Ayman O. Soubani, MD

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

Repeat cultures are indicated in specific scenarios, but for most patients, frequent and indiscriminate repetition after an initial positive culture is unnecessary and may be associated with excessive use of resources. Prospective studies and practice guidelines are needed to help further define the indications.

See related editorial

THE TENDENCY TO REPEAT CULTURES

Current literature lacks strong evidence for repeating previously positive blood cultures collected appropriately—ie, 10 mL of blood for aerobic culture and 10 mL for anaerobic culture from 2 different sites, and a positive result from both sets. However, because of the risk of serious complications of bacteremia, particularly in critically ill patients, many clinicians order multiple, repeated sets of blood cultures.

Tabriz et al¹ found that one-third of hospitalized patients got repeat cultures after an initial set, regardless of the result of the first set. Most (83.4%) of those cultures yielded no growth, 9.1% grew the same pathogen, and 5.0% were contaminated. Finding a new pathogen was rare, occurring in only 2.5% of repeated cultures.

Wiggers et al² reported an even higher number of repeat cultures ordered for patients who had an initially positive culture: 38.9%.² And in another study,³ half of the patients received more than 2 consecutive cultures.

Drawbacks

Unrestrained ordering of repeat blood cultures can increase the risk of a false-positive result, leading to more cultures, echocardiography, other imaging tests, and unnecessary antimicrobial therapy, all of which puts patients at risk of adverse effects of treatment and missed alternative diagnoses and increases the length and cost of hospitalization.⁴

Advantages

On the other hand, repeat blood cultures  may increase the diagnostic yield for conditions such as infective endocarditis and may have implications for the duration of antibiotic therapy.¹ The duration of therapy for bacteremia is usually determined from the last negative culture; hence, documenting clearance of bacteremia can determine a precise end-date for antibiotic therapy.

Bacteremia due to Staphylococcus aureus and to endovascular and epidural sources has been found to be independently associated with persistent bacteremia, detected in 6.6% of 1,801 index cases of bacteremia in a retrospective cohort study.² An endovascular source (adjusted odds ratio [OR] 7.66, 95% confidence interval [CI] 2.30–25.48), an epidural source (adjusted OR 26.99, 95% CI, 1.91–391.08), and S aureus bacteremia (adjusted OR 4.49, 95% CI 1.88–10.73) were independently associated with persistent bacteremia. Escherichia coli (5.1%, P =  .006), viridans group streptococci (1.7%, P =  .035), and beta-hemolytic streptococci (0%, P = .028) were associated with a lower likelihood of persistent bacteremia. Patients with persistent bacteremia were less likely to have achieved source control within 48 hours of the index event (29.7% vs 52.5%, P < .001).²

Repeating blood cultures after an initial positive result is superfluous, except in certain situations.

Suspected endovascular infection

Patients with endocarditis, thrombophlebitis, an indwelling device for epidural access, or a cardiovascular implantable electronic device should have repeat cultures after an initial positive culture. Implantable electronic device infection is suspected in the following cases: sustained positive blood culture (> 24 hours); relapsing bacteremia despite a course of appropriate antibiotic therapy; presence of an implantable cardioverter defibrillator; presence of a prosthetic cardiac valve; and an episode of bacteremia within 3 months of device placement.⁵

S aureus bacteremia

Repeat blood culture is warranted for S aureus bacteremia regardless of methicillin susceptibility.¹ But persistent methicillin-resistant S aureus (MRSA) bacteremia changes the management of these patients.⁶ For example, the source of infection should be identified, followed by debridement or drainage, and then either high-dose or combination antimicrobial therapy.⁶ Infective endocarditis from persistent MRSA bacteremia is an indication for surgery.⁶

Persistent S aureus bacteremia may change the duration of therapy, as the common practice is to continue treating uncomplicated gram-positive bacteremia for 14 days from the date of the first negative culture. Infection leading to infective endocarditis increases the duration of antibiotic therapy to at least 4 weeks.

Candidemia

Candidemia is an absolute indication for repeat blood culture.⁷ Patients with persistent candidemia should undergo imaging of the genitourinary tract, liver, and spleen as part of the evaluation for a deep-tissue source of infection.⁷ Also, if the patient is initially treated with an echinocandin, therapy can be transitioned to fluconazole if the isolate is azole-susceptible, the patient’s condition is clinically stable, and repeat cultures are negative.⁷ Therefore, repeating cultures has therapeutic implications.

Confirming response to therapy

In patients with infective endocarditis or other endovascular infection caused by S aureus, Enterococcus species, or gram-negative bacilli,¹ repeat blood culture should be done to confirm therapeutic response. Patients with infective endocarditis whose condition is stable can be discharged to receive outpatient parenteral antibiotic therapy. However, patients with uncontrolled heart failure, systemic emboli, abscess, persistent fever, or persistently positive cultures are not candidates for outpatient therapy and require repeat cultures.⁸

Multidrug-resistant gram-negative bacilli

Bacteremia due to multidrug-resistant gram-negative bacilli requires repeat blood cultures to document clearance of bacteremia and to ensure the efficacy of antibiotics, as these organisms pose a higher risk of treatment failure, and combination synergistic regimens may be needed if bacteremia does not clear.

Febrile neutropenia

Blood cultures are important in the management of febrile neutropenia. In a study by Rosenblum et al,⁹ repeat cultures were positive in 10.9% of patients with febrile neutropenia after an initial negative culture, but many of those organisms were of low pathogenicity, and a significant proportion were coagulase-negative staphylococci.¹⁰ Another study showed that the frequency of detecting new pathogens by repeat culture in recurrent febrile neutropenia was higher than that in persistent febrile neutropenia (8% vs 2%) (P = .0491); a history of recent bacteremia was identified as a significant predictor of positive culture in recurrent febrile neutropenia.¹¹

Persistent or new infection

Persistence of fever, leukocytosis, or other signs of infection 72 hours after appropriate antibiotic therapy is started requires follow-up blood cultures.

New episode of sepsis. A new episode of sepsis should be confirmed¹² using the systemic inflammatory response syndrome criteria, the newer definition of Sepsis-related Organ Failure Assessment (SOFA) in the intensive-care unit, or the quick SOFA in general units. If the patient develops new signs of sepsis after response to treatment for initial bacteremia, repeat blood cultures should be considered.

Central line-associated bloodstream infection requires repeat cultures.¹³ Persistence of bacteremia in this type of infection extends the duration of therapy, as most clinicians determine treatment duration from the last negative culture. Persistent bacteremia also influences the decision to salvage or remove the catheter. Microbiologic clearance of bacteremia on blood culture can also guide the time of reinsertion if the catheter was removed.

Concern for an unresolved focus of infection such as abscess, joint infection, or retained catheter is an indication for repeat blood cultures.

Bacteremia of unknown source. In clinical practice, we encounter scenarios in which blood cultures are positive but no source can be identified. In those situations, it is important to repeat blood cultures to document clearance. If bacteremia persists, we need to continue searching for the source.

Repeat blood cultures are not routinely indicated in patients with streptococcal bacteremia, uncomplicated gram-negative bacteremia, and bacteremia associated with localized infection such as cellulitis, community-acquired pneumonia, or pyelonephritis.^2,4 A study of patients with gram-negative bacteremia found that 17 repeated cultures needed to be drawn to yield 1 positive culture.¹⁴

Isolated fever or leukocytosis does not accurately predict bacteremia.⁴ A study that excluded neutropenic and intensive-care patients reported none of the initially negative cultures to be positive when repeated.¹⁵

Ordering repeat cultures in response to persistent fever is a common practice, even though fever is typical in the first 72 hours of antibiotic therapy. Such cultures rarely if ever reveal new pathogens, and results can be predicted based on cultures before the start of antibiotics.¹⁵ For patients on antibiotics, physicians should therefore wait for results of the preantibiotic cultures rather than order new cultures in response to persistent fever.¹⁵

WOULD WE MISS PERSISTENT BACTEREMIA?

In theory, not repeating blood cultures could miss persistent bacteremia, but this is unlikely if the concerns discussed above are considered. Further, persistent bacteremia would result in clinical signs and symptoms that should prompt repeat cultures.

FREQUENCY OF REPEAT BLOOD CULTURES

There are no evidence-based guidelines for the frequency of repeating cultures. The Infectious Diseases Society of America recommends repeating blood cultures 2 to 4 days after the index positive culture in the case of multidrug-resistant S aureus bacteremia, and every day or every other day for candidemia.^6,7,9

A study evaluating the practice patterns of repeating cultures after an initial bacteremia showed that 34.7% were done within 24 hours and 44.7% were done in 2 to 4 days.¹ There is no evidence that repeating blood cultures daily is necessary in these patients. As a general rule, it should be done 48 to 72 hours after a positive culture.

Repeat cultures are indicated in specific scenarios, but for most patients, frequent and indiscriminate repetition after an initial positive culture is unnecessary and may be associated with excessive use of resources. Prospective studies and practice guidelines are needed to help further define the indications.

See related editorial

THE TENDENCY TO REPEAT CULTURES

Current literature lacks strong evidence for repeating previously positive blood cultures collected appropriately—ie, 10 mL of blood for aerobic culture and 10 mL for anaerobic culture from 2 different sites, and a positive result from both sets. However, because of the risk of serious complications of bacteremia, particularly in critically ill patients, many clinicians order multiple, repeated sets of blood cultures.

Tabriz et al¹ found that one-third of hospitalized patients got repeat cultures after an initial set, regardless of the result of the first set. Most (83.4%) of those cultures yielded no growth, 9.1% grew the same pathogen, and 5.0% were contaminated. Finding a new pathogen was rare, occurring in only 2.5% of repeated cultures.

Wiggers et al² reported an even higher number of repeat cultures ordered for patients who had an initially positive culture: 38.9%.² And in another study,³ half of the patients received more than 2 consecutive cultures.

Drawbacks

Unrestrained ordering of repeat blood cultures can increase the risk of a false-positive result, leading to more cultures, echocardiography, other imaging tests, and unnecessary antimicrobial therapy, all of which puts patients at risk of adverse effects of treatment and missed alternative diagnoses and increases the length and cost of hospitalization.⁴

Advantages

On the other hand, repeat blood cultures  may increase the diagnostic yield for conditions such as infective endocarditis and may have implications for the duration of antibiotic therapy.¹ The duration of therapy for bacteremia is usually determined from the last negative culture; hence, documenting clearance of bacteremia can determine a precise end-date for antibiotic therapy.

Bacteremia due to Staphylococcus aureus and to endovascular and epidural sources has been found to be independently associated with persistent bacteremia, detected in 6.6% of 1,801 index cases of bacteremia in a retrospective cohort study.² An endovascular source (adjusted odds ratio [OR] 7.66, 95% confidence interval [CI] 2.30–25.48), an epidural source (adjusted OR 26.99, 95% CI, 1.91–391.08), and S aureus bacteremia (adjusted OR 4.49, 95% CI 1.88–10.73) were independently associated with persistent bacteremia. Escherichia coli (5.1%, P =  .006), viridans group streptococci (1.7%, P =  .035), and beta-hemolytic streptococci (0%, P = .028) were associated with a lower likelihood of persistent bacteremia. Patients with persistent bacteremia were less likely to have achieved source control within 48 hours of the index event (29.7% vs 52.5%, P < .001).²

Repeating blood cultures after an initial positive result is superfluous, except in certain situations.

Suspected endovascular infection

Patients with endocarditis, thrombophlebitis, an indwelling device for epidural access, or a cardiovascular implantable electronic device should have repeat cultures after an initial positive culture. Implantable electronic device infection is suspected in the following cases: sustained positive blood culture (> 24 hours); relapsing bacteremia despite a course of appropriate antibiotic therapy; presence of an implantable cardioverter defibrillator; presence of a prosthetic cardiac valve; and an episode of bacteremia within 3 months of device placement.⁵

S aureus bacteremia

Repeat blood culture is warranted for S aureus bacteremia regardless of methicillin susceptibility.¹ But persistent methicillin-resistant S aureus (MRSA) bacteremia changes the management of these patients.⁶ For example, the source of infection should be identified, followed by debridement or drainage, and then either high-dose or combination antimicrobial therapy.⁶ Infective endocarditis from persistent MRSA bacteremia is an indication for surgery.⁶

Persistent S aureus bacteremia may change the duration of therapy, as the common practice is to continue treating uncomplicated gram-positive bacteremia for 14 days from the date of the first negative culture. Infection leading to infective endocarditis increases the duration of antibiotic therapy to at least 4 weeks.

Candidemia

Candidemia is an absolute indication for repeat blood culture.⁷ Patients with persistent candidemia should undergo imaging of the genitourinary tract, liver, and spleen as part of the evaluation for a deep-tissue source of infection.⁷ Also, if the patient is initially treated with an echinocandin, therapy can be transitioned to fluconazole if the isolate is azole-susceptible, the patient’s condition is clinically stable, and repeat cultures are negative.⁷ Therefore, repeating cultures has therapeutic implications.

Confirming response to therapy

In patients with infective endocarditis or other endovascular infection caused by S aureus, Enterococcus species, or gram-negative bacilli,¹ repeat blood culture should be done to confirm therapeutic response. Patients with infective endocarditis whose condition is stable can be discharged to receive outpatient parenteral antibiotic therapy. However, patients with uncontrolled heart failure, systemic emboli, abscess, persistent fever, or persistently positive cultures are not candidates for outpatient therapy and require repeat cultures.⁸

Multidrug-resistant gram-negative bacilli

Bacteremia due to multidrug-resistant gram-negative bacilli requires repeat blood cultures to document clearance of bacteremia and to ensure the efficacy of antibiotics, as these organisms pose a higher risk of treatment failure, and combination synergistic regimens may be needed if bacteremia does not clear.

Febrile neutropenia

Blood cultures are important in the management of febrile neutropenia. In a study by Rosenblum et al,⁹ repeat cultures were positive in 10.9% of patients with febrile neutropenia after an initial negative culture, but many of those organisms were of low pathogenicity, and a significant proportion were coagulase-negative staphylococci.¹⁰ Another study showed that the frequency of detecting new pathogens by repeat culture in recurrent febrile neutropenia was higher than that in persistent febrile neutropenia (8% vs 2%) (P = .0491); a history of recent bacteremia was identified as a significant predictor of positive culture in recurrent febrile neutropenia.¹¹

Persistent or new infection

Persistence of fever, leukocytosis, or other signs of infection 72 hours after appropriate antibiotic therapy is started requires follow-up blood cultures.

New episode of sepsis. A new episode of sepsis should be confirmed¹² using the systemic inflammatory response syndrome criteria, the newer definition of Sepsis-related Organ Failure Assessment (SOFA) in the intensive-care unit, or the quick SOFA in general units. If the patient develops new signs of sepsis after response to treatment for initial bacteremia, repeat blood cultures should be considered.

Central line-associated bloodstream infection requires repeat cultures.¹³ Persistence of bacteremia in this type of infection extends the duration of therapy, as most clinicians determine treatment duration from the last negative culture. Persistent bacteremia also influences the decision to salvage or remove the catheter. Microbiologic clearance of bacteremia on blood culture can also guide the time of reinsertion if the catheter was removed.

Concern for an unresolved focus of infection such as abscess, joint infection, or retained catheter is an indication for repeat blood cultures.

Bacteremia of unknown source. In clinical practice, we encounter scenarios in which blood cultures are positive but no source can be identified. In those situations, it is important to repeat blood cultures to document clearance. If bacteremia persists, we need to continue searching for the source.

Repeat blood cultures are not routinely indicated in patients with streptococcal bacteremia, uncomplicated gram-negative bacteremia, and bacteremia associated with localized infection such as cellulitis, community-acquired pneumonia, or pyelonephritis.^2,4 A study of patients with gram-negative bacteremia found that 17 repeated cultures needed to be drawn to yield 1 positive culture.¹⁴

Isolated fever or leukocytosis does not accurately predict bacteremia.⁴ A study that excluded neutropenic and intensive-care patients reported none of the initially negative cultures to be positive when repeated.¹⁵

Ordering repeat cultures in response to persistent fever is a common practice, even though fever is typical in the first 72 hours of antibiotic therapy. Such cultures rarely if ever reveal new pathogens, and results can be predicted based on cultures before the start of antibiotics.¹⁵ For patients on antibiotics, physicians should therefore wait for results of the preantibiotic cultures rather than order new cultures in response to persistent fever.¹⁵

WOULD WE MISS PERSISTENT BACTEREMIA?

In theory, not repeating blood cultures could miss persistent bacteremia, but this is unlikely if the concerns discussed above are considered. Further, persistent bacteremia would result in clinical signs and symptoms that should prompt repeat cultures.

FREQUENCY OF REPEAT BLOOD CULTURES

There are no evidence-based guidelines for the frequency of repeating cultures. The Infectious Diseases Society of America recommends repeating blood cultures 2 to 4 days after the index positive culture in the case of multidrug-resistant S aureus bacteremia, and every day or every other day for candidemia.^6,7,9

A study evaluating the practice patterns of repeating cultures after an initial bacteremia showed that 34.7% were done within 24 hours and 44.7% were done in 2 to 4 days.¹ There is no evidence that repeating blood cultures daily is necessary in these patients. As a general rule, it should be done 48 to 72 hours after a positive culture.

Repeat cultures are indicated in specific scenarios, but for most patients, frequent and indiscriminate repetition after an initial positive culture is unnecessary and may be associated with excessive use of resources. Prospective studies and practice guidelines are needed to help further define the indications.

See related editorial

THE TENDENCY TO REPEAT CULTURES

Current literature lacks strong evidence for repeating previously positive blood cultures collected appropriately—ie, 10 mL of blood for aerobic culture and 10 mL for anaerobic culture from 2 different sites, and a positive result from both sets. However, because of the risk of serious complications of bacteremia, particularly in critically ill patients, many clinicians order multiple, repeated sets of blood cultures.

Tabriz et al¹ found that one-third of hospitalized patients got repeat cultures after an initial set, regardless of the result of the first set. Most (83.4%) of those cultures yielded no growth, 9.1% grew the same pathogen, and 5.0% were contaminated. Finding a new pathogen was rare, occurring in only 2.5% of repeated cultures.

Wiggers et al² reported an even higher number of repeat cultures ordered for patients who had an initially positive culture: 38.9%.² And in another study,³ half of the patients received more than 2 consecutive cultures.

Drawbacks

Unrestrained ordering of repeat blood cultures can increase the risk of a false-positive result, leading to more cultures, echocardiography, other imaging tests, and unnecessary antimicrobial therapy, all of which puts patients at risk of adverse effects of treatment and missed alternative diagnoses and increases the length and cost of hospitalization.⁴

Advantages

On the other hand, repeat blood cultures  may increase the diagnostic yield for conditions such as infective endocarditis and may have implications for the duration of antibiotic therapy.¹ The duration of therapy for bacteremia is usually determined from the last negative culture; hence, documenting clearance of bacteremia can determine a precise end-date for antibiotic therapy.

Bacteremia due to Staphylococcus aureus and to endovascular and epidural sources has been found to be independently associated with persistent bacteremia, detected in 6.6% of 1,801 index cases of bacteremia in a retrospective cohort study.² An endovascular source (adjusted odds ratio [OR] 7.66, 95% confidence interval [CI] 2.30–25.48), an epidural source (adjusted OR 26.99, 95% CI, 1.91–391.08), and S aureus bacteremia (adjusted OR 4.49, 95% CI 1.88–10.73) were independently associated with persistent bacteremia. Escherichia coli (5.1%, P =  .006), viridans group streptococci (1.7%, P =  .035), and beta-hemolytic streptococci (0%, P = .028) were associated with a lower likelihood of persistent bacteremia. Patients with persistent bacteremia were less likely to have achieved source control within 48 hours of the index event (29.7% vs 52.5%, P < .001).²

Repeating blood cultures after an initial positive result is superfluous, except in certain situations.

Suspected endovascular infection

Patients with endocarditis, thrombophlebitis, an indwelling device for epidural access, or a cardiovascular implantable electronic device should have repeat cultures after an initial positive culture. Implantable electronic device infection is suspected in the following cases: sustained positive blood culture (> 24 hours); relapsing bacteremia despite a course of appropriate antibiotic therapy; presence of an implantable cardioverter defibrillator; presence of a prosthetic cardiac valve; and an episode of bacteremia within 3 months of device placement.⁵

S aureus bacteremia

Repeat blood culture is warranted for S aureus bacteremia regardless of methicillin susceptibility.¹ But persistent methicillin-resistant S aureus (MRSA) bacteremia changes the management of these patients.⁶ For example, the source of infection should be identified, followed by debridement or drainage, and then either high-dose or combination antimicrobial therapy.⁶ Infective endocarditis from persistent MRSA bacteremia is an indication for surgery.⁶

Persistent S aureus bacteremia may change the duration of therapy, as the common practice is to continue treating uncomplicated gram-positive bacteremia for 14 days from the date of the first negative culture. Infection leading to infective endocarditis increases the duration of antibiotic therapy to at least 4 weeks.

Candidemia

Candidemia is an absolute indication for repeat blood culture.⁷ Patients with persistent candidemia should undergo imaging of the genitourinary tract, liver, and spleen as part of the evaluation for a deep-tissue source of infection.⁷ Also, if the patient is initially treated with an echinocandin, therapy can be transitioned to fluconazole if the isolate is azole-susceptible, the patient’s condition is clinically stable, and repeat cultures are negative.⁷ Therefore, repeating cultures has therapeutic implications.

Confirming response to therapy

In patients with infective endocarditis or other endovascular infection caused by S aureus, Enterococcus species, or gram-negative bacilli,¹ repeat blood culture should be done to confirm therapeutic response. Patients with infective endocarditis whose condition is stable can be discharged to receive outpatient parenteral antibiotic therapy. However, patients with uncontrolled heart failure, systemic emboli, abscess, persistent fever, or persistently positive cultures are not candidates for outpatient therapy and require repeat cultures.⁸

Multidrug-resistant gram-negative bacilli

Bacteremia due to multidrug-resistant gram-negative bacilli requires repeat blood cultures to document clearance of bacteremia and to ensure the efficacy of antibiotics, as these organisms pose a higher risk of treatment failure, and combination synergistic regimens may be needed if bacteremia does not clear.

Febrile neutropenia

Blood cultures are important in the management of febrile neutropenia. In a study by Rosenblum et al,⁹ repeat cultures were positive in 10.9% of patients with febrile neutropenia after an initial negative culture, but many of those organisms were of low pathogenicity, and a significant proportion were coagulase-negative staphylococci.¹⁰ Another study showed that the frequency of detecting new pathogens by repeat culture in recurrent febrile neutropenia was higher than that in persistent febrile neutropenia (8% vs 2%) (P = .0491); a history of recent bacteremia was identified as a significant predictor of positive culture in recurrent febrile neutropenia.¹¹

Persistent or new infection

Persistence of fever, leukocytosis, or other signs of infection 72 hours after appropriate antibiotic therapy is started requires follow-up blood cultures.

New episode of sepsis. A new episode of sepsis should be confirmed¹² using the systemic inflammatory response syndrome criteria, the newer definition of Sepsis-related Organ Failure Assessment (SOFA) in the intensive-care unit, or the quick SOFA in general units. If the patient develops new signs of sepsis after response to treatment for initial bacteremia, repeat blood cultures should be considered.

Central line-associated bloodstream infection requires repeat cultures.¹³ Persistence of bacteremia in this type of infection extends the duration of therapy, as most clinicians determine treatment duration from the last negative culture. Persistent bacteremia also influences the decision to salvage or remove the catheter. Microbiologic clearance of bacteremia on blood culture can also guide the time of reinsertion if the catheter was removed.

Concern for an unresolved focus of infection such as abscess, joint infection, or retained catheter is an indication for repeat blood cultures.

Bacteremia of unknown source. In clinical practice, we encounter scenarios in which blood cultures are positive but no source can be identified. In those situations, it is important to repeat blood cultures to document clearance. If bacteremia persists, we need to continue searching for the source.

Repeat blood cultures are not routinely indicated in patients with streptococcal bacteremia, uncomplicated gram-negative bacteremia, and bacteremia associated with localized infection such as cellulitis, community-acquired pneumonia, or pyelonephritis.^2,4 A study of patients with gram-negative bacteremia found that 17 repeated cultures needed to be drawn to yield 1 positive culture.¹⁴

Isolated fever or leukocytosis does not accurately predict bacteremia.⁴ A study that excluded neutropenic and intensive-care patients reported none of the initially negative cultures to be positive when repeated.¹⁵

Ordering repeat cultures in response to persistent fever is a common practice, even though fever is typical in the first 72 hours of antibiotic therapy. Such cultures rarely if ever reveal new pathogens, and results can be predicted based on cultures before the start of antibiotics.¹⁵ For patients on antibiotics, physicians should therefore wait for results of the preantibiotic cultures rather than order new cultures in response to persistent fever.¹⁵

WOULD WE MISS PERSISTENT BACTEREMIA?

In theory, not repeating blood cultures could miss persistent bacteremia, but this is unlikely if the concerns discussed above are considered. Further, persistent bacteremia would result in clinical signs and symptoms that should prompt repeat cultures.

FREQUENCY OF REPEAT BLOOD CULTURES

There are no evidence-based guidelines for the frequency of repeating cultures. The Infectious Diseases Society of America recommends repeating blood cultures 2 to 4 days after the index positive culture in the case of multidrug-resistant S aureus bacteremia, and every day or every other day for candidemia.^6,7,9

A study evaluating the practice patterns of repeating cultures after an initial bacteremia showed that 34.7% were done within 24 hours and 44.7% were done in 2 to 4 days.¹ There is no evidence that repeating blood cultures daily is necessary in these patients. As a general rule, it should be done 48 to 72 hours after a positive culture.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.