a precise exposure history. Most butchers work only with muscle tissue and have a negligible risk of Q fever. In retrospect, it became clear that he worked part‐time in a slaughterhouse, where highly infectious reproductive tract fluids can dry and aerosolize.

Commentary

Q fever was proposed as the name for a febrile illness affecting Australian slaughterhouse workers in 1937.1 The etiologic agent, C. burnetii, is a small, gram‐negative, obligate intracellular proteobacterium that exists in 2 distinct phases, specializing either in entering or persisting in macrophage lysosomes.2 Additionally, spores are formed and can persist in soil.

Q fever is an uncommonly recognized disease, in part because most infected persons have no symptoms or mild symptoms.3 In the United States, the estimated annual incidence has been 0.28 per million (about 50 cases per year) since 1999, when Q fever became a reportable disease due to bioterrorism concerns. In France, more frequent farming of goats and sheep may be responsible for the much higher annual incidence of 500 per million.4 Spread is usually occupational, via aerosol contact with the dried reproductive tract secretions of animals (mainly cattle, sheep, and goats), in a slaughterhouse or farm setting. However, wind‐borne dust can carry spores long distances, and spread can occur from household pets, unpasteurized dairy products, laboratory work, and possibly ticks.3 More than 30 cases have been reported in military personnel deployed to Iraq and Afghanistan, several without obvious exposures.5 One review noted a single reported case of intradermal inoculation,3 making this patient's lacerations a possible site of infection, but he was also at risk for inhalational exposurewhen he was later asked about the details of his work, he acknowledged working at a slaughterhouse as well as a supermarket.

Symptomatic patients are male in 77% of cases, can usually identify an occupational exposure, and have a mean age of 50 years.4 Fever, which lasts 5 to 57 days, as well as fatigue and headaches, begin after a 1‐week to 3‐week incubation period. Atypical pneumonia or rash may occur; meningoencephalitis and myocarditis portend a worse prognosis. As with this patient, 45% to 85% of patients suffer from hepatitis, although few have an abnormal bilirubin.3 Liver biopsy usually reveals granulomas, which may have a classic doughnut hole appearance,2, 3 although this patient ultimately received a diagnosis without the procedure. Acute Q fever rarely (5%) requires hospitalization, and fatalities are extremely rare.3

Chronic infection (ie, lasting >6 months) most often occurs as endocarditis, although chronic hepatitis, osteomyelitis, and infections of other sites occur. Interestingly, this patient's lupus anticoagulant may have been related to his underlying illness, as autoantibodies frequently occur in Q fever, especially in patients with hepatitis, many of whom develop smooth muscle antibodies, a positive Coombs test, antiprothrombinase, or other autoantibodies,3 and there is a high incidence of antiphospholipid antibodies, particularly anticardiolipin and lupus anticoagulant antibodies.6

Because C. burnetii is an obligate intracellular pathogen, culture requires either tissue or live animal inoculation, and the diagnosis is usually made serologically. Paired sera demonstrating seroconversion or a 4‐fold increase in titers are most conclusive, but a single sample may be used. Anti‐phase II antibodies are detectable in 90% of patients within 3 weeks of infection3 and peak at 2 months5; this patient's phase II sera (IgG > 1:200, IgM > 1:50) are said to be 100% predictive for acute Q fever.3 High‐titer anti‐phase I antibodies, in contrast, indicate chronic infection, and a titer 1:800 is one of the modified Duke criteria for endocarditis.5

Acute Q fever is generally treated with doxycycline for 14 days, although prolonged therapy may be advisable to prevent endocarditis if preexisting valvular lesions are present.2, 5 Fluoroquinolones are another option and may be especially useful for meningoencephalitis.5 Because acute Q fever is generally self‐limited, demonstrating a clear benefit to antibiotic therapy is difficult. The available evidence, which was largely obtained from Q fever pneumonia patients, suggests that tetracycline therapy shortens fever duration.3 Patients with Q fever hepatitis may have a protracted course. On the basis of anecdotal reports, some experts add prednisone (tapered from 40 mg daily over a week) for patients with Q fever hepatitis who fail to respond to doxycycline promptly.3 While this patient's fever was unchanged after a week of therapy, he was well into his treatment course when his diagnosis was ultimately confirmed. His physicians felt that prednisone would be of uncertain benefit and opted not to administer it.

Treatment of Q fever endocarditis is often delayed by the combination of negative blood cultures and a low (12%) rate of vegetation formation, increasing the risk of morbidity and mortality.3 Tetracycline monotherapy is associated with a greater than 50% risk of death,5 and even 4 years of treatment may fail to sterilize valve tissue.3 However, if hydroxychloroquine is given with doxycycline for at least 18 months to alkalize lysosomes and improve bacterial killing, the mortality rate can be lowered to about 5%.3, 5 Patients should be warned of the risk of photosensitivity, and monitored for retinal toxicity2 and serologic evidence of relapse.5

Before serologic results confirmed the diagnosis of Q fever, both the patient's clinicians and the discussant had to craft an antibiotic regimen for a suspected zoonosis. The patient received doxycycline, a good choice for leptospirosis,7 brucellosis,8 tularemia,9 and Q fever,3 all possible after livestock exposure, as well as ehrlichiosis.10 The discussant, who suspected tularemia, worried about the possibility of doxycycline resistance and selected ciprofloxacin instead. While fluoroquinolones are probably superior to doxycycline for mild to moderate tularemia,11, 12 aminoglycosides would be preferred for severe disease,9 and ciprofloxacin experience in leptospirosis7 and ehrlichiosis10 is limited. Neither selection would be optimal for brucellosis, for which either doxycycline or ciprofloxacin should be combined with another agent such as rifampin.8 The most reasonable empiric regimen is debatable, but in the absence of pathognomonic findings of tularemia, his treating physicians favored the broader activity of doxycycline.

Ultimately, the choice of antibiotics in this case hinged on the details of the patient's occupational exposures. His first 2 courses of antibiotics were based not on his exposure history, but on radiographic findings that were later proven spurious. The regimens selected by the discussant and by physicians at the referral hospital both targeted pathogens suggested by the patient's occupational history instead, but both were missing parts of the puzzle as well. The discussant thought the patient performed commercial butcher‐shop work, which is only rarely13 mentioned in the context of Q fever transmission. Several of the admitting physicians at the referral hospital were unaware of the importance of the butcher/slaughterhouse‐worker distinction. Physicians need a detailed understanding of both the exposure history and the biology of possible pathogens to craft an optimal differential diagnosis and empiric antibiotic regimen.

On the other hand, in most patients with fever of unknown origin (FUO; ie, >3 weeks with temperature >38.3 on multiple occasions, without a diagnosis after a weeklong evaluation),14 empiric antibiotic therapy is rarely a wise intervention. Clinicians should avoid blind administration of antibiotics as a diagnostic tool, given the inability to distinguish clinical responses from spontaneous resolution, or pinpoint a specific cause and thus a precise treatment plan and duration. However, empiric tetracyclines have been employed when intracellular pathogens were a suspected cause of FUO, as in one series of French patients in which Q fever was common.15 In this patient's case, no specific finding pointed to Q fever before the serologies became available, but the rare infections considered in this case can be considered doxycycline‐deficient states, meaning that empiric tetracycline therapy often leads to improvement. Recognizing doxycycline deficiency can guide therapy while definitive results are pending, and empiric doxycycline is particularly important if potentially aggressive zoonoses, such as Rocky Mountain spotted fever, are suspected.

A 47‐year‐old male presented to a community hospital with 5 weeks of daily fevers, accompanied by headache, myalgias, and malaise. He reported that his symptoms began abruptly 2 days after a weekend of camping in Connecticut.

This patient describes the onset of undifferentiated fever 2 days after a weekend of camping. Few infectious diseases have such short incubation periods, and either the accuracy of the history or the relationship of the camping trip to the present illness is thus questionable. However, more information about the onset and nature of the illness, and details about food, animal, water, mud, cave, wood chopping, and other environmental exposures during his trip is required. The exact dates of the camping trip may be helpful, as there is clear seasonality to vector‐borne diseases such as Lyme disease, babesiosis, ehrlichiosis, and rickettsial infections. Conditions unrelated to his camping trip, such as malignancies, rheumatologic conditions, and other infectious causes of prolonged fever, such as tuberculosis, endocarditis, or osteomyelitis, are more likely, given the duration of fever.

The fevers were accompanied by chills, without rigors, and subjectively worsened over the first 2 days. At that point, the patient began taking his temperature, and noted fevers of 38.5C to 40C occurring once or twice daily, generally in the afternoon or evening. The patient did not recall tick bites but did not carefully examine himself for ticks; he reported numerous mosquito bites during the trip. The patient camped in a tent and grilled meats and other food he had brought in a cooler. No family members or other travelers became ill. He denied spelunking, but had collected wood for camp fires, and acknowledged swimming in a freshwater pond during his trip, which occurred in August.

West Nile fever, St. Louis encephalitis, and eastern equine encephalitis are transmitted by mosquitoes in New England, but are unlikely causes of prolonged fever. Water exposure suggests the possibility of leptospirosis, and wood exposure suggests blastomycosis, but this usually presents with a pulmonary syndrome. Food‐borne illness seems unlikely. While no aspect of the history has pinpointed a specific diagnosis, exploring the progression of symptoms may offer a clue, and if he has undergone any previous evaluation, the results may significantly alter the differential diagnosis. For example, arthritis may develop weeks after fever in adult‐onset Still's disease, negative blood cultures would lower the probability of endocarditis, and common sites of pyrogenic malignancies (eg, liver, kidneys, and especially lymph nodes) may already have been imaged.

During the first 3 weeks of illness, the patient experienced daily fever and a gradual, 10‐pound weight loss. Over the next 10 days, he sought medical attention at 3 emergency departments. At one, a head computed tomography (CT) showed possible sinusitis, and he was prescribed a 7‐day course of clarithromycin, which he took without any improvement. At 2 others, he was told that his laboratory studies, and a CT of the abdomen, were normal, and that he had a viral syndrome. Several days later, and 5 weeks after the onset of symptoms, the development of dull right upper‐quadrant pain and mild nausea without vomiting prompted the current presentation to the community hospital. He reported several years of loose stools, but denied rash, arthritis, diarrhea, neck stiffness, cough, or other complaints.

A detailed past medical, social, and family history is required, with particular attention to ethnicity; immunocompromising conditions such as splenectomy or corticosteroid use; undiagnosed febrile diseases; severe, unusual, or recurrent infections; medication use; diet; sexual history; pet exposures; and any personal or family history of cancer. The development of right upper‐quadrant pain mandates attention to risk factors for viral hepatitis, known biliary pathology, or travel that might predispose the patient to pyogenic or amoebic liver abscess, and hematochezia, which could suggest a malignancy metastatic to the liver. Additionally, chronic diarrhea with new right upper‐quadrant pain may represent inflammatory bowel disease complicated by primary sclerosing cholangitis (PSC).

The patient was a Caucasian male of Mediterranean ancestry with thalassemia minor. He had undergone dilation of a benign esophageal stricture, but no surgical procedures, and he had never experienced unexplained fever or unusual infections. Medication exposure was limited to occasional use of acetaminophen for fever, and he had no known allergies. His diet was unremarkable and included no well water or unpasteurized dairy products. He denied risk factors for tuberculosis. He drank 2 to 10 beers a day, 5 times a week, had last smoked 10 years previously, and had never used illicit drugs. He denied any high‐risk sexual contacts and was monogamous with his wife, with whom he had 2 children. The family owned no pets and no relatives had suffered from malignant, rheumatologic, or febrile illness, with the exception of hand, foot, and mouth infection in an infant son, 1 year previously. The patient had never traveled outside of New England.

The history has uncovered several clues, but their relevance is doubtful. His ethnicity suggests possible familial Mediterranean fever, but recurrent abdominal pain and polyserositis, rather than a single prolonged episode, would be expected with this disease. A transfusion history should be obtained to explore the possibility of viral hepatitis. While iron overload can predispose patients to various infections including liver abscess, thalassemia minor should not require transfusion. Esophageal stricture could conceivably be due to histoplasmosis (complicated by mediastinal fibrosis) or tuberculosis, but is probably unrelated to his present illness. His excessive alcohol intake increases his risk for esophageal cancer and liver disease, but it is unlikely that metastatic disease to the liver would present with fever without preceding dysphagia, or that alcoholic hepatitis could have escaped detection after evaluations by several physicians.

We need to learn the details of the patient's physical examination. Given the development of right upper‐quadrant pain, I would particularly like to know if he had hepatosplenomegaly and if a Murphy's sign was present.

His temperature ranged from 36.9C to 39.8C, his pulse was 76 beats per minute with minimal elevations during fever spikes, and his respirations were 18 per minute. His blood pressure was 105/70 mm Hg. He was a well‐developed, overweight male with scleral icterus. He had good dentition and an oropharynx free of lesions. Cardiac examination demonstrated a regular rhythm with a normal S1 and S2, without murmurs or peripheral stigmata of infectious endocarditis. A smooth, minimally tender liver edge was palpable 2 cm below the costal margin; the spleen was nonpalpable. Murphy's sign was absent. There was no lymphadenopathy or rash. He had multiple, shallow, uninfected lacerations of both hands in various stages of healing. The remainder of his examination was normal.

The patient has obvious liver involvement. The pulse‐temperature dissociation suggests a variety of infections, including salmonellosis, psittacosis, typhoid fever, leptospirosis, tularemia, brucellosis, legionellosis, and mycoplasma pneumoniae infection. The patient should be asked how and when he injured his hands, as fresh water exposure can transmit leptospirosis across broken skin. However, while severe leptospirosis can cause fever and jaundice, the long duration of illness is not typical. The cryptogenic form of tularemiawhich can manifest as a typhoidal illnessshould be considered, given that tularemia is present in the area the patient visited; he should be asked about exposure to rabbits.

At this point, I would like to see a standard biochemical profile, a liver panel, a complete blood count and differential, urinalysis, chest X‐ray, and an electrocardiogram. I would examine thick and thin Wright‐Giemsa‐stained smears for evidence of babesiosis. Blood cultures should be held for at least 2 weeks to recover fastidious organisms like Francisella tularensis and Brucella sp. Bone marrow cultures should be obtained; they are more sensitive for mycobacteria and Brucella, and may also yield fungal pathogens. Serologies for a variety of infectious diseases, such as leptospirosis, typhoid fever, and tularemia, will be required if other diagnostic tests are unrevealing.

His white cell count was 8,100/L, with a normal differential, and his hemoglobin was 10 g/dL (normal range, 1417), with a mean corpuscular hemoglobin of 63 m³ (normal range, 8298). The platelet count was 303,000/L. Serum electrolytes were normal. His aspartate aminotransferase was 58 U/L and his alanine aminotransferase was 60 U/L (normal range for both, 1045). Bilirubin was 2.6 mg/dL (normal, <1.2); direct bilirubin was 0.9 mg/dL. Alkaline phosphatase was 150 U/L. Lactate dehydrogenase was 342 U/L (normal range, 2251). A lipase was 62 U/L. International normalized ratio (INR) was 1.4 with an activated partial thromboplastin time (aPTT) of 52 seconds (normal range, 2533). Erythrocyte sedimentation rate (ESR) was 50 mm/hour (normal range, 015). Iron studies showed a suppressed iron and iron‐binding capacity and elevated haptoglobin and ferritin (1878 ng/L; normal range, 22322). Several blood cultures obtained at admission showed no growth after 48 hours of incubation.

The anemia, low mean cell volume (MCV), and elevated ferritin and ESR are consistent with anemia of chronic disease, superimposed upon thalassemia minor. Transaminase elevations occur in a plethora of infectious processes. The elevated INR and aPTT are concerning, and may indicate a septic or malignant process with disseminated intravascular coagulation (DIC). While there is no mention of clinical DIC, it would be appropriate to obtain D‐dimers, fibrin degradation products, and a fibrinogen level. The platelet count is normal, which is reassuring.

Before initiating any empiric antimicrobials, I would obtain an abdominal ultrasound, and possibly an abdominal CT. Hepatitis (especially B and C), cytomegalovirus, and Epstein‐Barr virus serologies should be obtained. A variety of conditions including leptospirosis, tularemia, and babesiosis are possible; specific laboratory testing is required to guide therapy.

Ultrasound showed a thickened gallbladder; the liver was slightly enlarged with normal echotexture. Magnetic resonance cholangiopancreatography (MRCP) showed diffuse sequential beading and scarring of his extrahepatic biliary ducts.

There is no evidence of biliary stones, intrahepatic tumor, or abscess to explain the fever and hepatitis, although it would be helpful to know what other abdominal structures were imaged. The MRCP finding increases my suspicion of PSC, possibly complicated by infection, although the biliary abnormalities may be incidental, and an unrelated process may be responsible for the clinical presentation.

His physicians considered the possibilities of PSC and cholangiopathy due to as‐yet undiagnosed acquired immunodeficiency syndrome. Ampicillin‐sulbactam, ceftazidime, and gentamicin were administered for possible bacterial cholangitis, and endoscopic retrograde cholangiopancreatography was performed. This procedure showed only slight narrowing of his common bile duct, which was felt to be a normal variant. He felt no better after several days of antibiotic therapy, and was transferred to a tertiary care center for further evaluation. Repeat physical exam and laboratory studies were essentially unchanged. The patient explained that his hand lacerations were sustained during his work as a butcher who worked with lamb, beef, rabbit, and poultry. He rarely wore protective gloves because they induced contact dermatitis.

Tularemia becomes more likely given his history of rabbit butchering. Salmonellosis and leptospirosis also remain possible. Typhoid fever and brucellosis are unlikely unless the patient worked with imported exotic animals. At this point, given the systemic illness, empiric antibacterial therapy is reasonable. Of the chosen antimicrobials, only the gentamicin would reliably treat tularemia. I would stop ampicillin‐sulbactam and ceftazidime and replace gentamicin with ciprofloxacin, an effective and better‐tolerated agent for tularemia. Cultures of blood and bone marrow aspirate should be obtained. Stool should be cultured for Salmonella. Tularemia, leptospirosis, and typhoid serologies should be sent to a reference laboratory. At this point in the patient's illness, high‐titered antibodies should be present. However, it would be ideal to compare titers with those from previous serum sample, if possible.

The patient's antimicrobials were narrowed to doxycycline alone, for suspected zoonotic infection, but his fevers were unchanged after 1 week of treatment. Hepatitis serologies, human immunodeficiency virus (HIV) antibody, and smears for ehrlichiosis and babesiosis were negative. He had a positive immunoglobulin (Ig)G and a negative IgM for Epstein‐Barr virus and cytomegalovirus. Tularemia, ehrlichiosis, leptospirosis, brucellosis, and Query fever (Q fever) serologies were ordered. The elevated aPTT did not correct when his serum was mixed with normal serum. Thrombin was normal; factor VIII, von Willebrand (VW) factor, and VW cofactor were mildly elevated. Lupus anticoagulant was detected. A hepatologist declined to obtain a liver biopsy, citing the elevated aPTT and pending serologies. Given his clinical stability, the patient was discharged on doxycycline to await further results.

My highest suspicion is for tularemia, and I would switch antibiotic treatment to ciprofloxacin, awaiting serological results. Some in vitro studies have suggested that F. tularensis may often be resistant to doxycycline, and recent clinical experience has shown fluoroquinolones are superior to doxycycline in the treatment of tularemia.

His serologic results were as follows: tularemia, 1:32 (positive, 1:128); ehrlichia, 1:128 (granulocytic) and <1:64 (monocytic; normal for both, <1:64); leptospira, agglutinated nonspecifically; Brucella IgG and IgM 1 (negative, <9), Q fever (coxiella) IgG 1 + 2, IgM 1 + 2, all positive at 1:256 (<1:16). A transesophageal echocardiogram showed no evidence of endocarditis. The patient was treated with 10 weeks of doxycycline for Q fever hepatitis. His fever, headache, and laboratory abnormalities resolved, and he remained well after the completion of therapy.

The serologies suggest the patient had Coxiella burnetii hepatitis, and illustrate the value of a precise exposure history. Most butchers work only with muscle tissue and have a negligible risk of Q fever. In retrospect, it became clear that he worked part‐time in a slaughterhouse, where highly infectious reproductive tract fluids can dry and aerosolize.

Commentary

Q fever was proposed as the name for a febrile illness affecting Australian slaughterhouse workers in 1937.1 The etiologic agent, C. burnetii, is a small, gram‐negative, obligate intracellular proteobacterium that exists in 2 distinct phases, specializing either in entering or persisting in macrophage lysosomes.2 Additionally, spores are formed and can persist in soil.

Q fever is an uncommonly recognized disease, in part because most infected persons have no symptoms or mild symptoms.3 In the United States, the estimated annual incidence has been 0.28 per million (about 50 cases per year) since 1999, when Q fever became a reportable disease due to bioterrorism concerns. In France, more frequent farming of goats and sheep may be responsible for the much higher annual incidence of 500 per million.4 Spread is usually occupational, via aerosol contact with the dried reproductive tract secretions of animals (mainly cattle, sheep, and goats), in a slaughterhouse or farm setting. However, wind‐borne dust can carry spores long distances, and spread can occur from household pets, unpasteurized dairy products, laboratory work, and possibly ticks.3 More than 30 cases have been reported in military personnel deployed to Iraq and Afghanistan, several without obvious exposures.5 One review noted a single reported case of intradermal inoculation,3 making this patient's lacerations a possible site of infection, but he was also at risk for inhalational exposurewhen he was later asked about the details of his work, he acknowledged working at a slaughterhouse as well as a supermarket.

Symptomatic patients are male in 77% of cases, can usually identify an occupational exposure, and have a mean age of 50 years.4 Fever, which lasts 5 to 57 days, as well as fatigue and headaches, begin after a 1‐week to 3‐week incubation period. Atypical pneumonia or rash may occur; meningoencephalitis and myocarditis portend a worse prognosis. As with this patient, 45% to 85% of patients suffer from hepatitis, although few have an abnormal bilirubin.3 Liver biopsy usually reveals granulomas, which may have a classic doughnut hole appearance,2, 3 although this patient ultimately received a diagnosis without the procedure. Acute Q fever rarely (5%) requires hospitalization, and fatalities are extremely rare.3

Chronic infection (ie, lasting >6 months) most often occurs as endocarditis, although chronic hepatitis, osteomyelitis, and infections of other sites occur. Interestingly, this patient's lupus anticoagulant may have been related to his underlying illness, as autoantibodies frequently occur in Q fever, especially in patients with hepatitis, many of whom develop smooth muscle antibodies, a positive Coombs test, antiprothrombinase, or other autoantibodies,3 and there is a high incidence of antiphospholipid antibodies, particularly anticardiolipin and lupus anticoagulant antibodies.6

Because C. burnetii is an obligate intracellular pathogen, culture requires either tissue or live animal inoculation, and the diagnosis is usually made serologically. Paired sera demonstrating seroconversion or a 4‐fold increase in titers are most conclusive, but a single sample may be used. Anti‐phase II antibodies are detectable in 90% of patients within 3 weeks of infection3 and peak at 2 months5; this patient's phase II sera (IgG > 1:200, IgM > 1:50) are said to be 100% predictive for acute Q fever.3 High‐titer anti‐phase I antibodies, in contrast, indicate chronic infection, and a titer 1:800 is one of the modified Duke criteria for endocarditis.5

Acute Q fever is generally treated with doxycycline for 14 days, although prolonged therapy may be advisable to prevent endocarditis if preexisting valvular lesions are present.2, 5 Fluoroquinolones are another option and may be especially useful for meningoencephalitis.5 Because acute Q fever is generally self‐limited, demonstrating a clear benefit to antibiotic therapy is difficult. The available evidence, which was largely obtained from Q fever pneumonia patients, suggests that tetracycline therapy shortens fever duration.3 Patients with Q fever hepatitis may have a protracted course. On the basis of anecdotal reports, some experts add prednisone (tapered from 40 mg daily over a week) for patients with Q fever hepatitis who fail to respond to doxycycline promptly.3 While this patient's fever was unchanged after a week of therapy, he was well into his treatment course when his diagnosis was ultimately confirmed. His physicians felt that prednisone would be of uncertain benefit and opted not to administer it.

Treatment of Q fever endocarditis is often delayed by the combination of negative blood cultures and a low (12%) rate of vegetation formation, increasing the risk of morbidity and mortality.3 Tetracycline monotherapy is associated with a greater than 50% risk of death,5 and even 4 years of treatment may fail to sterilize valve tissue.3 However, if hydroxychloroquine is given with doxycycline for at least 18 months to alkalize lysosomes and improve bacterial killing, the mortality rate can be lowered to about 5%.3, 5 Patients should be warned of the risk of photosensitivity, and monitored for retinal toxicity2 and serologic evidence of relapse.5

Before serologic results confirmed the diagnosis of Q fever, both the patient's clinicians and the discussant had to craft an antibiotic regimen for a suspected zoonosis. The patient received doxycycline, a good choice for leptospirosis,7 brucellosis,8 tularemia,9 and Q fever,3 all possible after livestock exposure, as well as ehrlichiosis.10 The discussant, who suspected tularemia, worried about the possibility of doxycycline resistance and selected ciprofloxacin instead. While fluoroquinolones are probably superior to doxycycline for mild to moderate tularemia,11, 12 aminoglycosides would be preferred for severe disease,9 and ciprofloxacin experience in leptospirosis7 and ehrlichiosis10 is limited. Neither selection would be optimal for brucellosis, for which either doxycycline or ciprofloxacin should be combined with another agent such as rifampin.8 The most reasonable empiric regimen is debatable, but in the absence of pathognomonic findings of tularemia, his treating physicians favored the broader activity of doxycycline.

Ultimately, the choice of antibiotics in this case hinged on the details of the patient's occupational exposures. His first 2 courses of antibiotics were based not on his exposure history, but on radiographic findings that were later proven spurious. The regimens selected by the discussant and by physicians at the referral hospital both targeted pathogens suggested by the patient's occupational history instead, but both were missing parts of the puzzle as well. The discussant thought the patient performed commercial butcher‐shop work, which is only rarely13 mentioned in the context of Q fever transmission. Several of the admitting physicians at the referral hospital were unaware of the importance of the butcher/slaughterhouse‐worker distinction. Physicians need a detailed understanding of both the exposure history and the biology of possible pathogens to craft an optimal differential diagnosis and empiric antibiotic regimen.

On the other hand, in most patients with fever of unknown origin (FUO; ie, >3 weeks with temperature >38.3 on multiple occasions, without a diagnosis after a weeklong evaluation),14 empiric antibiotic therapy is rarely a wise intervention. Clinicians should avoid blind administration of antibiotics as a diagnostic tool, given the inability to distinguish clinical responses from spontaneous resolution, or pinpoint a specific cause and thus a precise treatment plan and duration. However, empiric tetracyclines have been employed when intracellular pathogens were a suspected cause of FUO, as in one series of French patients in which Q fever was common.15 In this patient's case, no specific finding pointed to Q fever before the serologies became available, but the rare infections considered in this case can be considered doxycycline‐deficient states, meaning that empiric tetracycline therapy often leads to improvement. Recognizing doxycycline deficiency can guide therapy while definitive results are pending, and empiric doxycycline is particularly important if potentially aggressive zoonoses, such as Rocky Mountain spotted fever, are suspected.

A 47‐year‐old male presented to a community hospital with 5 weeks of daily fevers, accompanied by headache, myalgias, and malaise. He reported that his symptoms began abruptly 2 days after a weekend of camping in Connecticut.

This patient describes the onset of undifferentiated fever 2 days after a weekend of camping. Few infectious diseases have such short incubation periods, and either the accuracy of the history or the relationship of the camping trip to the present illness is thus questionable. However, more information about the onset and nature of the illness, and details about food, animal, water, mud, cave, wood chopping, and other environmental exposures during his trip is required. The exact dates of the camping trip may be helpful, as there is clear seasonality to vector‐borne diseases such as Lyme disease, babesiosis, ehrlichiosis, and rickettsial infections. Conditions unrelated to his camping trip, such as malignancies, rheumatologic conditions, and other infectious causes of prolonged fever, such as tuberculosis, endocarditis, or osteomyelitis, are more likely, given the duration of fever.

The fevers were accompanied by chills, without rigors, and subjectively worsened over the first 2 days. At that point, the patient began taking his temperature, and noted fevers of 38.5C to 40C occurring once or twice daily, generally in the afternoon or evening. The patient did not recall tick bites but did not carefully examine himself for ticks; he reported numerous mosquito bites during the trip. The patient camped in a tent and grilled meats and other food he had brought in a cooler. No family members or other travelers became ill. He denied spelunking, but had collected wood for camp fires, and acknowledged swimming in a freshwater pond during his trip, which occurred in August.

West Nile fever, St. Louis encephalitis, and eastern equine encephalitis are transmitted by mosquitoes in New England, but are unlikely causes of prolonged fever. Water exposure suggests the possibility of leptospirosis, and wood exposure suggests blastomycosis, but this usually presents with a pulmonary syndrome. Food‐borne illness seems unlikely. While no aspect of the history has pinpointed a specific diagnosis, exploring the progression of symptoms may offer a clue, and if he has undergone any previous evaluation, the results may significantly alter the differential diagnosis. For example, arthritis may develop weeks after fever in adult‐onset Still's disease, negative blood cultures would lower the probability of endocarditis, and common sites of pyrogenic malignancies (eg, liver, kidneys, and especially lymph nodes) may already have been imaged.

During the first 3 weeks of illness, the patient experienced daily fever and a gradual, 10‐pound weight loss. Over the next 10 days, he sought medical attention at 3 emergency departments. At one, a head computed tomography (CT) showed possible sinusitis, and he was prescribed a 7‐day course of clarithromycin, which he took without any improvement. At 2 others, he was told that his laboratory studies, and a CT of the abdomen, were normal, and that he had a viral syndrome. Several days later, and 5 weeks after the onset of symptoms, the development of dull right upper‐quadrant pain and mild nausea without vomiting prompted the current presentation to the community hospital. He reported several years of loose stools, but denied rash, arthritis, diarrhea, neck stiffness, cough, or other complaints.

A detailed past medical, social, and family history is required, with particular attention to ethnicity; immunocompromising conditions such as splenectomy or corticosteroid use; undiagnosed febrile diseases; severe, unusual, or recurrent infections; medication use; diet; sexual history; pet exposures; and any personal or family history of cancer. The development of right upper‐quadrant pain mandates attention to risk factors for viral hepatitis, known biliary pathology, or travel that might predispose the patient to pyogenic or amoebic liver abscess, and hematochezia, which could suggest a malignancy metastatic to the liver. Additionally, chronic diarrhea with new right upper‐quadrant pain may represent inflammatory bowel disease complicated by primary sclerosing cholangitis (PSC).

The patient was a Caucasian male of Mediterranean ancestry with thalassemia minor. He had undergone dilation of a benign esophageal stricture, but no surgical procedures, and he had never experienced unexplained fever or unusual infections. Medication exposure was limited to occasional use of acetaminophen for fever, and he had no known allergies. His diet was unremarkable and included no well water or unpasteurized dairy products. He denied risk factors for tuberculosis. He drank 2 to 10 beers a day, 5 times a week, had last smoked 10 years previously, and had never used illicit drugs. He denied any high‐risk sexual contacts and was monogamous with his wife, with whom he had 2 children. The family owned no pets and no relatives had suffered from malignant, rheumatologic, or febrile illness, with the exception of hand, foot, and mouth infection in an infant son, 1 year previously. The patient had never traveled outside of New England.

The history has uncovered several clues, but their relevance is doubtful. His ethnicity suggests possible familial Mediterranean fever, but recurrent abdominal pain and polyserositis, rather than a single prolonged episode, would be expected with this disease. A transfusion history should be obtained to explore the possibility of viral hepatitis. While iron overload can predispose patients to various infections including liver abscess, thalassemia minor should not require transfusion. Esophageal stricture could conceivably be due to histoplasmosis (complicated by mediastinal fibrosis) or tuberculosis, but is probably unrelated to his present illness. His excessive alcohol intake increases his risk for esophageal cancer and liver disease, but it is unlikely that metastatic disease to the liver would present with fever without preceding dysphagia, or that alcoholic hepatitis could have escaped detection after evaluations by several physicians.

We need to learn the details of the patient's physical examination. Given the development of right upper‐quadrant pain, I would particularly like to know if he had hepatosplenomegaly and if a Murphy's sign was present.

His temperature ranged from 36.9C to 39.8C, his pulse was 76 beats per minute with minimal elevations during fever spikes, and his respirations were 18 per minute. His blood pressure was 105/70 mm Hg. He was a well‐developed, overweight male with scleral icterus. He had good dentition and an oropharynx free of lesions. Cardiac examination demonstrated a regular rhythm with a normal S1 and S2, without murmurs or peripheral stigmata of infectious endocarditis. A smooth, minimally tender liver edge was palpable 2 cm below the costal margin; the spleen was nonpalpable. Murphy's sign was absent. There was no lymphadenopathy or rash. He had multiple, shallow, uninfected lacerations of both hands in various stages of healing. The remainder of his examination was normal.

The patient has obvious liver involvement. The pulse‐temperature dissociation suggests a variety of infections, including salmonellosis, psittacosis, typhoid fever, leptospirosis, tularemia, brucellosis, legionellosis, and mycoplasma pneumoniae infection. The patient should be asked how and when he injured his hands, as fresh water exposure can transmit leptospirosis across broken skin. However, while severe leptospirosis can cause fever and jaundice, the long duration of illness is not typical. The cryptogenic form of tularemiawhich can manifest as a typhoidal illnessshould be considered, given that tularemia is present in the area the patient visited; he should be asked about exposure to rabbits.

At this point, I would like to see a standard biochemical profile, a liver panel, a complete blood count and differential, urinalysis, chest X‐ray, and an electrocardiogram. I would examine thick and thin Wright‐Giemsa‐stained smears for evidence of babesiosis. Blood cultures should be held for at least 2 weeks to recover fastidious organisms like Francisella tularensis and Brucella sp. Bone marrow cultures should be obtained; they are more sensitive for mycobacteria and Brucella, and may also yield fungal pathogens. Serologies for a variety of infectious diseases, such as leptospirosis, typhoid fever, and tularemia, will be required if other diagnostic tests are unrevealing.

His white cell count was 8,100/L, with a normal differential, and his hemoglobin was 10 g/dL (normal range, 1417), with a mean corpuscular hemoglobin of 63 m³ (normal range, 8298). The platelet count was 303,000/L. Serum electrolytes were normal. His aspartate aminotransferase was 58 U/L and his alanine aminotransferase was 60 U/L (normal range for both, 1045). Bilirubin was 2.6 mg/dL (normal, <1.2); direct bilirubin was 0.9 mg/dL. Alkaline phosphatase was 150 U/L. Lactate dehydrogenase was 342 U/L (normal range, 2251). A lipase was 62 U/L. International normalized ratio (INR) was 1.4 with an activated partial thromboplastin time (aPTT) of 52 seconds (normal range, 2533). Erythrocyte sedimentation rate (ESR) was 50 mm/hour (normal range, 015). Iron studies showed a suppressed iron and iron‐binding capacity and elevated haptoglobin and ferritin (1878 ng/L; normal range, 22322). Several blood cultures obtained at admission showed no growth after 48 hours of incubation.

The anemia, low mean cell volume (MCV), and elevated ferritin and ESR are consistent with anemia of chronic disease, superimposed upon thalassemia minor. Transaminase elevations occur in a plethora of infectious processes. The elevated INR and aPTT are concerning, and may indicate a septic or malignant process with disseminated intravascular coagulation (DIC). While there is no mention of clinical DIC, it would be appropriate to obtain D‐dimers, fibrin degradation products, and a fibrinogen level. The platelet count is normal, which is reassuring.

Before initiating any empiric antimicrobials, I would obtain an abdominal ultrasound, and possibly an abdominal CT. Hepatitis (especially B and C), cytomegalovirus, and Epstein‐Barr virus serologies should be obtained. A variety of conditions including leptospirosis, tularemia, and babesiosis are possible; specific laboratory testing is required to guide therapy.

Ultrasound showed a thickened gallbladder; the liver was slightly enlarged with normal echotexture. Magnetic resonance cholangiopancreatography (MRCP) showed diffuse sequential beading and scarring of his extrahepatic biliary ducts.

There is no evidence of biliary stones, intrahepatic tumor, or abscess to explain the fever and hepatitis, although it would be helpful to know what other abdominal structures were imaged. The MRCP finding increases my suspicion of PSC, possibly complicated by infection, although the biliary abnormalities may be incidental, and an unrelated process may be responsible for the clinical presentation.

His physicians considered the possibilities of PSC and cholangiopathy due to as‐yet undiagnosed acquired immunodeficiency syndrome. Ampicillin‐sulbactam, ceftazidime, and gentamicin were administered for possible bacterial cholangitis, and endoscopic retrograde cholangiopancreatography was performed. This procedure showed only slight narrowing of his common bile duct, which was felt to be a normal variant. He felt no better after several days of antibiotic therapy, and was transferred to a tertiary care center for further evaluation. Repeat physical exam and laboratory studies were essentially unchanged. The patient explained that his hand lacerations were sustained during his work as a butcher who worked with lamb, beef, rabbit, and poultry. He rarely wore protective gloves because they induced contact dermatitis.

Tularemia becomes more likely given his history of rabbit butchering. Salmonellosis and leptospirosis also remain possible. Typhoid fever and brucellosis are unlikely unless the patient worked with imported exotic animals. At this point, given the systemic illness, empiric antibacterial therapy is reasonable. Of the chosen antimicrobials, only the gentamicin would reliably treat tularemia. I would stop ampicillin‐sulbactam and ceftazidime and replace gentamicin with ciprofloxacin, an effective and better‐tolerated agent for tularemia. Cultures of blood and bone marrow aspirate should be obtained. Stool should be cultured for Salmonella. Tularemia, leptospirosis, and typhoid serologies should be sent to a reference laboratory. At this point in the patient's illness, high‐titered antibodies should be present. However, it would be ideal to compare titers with those from previous serum sample, if possible.

The patient's antimicrobials were narrowed to doxycycline alone, for suspected zoonotic infection, but his fevers were unchanged after 1 week of treatment. Hepatitis serologies, human immunodeficiency virus (HIV) antibody, and smears for ehrlichiosis and babesiosis were negative. He had a positive immunoglobulin (Ig)G and a negative IgM for Epstein‐Barr virus and cytomegalovirus. Tularemia, ehrlichiosis, leptospirosis, brucellosis, and Query fever (Q fever) serologies were ordered. The elevated aPTT did not correct when his serum was mixed with normal serum. Thrombin was normal; factor VIII, von Willebrand (VW) factor, and VW cofactor were mildly elevated. Lupus anticoagulant was detected. A hepatologist declined to obtain a liver biopsy, citing the elevated aPTT and pending serologies. Given his clinical stability, the patient was discharged on doxycycline to await further results.

My highest suspicion is for tularemia, and I would switch antibiotic treatment to ciprofloxacin, awaiting serological results. Some in vitro studies have suggested that F. tularensis may often be resistant to doxycycline, and recent clinical experience has shown fluoroquinolones are superior to doxycycline in the treatment of tularemia.

His serologic results were as follows: tularemia, 1:32 (positive, 1:128); ehrlichia, 1:128 (granulocytic) and <1:64 (monocytic; normal for both, <1:64); leptospira, agglutinated nonspecifically; Brucella IgG and IgM 1 (negative, <9), Q fever (coxiella) IgG 1 + 2, IgM 1 + 2, all positive at 1:256 (<1:16). A transesophageal echocardiogram showed no evidence of endocarditis. The patient was treated with 10 weeks of doxycycline for Q fever hepatitis. His fever, headache, and laboratory abnormalities resolved, and he remained well after the completion of therapy.

The serologies suggest the patient had Coxiella burnetii hepatitis, and illustrate the value of a precise exposure history. Most butchers work only with muscle tissue and have a negligible risk of Q fever. In retrospect, it became clear that he worked part‐time in a slaughterhouse, where highly infectious reproductive tract fluids can dry and aerosolize.

Commentary

Q fever was proposed as the name for a febrile illness affecting Australian slaughterhouse workers in 1937.1 The etiologic agent, C. burnetii, is a small, gram‐negative, obligate intracellular proteobacterium that exists in 2 distinct phases, specializing either in entering or persisting in macrophage lysosomes.2 Additionally, spores are formed and can persist in soil.

Q fever is an uncommonly recognized disease, in part because most infected persons have no symptoms or mild symptoms.3 In the United States, the estimated annual incidence has been 0.28 per million (about 50 cases per year) since 1999, when Q fever became a reportable disease due to bioterrorism concerns. In France, more frequent farming of goats and sheep may be responsible for the much higher annual incidence of 500 per million.4 Spread is usually occupational, via aerosol contact with the dried reproductive tract secretions of animals (mainly cattle, sheep, and goats), in a slaughterhouse or farm setting. However, wind‐borne dust can carry spores long distances, and spread can occur from household pets, unpasteurized dairy products, laboratory work, and possibly ticks.3 More than 30 cases have been reported in military personnel deployed to Iraq and Afghanistan, several without obvious exposures.5 One review noted a single reported case of intradermal inoculation,3 making this patient's lacerations a possible site of infection, but he was also at risk for inhalational exposurewhen he was later asked about the details of his work, he acknowledged working at a slaughterhouse as well as a supermarket.

Symptomatic patients are male in 77% of cases, can usually identify an occupational exposure, and have a mean age of 50 years.4 Fever, which lasts 5 to 57 days, as well as fatigue and headaches, begin after a 1‐week to 3‐week incubation period. Atypical pneumonia or rash may occur; meningoencephalitis and myocarditis portend a worse prognosis. As with this patient, 45% to 85% of patients suffer from hepatitis, although few have an abnormal bilirubin.3 Liver biopsy usually reveals granulomas, which may have a classic doughnut hole appearance,2, 3 although this patient ultimately received a diagnosis without the procedure. Acute Q fever rarely (5%) requires hospitalization, and fatalities are extremely rare.3

Chronic infection (ie, lasting >6 months) most often occurs as endocarditis, although chronic hepatitis, osteomyelitis, and infections of other sites occur. Interestingly, this patient's lupus anticoagulant may have been related to his underlying illness, as autoantibodies frequently occur in Q fever, especially in patients with hepatitis, many of whom develop smooth muscle antibodies, a positive Coombs test, antiprothrombinase, or other autoantibodies,3 and there is a high incidence of antiphospholipid antibodies, particularly anticardiolipin and lupus anticoagulant antibodies.6

Because C. burnetii is an obligate intracellular pathogen, culture requires either tissue or live animal inoculation, and the diagnosis is usually made serologically. Paired sera demonstrating seroconversion or a 4‐fold increase in titers are most conclusive, but a single sample may be used. Anti‐phase II antibodies are detectable in 90% of patients within 3 weeks of infection3 and peak at 2 months5; this patient's phase II sera (IgG > 1:200, IgM > 1:50) are said to be 100% predictive for acute Q fever.3 High‐titer anti‐phase I antibodies, in contrast, indicate chronic infection, and a titer 1:800 is one of the modified Duke criteria for endocarditis.5

Acute Q fever is generally treated with doxycycline for 14 days, although prolonged therapy may be advisable to prevent endocarditis if preexisting valvular lesions are present.2, 5 Fluoroquinolones are another option and may be especially useful for meningoencephalitis.5 Because acute Q fever is generally self‐limited, demonstrating a clear benefit to antibiotic therapy is difficult. The available evidence, which was largely obtained from Q fever pneumonia patients, suggests that tetracycline therapy shortens fever duration.3 Patients with Q fever hepatitis may have a protracted course. On the basis of anecdotal reports, some experts add prednisone (tapered from 40 mg daily over a week) for patients with Q fever hepatitis who fail to respond to doxycycline promptly.3 While this patient's fever was unchanged after a week of therapy, he was well into his treatment course when his diagnosis was ultimately confirmed. His physicians felt that prednisone would be of uncertain benefit and opted not to administer it.

Treatment of Q fever endocarditis is often delayed by the combination of negative blood cultures and a low (12%) rate of vegetation formation, increasing the risk of morbidity and mortality.3 Tetracycline monotherapy is associated with a greater than 50% risk of death,5 and even 4 years of treatment may fail to sterilize valve tissue.3 However, if hydroxychloroquine is given with doxycycline for at least 18 months to alkalize lysosomes and improve bacterial killing, the mortality rate can be lowered to about 5%.3, 5 Patients should be warned of the risk of photosensitivity, and monitored for retinal toxicity2 and serologic evidence of relapse.5

Before serologic results confirmed the diagnosis of Q fever, both the patient's clinicians and the discussant had to craft an antibiotic regimen for a suspected zoonosis. The patient received doxycycline, a good choice for leptospirosis,7 brucellosis,8 tularemia,9 and Q fever,3 all possible after livestock exposure, as well as ehrlichiosis.10 The discussant, who suspected tularemia, worried about the possibility of doxycycline resistance and selected ciprofloxacin instead. While fluoroquinolones are probably superior to doxycycline for mild to moderate tularemia,11, 12 aminoglycosides would be preferred for severe disease,9 and ciprofloxacin experience in leptospirosis7 and ehrlichiosis10 is limited. Neither selection would be optimal for brucellosis, for which either doxycycline or ciprofloxacin should be combined with another agent such as rifampin.8 The most reasonable empiric regimen is debatable, but in the absence of pathognomonic findings of tularemia, his treating physicians favored the broader activity of doxycycline.