In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

 

 

The standard of care

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

 

 

The standard of care

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

 

 

The standard of care

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

Many of the adverse effects of the small-molecule drugs such as azathioprine (Imuran) and methotrexate are those expected from chemical toxicity or inhibition of proliferation, eg, aminotransferase elevation, leukopenia, and alopecia. Mycophenolate mofetil (CellCept) uniquely can cause profound anemia, cyclophosphamide (Cytoxan) elicits cystitis, and many of these drugs trigger virus-associated malignancies. In perhaps 8% of patients, azathioprine causes a systemic hypersensitivity reaction with high fevers, variable rash, leukocytosis, and elevated aminotransferase levels shortly after it is started. Yet we are often slow to recognize this syndrome, as we tend to search for an infection and forget that even immunosuppressive drugs can cause systemic allergic-type reactions. A similar syndrome following initiation of phenytoin (Dilantin) would be recognized far more rapidly.

But the biologic agents, which target specific components of the immune system, resulting in focal immunosuppression and a disturbance in the homeostatic balance of the immune system, elicit some of the more challenging and sometimes paradoxical side effects. Interferon alfa, which has antiviral effects, is also used as an immunomodulator to treat Behçet disease and as part of regimens that treat specific malignancies. Perhaps because it up-regulates the expression of major histocompatibility complex class II molecules on antigen-presenting cells, interferon therapy also triggers several organ-specific autoimmune syndromes, including autoimmune thrombocytopenia, hypothyroidism, hemolytic anemia, hepatitis, and psoriasis.

Even more challenging to understand and sometimes to treat are the inflammatory effects of anti-tumor necrosis factor agents. Drugs of this class can evoke a demyelinating syndrome similar to multiple sclerosis. Further, even though they are used to treat psoriasis, they can also provoke a psoriasiform, often palmar and pustular, reaction.

So as we continue to adopt targeted immunologic therapies and revel in their efficacy, we need to remain humbled by what we don’t yet fully understand about the complexity of what the 19th century physiologist Claude Bernard termed the milieu intérieur (homeostasis) and keep in mind that even the most specific of drugs can have untoward biologic effects by weirdly disrupting our finely balanced immune system.

A 54-year-old woman with hepatitis C virus infection presents with generalized rash, pruritus, and fever over the past week. The rash appeared on her left arm after she received her fifth weekly injection of pegylated interferon alfa 2b, in combination with daily oral ribavirin (Copegus, Rebetol). Over the course of 3 days, it spread to her face and the rest of her body.

Q: What is the most likely clinical diagnosis?

• Stevens-Johnson syndrome
• Mixed cryoglobulinemia
• Acute eczematous drug eruption
• Lichen planus

A: Acute eczematous drug eruption is the most likely diagnosis.

The clinical presentation and laboratory findings suggest (the latter by exclusion) that our patient had an allergic drug reaction to the interferon or to the ribavirin therapy, or to both. Although this combination is a standard treatment for chronic hepatitis C, some patients experience adverse reactions that lead to its discontinuation. Local injection-site reactions are the most prevalent, affecting up to 12% of patients, whereas eczematous dermatoses manifest less commonly, occurring in up to 5% of patients.¹

While awaiting the results of skin biopsy, a careful evaluation of the clinical features of the physical examination and an appropriate laboratory evaluation can rule out other important conditions in the differential diagnosis.

The absence of mucous membrane involvement steers the diagnosis away from Stevens-Johnson syndrome, a life-threatening hypersensitivity condition often triggered by drugs, malignant tumors, and viral infections, which may also affect internal organs. In this condition, skin biopsy specimens would be distinguished by subepidermal bullae and epidermal cell necrosis—neither of which was seen in our patient.

Mixed cryoglobulinemia should always be considered in hepatitis C patients because of the strong association between this infection and the development of cryoglobulins. The rash usually is purpuric, but it may be pleomorphic.^2,3 This vasculitis often manifests with excess cryoglobulins, elevated rheumatoid factor, and low titers of complement in the blood due to consumption by immune complexes. Tissue biopsy would usually show typical vascular changes if performed on fresh lesions.^4,5 The normal levels of these components in our patient coupled with the appearance of her skin makes cryoglobulinemia a less likely cause.

Furthermore, hepatitis C infection, whether or not treated with interferon and ribavirin, can cause an onset or recurrence of other dermatologic conditions, notably lichen planus, psoriasis, vitiligo, and systemic lupus erythematosus.^1–4

In lichen planus, the rash is often described as flat-topped, pruritic, and violaceous. It may involve the extremities, the genitalia, and the oral cavity.^4,5 The difference in quality of the rash compared with the rash in our patient makes lichen planus less likely.

Exclusion of the other conditions in the differential diagnosis, in addition to results from a definitive punch biopsy, solidified the diagnosis in our patient. Skin biopsy of the patient’s lower-extremity lesions revealed spongiotic dermatitis with lymphocytes, neutrophils, and few eosinophils—a finding characteristic of an acute eczematous drug eruption. Improvement of her rash after discontinuation of interferon and ribavirin further supported this conclusion, although it was unclear whether one or both agents were responsible.

OUTCOME

Management of acute eczematous drug eruption entails stopping the offending drug and alleviating the symptoms. Our patient’s non-life-threatening rash improved dramatically with cessation of interferon and ribavirin. She received a single dose of a systemic corticosteroid initially, out of concern for a severe medication-induced reaction (ie, Stevens-Johnson syndrome), but she was otherwise maintained with diphenhydramine (Benadryl) and a multivitamin ointment for the rash throughout her 9-day hospital stay. Her pruritus was well controlled with hydroxyzine (Atarax, Vistaril). At discharge, she was referred back to her hepatologist for further treatment of her hepatitis C, possibly with interferon and ribavirin again.

TAKE-HOME MESSAGE

Adverse reactions to interferon and ribavirin treatment in hepatitis C patients can manifest dermatologically, and the combination therapy should be discontinued to prevent further insult. A broad variety of conditions in the differential diagnosis should be taken into account, but dermatologic conditions that occur or recur specifically in hepatitis C patients should be considered as well.

A 54-year-old woman with hepatitis C virus infection presents with generalized rash, pruritus, and fever over the past week. The rash appeared on her left arm after she received her fifth weekly injection of pegylated interferon alfa 2b, in combination with daily oral ribavirin (Copegus, Rebetol). Over the course of 3 days, it spread to her face and the rest of her body.

Q: What is the most likely clinical diagnosis?

• Stevens-Johnson syndrome
• Mixed cryoglobulinemia
• Acute eczematous drug eruption
• Lichen planus

A: Acute eczematous drug eruption is the most likely diagnosis.

The clinical presentation and laboratory findings suggest (the latter by exclusion) that our patient had an allergic drug reaction to the interferon or to the ribavirin therapy, or to both. Although this combination is a standard treatment for chronic hepatitis C, some patients experience adverse reactions that lead to its discontinuation. Local injection-site reactions are the most prevalent, affecting up to 12% of patients, whereas eczematous dermatoses manifest less commonly, occurring in up to 5% of patients.¹

While awaiting the results of skin biopsy, a careful evaluation of the clinical features of the physical examination and an appropriate laboratory evaluation can rule out other important conditions in the differential diagnosis.

The absence of mucous membrane involvement steers the diagnosis away from Stevens-Johnson syndrome, a life-threatening hypersensitivity condition often triggered by drugs, malignant tumors, and viral infections, which may also affect internal organs. In this condition, skin biopsy specimens would be distinguished by subepidermal bullae and epidermal cell necrosis—neither of which was seen in our patient.

Mixed cryoglobulinemia should always be considered in hepatitis C patients because of the strong association between this infection and the development of cryoglobulins. The rash usually is purpuric, but it may be pleomorphic.^2,3 This vasculitis often manifests with excess cryoglobulins, elevated rheumatoid factor, and low titers of complement in the blood due to consumption by immune complexes. Tissue biopsy would usually show typical vascular changes if performed on fresh lesions.^4,5 The normal levels of these components in our patient coupled with the appearance of her skin makes cryoglobulinemia a less likely cause.

Furthermore, hepatitis C infection, whether or not treated with interferon and ribavirin, can cause an onset or recurrence of other dermatologic conditions, notably lichen planus, psoriasis, vitiligo, and systemic lupus erythematosus.^1–4

In lichen planus, the rash is often described as flat-topped, pruritic, and violaceous. It may involve the extremities, the genitalia, and the oral cavity.^4,5 The difference in quality of the rash compared with the rash in our patient makes lichen planus less likely.

Exclusion of the other conditions in the differential diagnosis, in addition to results from a definitive punch biopsy, solidified the diagnosis in our patient. Skin biopsy of the patient’s lower-extremity lesions revealed spongiotic dermatitis with lymphocytes, neutrophils, and few eosinophils—a finding characteristic of an acute eczematous drug eruption. Improvement of her rash after discontinuation of interferon and ribavirin further supported this conclusion, although it was unclear whether one or both agents were responsible.

OUTCOME

Management of acute eczematous drug eruption entails stopping the offending drug and alleviating the symptoms. Our patient’s non-life-threatening rash improved dramatically with cessation of interferon and ribavirin. She received a single dose of a systemic corticosteroid initially, out of concern for a severe medication-induced reaction (ie, Stevens-Johnson syndrome), but she was otherwise maintained with diphenhydramine (Benadryl) and a multivitamin ointment for the rash throughout her 9-day hospital stay. Her pruritus was well controlled with hydroxyzine (Atarax, Vistaril). At discharge, she was referred back to her hepatologist for further treatment of her hepatitis C, possibly with interferon and ribavirin again.

TAKE-HOME MESSAGE

Adverse reactions to interferon and ribavirin treatment in hepatitis C patients can manifest dermatologically, and the combination therapy should be discontinued to prevent further insult. A broad variety of conditions in the differential diagnosis should be taken into account, but dermatologic conditions that occur or recur specifically in hepatitis C patients should be considered as well.

A 54-year-old woman with hepatitis C virus infection presents with generalized rash, pruritus, and fever over the past week. The rash appeared on her left arm after she received her fifth weekly injection of pegylated interferon alfa 2b, in combination with daily oral ribavirin (Copegus, Rebetol). Over the course of 3 days, it spread to her face and the rest of her body.

Q: What is the most likely clinical diagnosis?

• Stevens-Johnson syndrome
• Mixed cryoglobulinemia
• Acute eczematous drug eruption
• Lichen planus

A: Acute eczematous drug eruption is the most likely diagnosis.

The clinical presentation and laboratory findings suggest (the latter by exclusion) that our patient had an allergic drug reaction to the interferon or to the ribavirin therapy, or to both. Although this combination is a standard treatment for chronic hepatitis C, some patients experience adverse reactions that lead to its discontinuation. Local injection-site reactions are the most prevalent, affecting up to 12% of patients, whereas eczematous dermatoses manifest less commonly, occurring in up to 5% of patients.¹

While awaiting the results of skin biopsy, a careful evaluation of the clinical features of the physical examination and an appropriate laboratory evaluation can rule out other important conditions in the differential diagnosis.

The absence of mucous membrane involvement steers the diagnosis away from Stevens-Johnson syndrome, a life-threatening hypersensitivity condition often triggered by drugs, malignant tumors, and viral infections, which may also affect internal organs. In this condition, skin biopsy specimens would be distinguished by subepidermal bullae and epidermal cell necrosis—neither of which was seen in our patient.

Mixed cryoglobulinemia should always be considered in hepatitis C patients because of the strong association between this infection and the development of cryoglobulins. The rash usually is purpuric, but it may be pleomorphic.^2,3 This vasculitis often manifests with excess cryoglobulins, elevated rheumatoid factor, and low titers of complement in the blood due to consumption by immune complexes. Tissue biopsy would usually show typical vascular changes if performed on fresh lesions.^4,5 The normal levels of these components in our patient coupled with the appearance of her skin makes cryoglobulinemia a less likely cause.

Furthermore, hepatitis C infection, whether or not treated with interferon and ribavirin, can cause an onset or recurrence of other dermatologic conditions, notably lichen planus, psoriasis, vitiligo, and systemic lupus erythematosus.^1–4

In lichen planus, the rash is often described as flat-topped, pruritic, and violaceous. It may involve the extremities, the genitalia, and the oral cavity.^4,5 The difference in quality of the rash compared with the rash in our patient makes lichen planus less likely.

Exclusion of the other conditions in the differential diagnosis, in addition to results from a definitive punch biopsy, solidified the diagnosis in our patient. Skin biopsy of the patient’s lower-extremity lesions revealed spongiotic dermatitis with lymphocytes, neutrophils, and few eosinophils—a finding characteristic of an acute eczematous drug eruption. Improvement of her rash after discontinuation of interferon and ribavirin further supported this conclusion, although it was unclear whether one or both agents were responsible.

OUTCOME

Management of acute eczematous drug eruption entails stopping the offending drug and alleviating the symptoms. Our patient’s non-life-threatening rash improved dramatically with cessation of interferon and ribavirin. She received a single dose of a systemic corticosteroid initially, out of concern for a severe medication-induced reaction (ie, Stevens-Johnson syndrome), but she was otherwise maintained with diphenhydramine (Benadryl) and a multivitamin ointment for the rash throughout her 9-day hospital stay. Her pruritus was well controlled with hydroxyzine (Atarax, Vistaril). At discharge, she was referred back to her hepatologist for further treatment of her hepatitis C, possibly with interferon and ribavirin again.

TAKE-HOME MESSAGE

Adverse reactions to interferon and ribavirin treatment in hepatitis C patients can manifest dermatologically, and the combination therapy should be discontinued to prevent further insult. A broad variety of conditions in the differential diagnosis should be taken into account, but dermatologic conditions that occur or recur specifically in hepatitis C patients should be considered as well.

Some 90% of patients with cancer experience pain during their illness.¹ The pain usually worsens as the disease progresses, and patients may experience different types of pain.

Persistent pain decreases function, appetite, and sleep, induces fear, causes depression, and generally lowers the quality of life.² Persistent pain is demoralizing and debilitating for patients and their caregivers.³

Adequate pain control is important to ensure that patients can function productively, maintain social relationships, and improve their quality of life.² Yet 86% of practicing physicians surveyed believed that most cancer patients with pain were undermedicated,² and most felt that pain management is unsuccessful in more than half of patients who seek help.³

The critical importance of pain management has been emphasized by the World Health Organization (WHO), by international and national professional organizations, and by government agencies. All practitioners who care for cancer patients need to be well educated in managing cancer pain, a key part of which is to educate patients about the process and what to expect. This results in better pain control.⁴

Although much has been written on the management of cancer pain in a referral setting, little has been published on how to manage it in primary care. In this article, we discuss common questions faced by generalists. We emphasize the use of opioids, perhaps the most challenging aspect of cancer pain management. We also discuss when consultation with a specialist in pain management or a palliative medicine specialist is especially helpful.

WHAT ARE THE DIFFERENT TYPES OF PAIN SYNDROMES?

Pain is classified in several ways^1–6:

Nociceptive vs neuropathic. Nociceptive pain comprises somatic and visceral components and is the result of continued tissue injury.⁴ Neuropathic pain is due to injury to the peripheral and central nervous systems and occurs within an area of sensory or motor deficit.

Continuous vs intermittent. Continuous pain, even if controlled, can have breakthroughs, ie, flares of pain above the controlled baseline level. Intermittent pain is a pain flare without chronic baseline pain. Intermittent pain is further divided into incident pain (ie, on movement) and end-of-dose failure (ie, pain occurring just before the next scheduled opioid dose).⁵ Pain specialists continue to debate the meaning and the use of these terms.

Malignant vs nonmalignant. Cancer pain is multifactorial,¹ being induced by the disease itself, by the treatment of cancer, and by pain unrelated to cancer or its treatment (eg, osteoarthritis or diabetic neuropathy).²

Familiarity with the causes and the types of pain, including pain related to cancer, is important, as this influences treatment decisions.

HOW IS PAIN ASSESSED?

The assessment of pain is vital in managing it.

Since pain is inherently subjective, the patient’s self-report is the gold standard.⁴ Characteristics of the pain along with a physical examination, laboratory testing, and imaging studies can define the pathophysiology of the pain and influence the decision to undertake further assessment or specific therapies.

Patients and physicians can use various scales, such as a visual analog scale, a numerical rating scale, a graphic scale, a verbal scale, a word descriptor scale, and a functional pain scale. A verbal scale can be used if the patient is alert, or a nonverbal scale if the patient has impaired cognition or speaks a different language. Intensity is the most common dimension evaluated in cancer pain, primarily via a numerical or visual analog scale. A numerical scale score of 0 to 10 has been found to be as effective as a visual analog scale (0 to 100 mm),^7,8 and the numerical rating scale is generally preferred as a measure of pain intensity.⁹

There are no clear guidelines for selecting one scale over another.⁷ A clinically meaningful response (ie, meaningful to patients) is at least a two-point decrease on the 10-point numerical scale or a 13-mm decrease on the 100-mm visual analog scale. A decrease in the percentage of the pain relates to global improvement better than an absolute reduction on the numerical scale.

WHAT PROBLEMS ARE ENCOUNTERED IN MANAGING CANCER PAIN?

WHAT ARE THE DIFFERENT WAYS TO MANAGE CANCER PAIN?

Pain should be treated promptly and aggressively, because if untreated it can lead to delays in healing, changes in the central nervous system (eg, sensitization, plasticity), chronic stress, family stress, depression, job loss, and even suicide.^12–14

Comprehensive pain management improves outcomes and includes the rational use of opioids and adjuvant analgesics, physical rehabilitation, cognitive behavioral (non-drug) therapies, family counseling, interventional procedures (kyphoplasty, nerve blocks, local injections, spinal analgesia), and complementary therapies such as acupuncture.¹² Adjuvant analgesics include antidepressants, anticonvulsants, and local anesthetics.

HOW DO OPIOIDS RELIEVE CANCER PAIN?

Opioids bind to receptors in tissues throughout the body, including in the central and peripheral nervous systems¹⁵ and the digestive tract. The binding of an opioid to an opioid receptor—including mu, kappa, and delta receptors and orphan receptor-like ligand-1—initiates a cascade of intracellular reactions. Due to the nature of different interactions of opioids with each of these receptors, individuals vary in their response to opioids.¹⁵

WHAT ARE THE CHARACTERISTICS OF COMMON OPIOIDS?

• Step 1. Mild pain calls for a nonopioid analgesic with or without an adjuvant (more about adjuvants below).
• Step 2. Mild or moderate pain that persists or increases calls for a weak opioid such as codeine, tramadol (Ultram), or hydrocodone, with or without a nonopioid and with or without an adjuvant.
• Step 3. Severe pain calls for a strong opioid with or without a nonopioid, and with or without an adjuvant.

Morphine, the prototypical opioid, is well studied and versatile, as it can be given orally, parenterally, rectally, or intraspinally. It is readily available in the United States and Western Europe but not in some parts of the world, such as Asia and Africa. It is also cost-effective.

Hydromorphone (Dilaudid) is similar to morphine in terms of versatility, cost, and effectiveness in pain management. An extended-release form (Exalgo) is now available in the United States.

Oxycodone is readily available in both slow-release (eg, OxyContin) and immediate-release (eg, Oxy-IR) preparations and is also cost-effective. However, there is no parenteral formulation in the United States.

Methadone is inexpensive and can be used as a long-acting or an immediate-release opioid. However, it should be used with caution in patients with a prolonged QTc interval: in general, a QTc interval of 430 to 450 msec is not a contraindication, but there is a risk of torsades de pointes when the QTc is greater than 500 msec. The physician should also look for drug interactions when prescribing methadone, which is metabolized in the liver via the cytochrome P450 3A4 system. Methadone use can also lead to respiratory depression, prolonged QTc interval, and sudden death.

Buprenorphine can be used as a third- or fourth-tier opioid for patients with both kidney and liver failure. It can be given sublingually or parenterally. It may not be readily available, may not be covered by insurance, and is expensive.

Selecting an opioid to try first

The following are some general considerations when selecting an opioid to try first:

• Does the patient have a history of organ failure? Has the patient had a therapeutic response to, or adverse effects from, a particular opioid in the past?
• Which route would best fit the patient’s needs? (Oral is always preferable.)
• How often will breakthrough dosing be required? (In general, the breakthrough dose is administered at the drug’s half-life, but it can be administered between 1 and 4 hours.)
• How much will it cost? (Consider the cost, insurance coverage, and co-pays.)

Table 2 shows different characteristics of commonly used opioids, including route of administration, onset of action, peak effect, and duration of action.¹

WHAT ARE THE EQUIANALGESIC DOSES OF COMMONLY USED OPIOIDS?

Table 3 lists equianalgesic doses and route conversions of commonly used opioids.^18–20

WHAT ARE THE PRINCIPLES BEHIND OPIOID DOSING?

Table 4 shows important strategies for opioid dosing. An in-depth discussion of specific opioid dosing strategies is beyond the scope of this article.⁵

WHAT ARE THE COMMON ADVERSE EFFECTS OF OPIOIDS?

Adverse effects are among the most common reasons for failure of opioids to relieve pain. If these effects are not anticipated and treated prophylactically, patients may avoid taking their opioid drugs or may complain that they are “allergic” to them. In reality, true allergy to any of the opioids is rare. Patients comply better if they are taught to expect that most adverse effects are either preventable or manageable.²¹ A simple strategy includes reducing the opioid dose by 25% to 50%, using different opioids (“rotation”), changing the route of administration, and directly treating adverse effects.^21,22

WHAT IS OPIOID ROTATION AND HOW IS IT DONE?

Opioid rotation involves changing to a different drug using the same administration route, with the aim of improving the analgesic response or reducing adverse effects.¹⁶ It may be useful in widening the therapeutic window, ie, establishing a more advantageous relationship between analgesia and toxicity.¹⁶ This strategy applies, for example, to patients who have an adverse reaction to morphine, and who may need rotation to fentanyl or methadone.

The major indication for switching opioids is poorly controlled pain with unacceptable adverse effects due to opioid toxicity, the rapid development of tolerance, refractory pain, or difficult pain syndromes.²⁴ A recent prospective study showed that 42% of patients underwent opioid rotation, and the two most common reasons were inadequate analgesia and severe adverse effects.²⁵ Opioid rotation resulted in relief of confusion (72%), nausea and vomiting (68%), and drowsiness (53%).²⁵

Before trying opioid rotation, review the patient’s pain syndromes and the use of an adjuvant analgesic, and assess for evidence of opioid toxicity or contributing abnormal biochemical factors such as hydration status.^24,26 Most opioids are mu-receptor agonists and may exhibit cross-tolerance, a phenomenon in which the alternative drug does not have the expected effects because of similar pharmacologic action of the first drug. Because the degree of cross-tolerance may change as opioid doses are escalated, it is advisable to proceed with caution when switching from one opioid to another in patients who are receiving very high doses. Opioid rotation generally would be ineffective if there is complete analgesic cross-tolerance between opioids.

The common equivalency conversion tables are based either on studies in patients who received low doses of opioids or on single-dose studies.^16,24 By substituting opioids and using lower doses than expected according to the equivalency conversion tables (generally a 25% to 30% decrease), it is possible in most cases to reduce or relieve the symptoms of opioid toxicity and to manage patients highly tolerant to previous opioids while improving analgesia.²⁴

Alternatives to opioid rotation are route conversion (oral to parenteral or spinal), addition of an adjuvant analgesic, and opioid dose reduction.

WHAT IS OPIOID TOXICITY AND HOW IS IT MANAGED?

Opioid overdose is commonly the result of an error in pain assessment, opioid prescribing, or dose administration. Opioid overdose classically presents as sedation or respiratory depression. The combination of coma, reduced respiratory rate, and pinpoint pupils is highly suggestive of opioid toxicity, and treatment should be initiated promptly.

This scenario, however, is the extreme example of opioid overdose, and it is rare when a patient is given the correct opioid dose titrated gradually over a period of time. The more common scenario is when a patient’s pain has finally been managed and the patient is resting comfortably with slow respirations. This would not warrant naloxone (Narcan) administration but rather close observation and monitoring of vital signs.

Naloxone has antagonist activity at all of the receptor sites.²⁷ It is important to be alert for acute opioid withdrawal in patients taking high-dose opioids for a long time.²⁷ There are no guidelines as to the route of administration and the dosing of naloxone. Table 6 summarizes the management of opioid overdose using naloxone.⁵

WHAT IS THE ROLE OF ADJUVANTS?

An adjuvant analgesic is any drug with a primary indication other than pain, but with analgesic properties in some painful conditions. Adjuvants are best used when a patient cannot obtain satisfactory pain relief from an opioid.²⁸ Antidepressants, anticonvulsants, neuroleptics, antiarrhythmics, antihistamines, N-methyl-d-aspartate (NMDA) receptor antagonists, steroids, muscle relaxants, bisphosphonates, and radiopharmaceuticals can be adjuvant agents.²⁹

Adjuvants are generally used to complement the analgesic effects of opioids to achieve optimal pain control with a minimum of adverse effects.²⁸ The following scenarios should prompt the use of adjuvants in clinical practice²⁸:

• The toxic limit of a primary pain medication has been reached.
• The therapeutic benefit of the primary pain medication has reached a plateau.
• The primary analgesic could not be used because of substance-abuse behavior, multiple organ failure, allergy, etc.
• The patient has multiple pain syndromes.
• The patient has additional symptoms unrelated to pain, eg, insomnia or depression.

Table 7 lists adjuvants with specific indications and points to remember when prescribing them.^28,29

WHAT IS THE ROLE OF NSAIDs FOR CANCER PAIN?

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established role in treating cancer-related pain, either on their own for mild pain or in combination with opioids for moderate to severe pain, leading to additive analgesia. Using NSAIDs as adjuvants is common practice in certain cancer pain syndromes, such as malignant bone pain, although there is considerable variation in response.³¹

NSAIDs have long been known to inhibit peripheral prostaglandin synthesis, but recently they have also been suggested to have a central action. The central effect is related to NMDA receptor-induced activation of the nitric oxide system.³¹

NSAIDs have ceiling effects, and there is no therapeutic advantage to increasing the dose beyond that which is recommended.

Ketorolac (Toradol), indomethacin (Indocin), and diclofenac (Voltaren) have potent analgesic activity, whereas the “oxicam” NSAIDs show predominantly anti-inflammatory effects.³⁰

No NSAID is clearly superior for a particular type of pain. Certain NSAIDs block the NMDA receptor and inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. There is a poor correlation between the analgesic effects of NSAIDs and cyclo-oxygenase inhibition. There is no evidence to support the use of selective cyclo-oxygenase-2 inhibitors for cancer pain, and these agents have no advantage over nonselective NSAIDs on the basis of limited gastrointestinal toxicity.³²

In cancer pain, NSAIDs may delay the development of tolerance and allow lower doses of opioids to be used, with fewer central nervous system side effects.^31,32 Despite the extensive use of NSAIDs, relatively few randomized studies have documented their efficacy in cancer pain compared with other chronic pain syndromes. Data on safe and effective doses from studies of nonmalignant pain may not apply to cancer pain, since cancer patients often have several serious conditions and are on multiple medications. In addition, the potential for adverse effects of NSAIDs (gastrointestinal bleeding, renal failure, thrombosis) may be greater in patients with advanced cancer.

In conclusion, NSAIDs may help if used judiciously in somatic pain and visceral pain, and perhaps even in neuropathic pain.³¹

HOW IS CANCER PAIN MANAGED IN PATIENTS WITH ORGAN FAILURE?

• Opioids that can be used in liver failure or cirrhosis: morphine, hydromorphone, methadone, levorphanol, buprenorphine.
• Opioids that can be used in renal failure: methadone, fentanyl, and buprenorphine are safest; oxycodone and hydromorphone are moderately safe; morphine is the least safe.^35,36
• Opioids that can be used in both kidney and liver failure: methadone, buprenorphine.

HOW CAN PROBLEMS RELATED TO SUBSTANCE ABUSE BE AVOIDED?

Substance abuse is less a problem in managing cancer pain than in chronic nonmalignant pain. Prescribing opioids safely is challenging, and very little has been published on substance abuse and the management of cancer pain. However, in the absence of practice guidelines, the best approach is to establish a dosing structure, control prescription refills, and monitor the patient.

Abuse is the misuse of an opioid via self-titration or altering the dosing schedule or route of administration. Patients who misuse opioids—ie, take them differently than prescribed—are not necessarily addicted.

Addiction is the abuse of a drug associated with psychological dependence, despite harm.

Diversion can occur without addiction and is done for financial gain, and this is the worst offense as it may harm others.

Pseudoaddiction is abnormal, demanding, often hostile behavior resulting from uncontrolled pain; once the pain is controlled, the behavior resolves.

Behaviors such as forging prescriptions, stealing or borrowing drugs, frequently “losing” prescriptions, and resisting changes to medication despite adverse effects are more predictive of addiction than are behaviors such as aggressive complaining about the need for more drugs, drug-hoarding, and unsanctioned dose escalations or other forms of noncompliance, as the latter three are more likely to indicate poorly controlled pain.³⁷

Predictors of opioid abuse include a family history or a personal history of alcohol or drug abuse (including prescription drugs); a history of psychiatric illness (including anxiety disorder); male sex; nonwhite race; a history of driving under the influence of alcohol or drugs; a record of drug-related convictions; lost or stolen prescriptions; and using supplemental sources to obtain opioids.³⁸ Socioeconomic status and disability level were not found to be significant predictors.³⁸

Different scales are available to predict the risk of aberrant drug behavior in patients on chronic opioid therapy. Of the many available, the Screener and Opioid Assessment for Patients With Pain and the Current Opioid Misuse Measure assess all the key factors.³⁸

After an assessment, the next step is monitoring. Unfortunately, no specific method has been validated. In one study, urine toxicology testing was more effective at identifying problems than monitoring patient behavior alone, and monitoring behavior alone would have resulted in missing about half of the patients with a problem.³⁹ The same study showed that even in the absence of aberrant drug-related behavior based on predictors, a significant number of urine toxicology screens were positive.³⁹

A negative urine screen for the patient’s opioid suggests diversion. The clinician should order a screen for the prescribed opioid because a general screen may not detect nonmorphine opioids. A general screen may detect polysubstance abuse, which is common in individuals with addiction.

Table 9 summarizes a strategy to manage opioid therapy in patients with history of substance abuse.⁴⁰

WHAT IS THE ROLE OF COMPLEMENTARY AND ALTERNATIVE THERAPIES?

Complementary and alternative medicine therapies are commonly used by cancer patients, with an average prevalence rate of 31%.^41–43 As the names suggest, they have been used both as an alternative to and as a complement to conventional medicine. Practitioners of complementary and alternative medicine emphasize its holistic, individualistic, empowering, and educational nature.

Patients do not routinely ask their physicians about these therapies,⁴⁴ and physicians often have only a limited knowledge of them.⁴⁵ Surveys of North American physicians showed that they view certain of these therapies as legitimate and effective.^46,47

The role of complementary and alternative medicine in cancer pain has been the subject of debate, as relatively little is known about adverse effects and drug interactions. Nevertheless, the American Cancer Society and the National Comprehensive Cancer Network guidelines on cancer pain recommend nonpharmacologic treatment be added for patients who report a pain score of 4 or greater on a 10-point scale after analgesic adjustment.^48,49

Most studies of complementary and alternative therapies for cancer pain are of poor quality, with significant shortcomings in methodology and study design and with no clear definition of outcomes.⁵⁰

Acupuncture is probably the most studied of these therapies, but clinical trials so far have not shown it to be an effective adjunct analgesic for cancer pain.⁵¹ A placebo-controlled, blinded randomized trial using auricular acupuncture showed a pain score decrease of 36% from baseline at 2 months compared with controls.⁵²

Studies involving cognitive therapy, supportive psychotherapy, and hypnosis showed modest benefit.^53,54 Two trials involving relaxation and imagery reduced cancer pain compared with controls.^55,56

Studies of massage therapy have shown mixed results; two studies reported a significant reduction in pain immediately after intervention, and no study found pain relief after 4 weeks.^57–60 Studies involving Reiki and touch therapy were inconclusive.^60,61

Music therapy has been used to treat patients physically, psychologically, socially, emotionally, and spiritually, with evidence still equivocal. A large prospective observational study involving 200 patients conducted by Gallagher et al⁶² showed pain was reduced by 30% after music therapy intervention. The same study showed a reduction in depression and anxiety.⁶² Music therapy could be used as a component of a multimodal approach to pain.

Herbal preparations are often used to treat cancer and symptoms by patients and naturalists. Some herbal medicines are known to cause toxicity in cancer patients. Examples are PC-SPES, mistletoe, and saw palmetto.⁶³

At this juncture, there is some evidence that some complementary and alternative therapies can relieve cancer pain, and the most promising therapy seems to be related to mind-body medicine (eg, biofeedback, relaxation techniques). But before we can legitimately integrate these therapies into the management of cancer pain, we need large randomized controlled trials to determine if they are effective in patients on chronic high-dose opioids and if they decrease the need for opioids.

Some 90% of patients with cancer experience pain during their illness.¹ The pain usually worsens as the disease progresses, and patients may experience different types of pain.

Persistent pain decreases function, appetite, and sleep, induces fear, causes depression, and generally lowers the quality of life.² Persistent pain is demoralizing and debilitating for patients and their caregivers.³

Adequate pain control is important to ensure that patients can function productively, maintain social relationships, and improve their quality of life.² Yet 86% of practicing physicians surveyed believed that most cancer patients with pain were undermedicated,² and most felt that pain management is unsuccessful in more than half of patients who seek help.³

The critical importance of pain management has been emphasized by the World Health Organization (WHO), by international and national professional organizations, and by government agencies. All practitioners who care for cancer patients need to be well educated in managing cancer pain, a key part of which is to educate patients about the process and what to expect. This results in better pain control.⁴

Although much has been written on the management of cancer pain in a referral setting, little has been published on how to manage it in primary care. In this article, we discuss common questions faced by generalists. We emphasize the use of opioids, perhaps the most challenging aspect of cancer pain management. We also discuss when consultation with a specialist in pain management or a palliative medicine specialist is especially helpful.

WHAT ARE THE DIFFERENT TYPES OF PAIN SYNDROMES?

Pain is classified in several ways^1–6:

Nociceptive vs neuropathic. Nociceptive pain comprises somatic and visceral components and is the result of continued tissue injury.⁴ Neuropathic pain is due to injury to the peripheral and central nervous systems and occurs within an area of sensory or motor deficit.

Continuous vs intermittent. Continuous pain, even if controlled, can have breakthroughs, ie, flares of pain above the controlled baseline level. Intermittent pain is a pain flare without chronic baseline pain. Intermittent pain is further divided into incident pain (ie, on movement) and end-of-dose failure (ie, pain occurring just before the next scheduled opioid dose).⁵ Pain specialists continue to debate the meaning and the use of these terms.

Malignant vs nonmalignant. Cancer pain is multifactorial,¹ being induced by the disease itself, by the treatment of cancer, and by pain unrelated to cancer or its treatment (eg, osteoarthritis or diabetic neuropathy).²

Familiarity with the causes and the types of pain, including pain related to cancer, is important, as this influences treatment decisions.

HOW IS PAIN ASSESSED?

The assessment of pain is vital in managing it.

Since pain is inherently subjective, the patient’s self-report is the gold standard.⁴ Characteristics of the pain along with a physical examination, laboratory testing, and imaging studies can define the pathophysiology of the pain and influence the decision to undertake further assessment or specific therapies.

Patients and physicians can use various scales, such as a visual analog scale, a numerical rating scale, a graphic scale, a verbal scale, a word descriptor scale, and a functional pain scale. A verbal scale can be used if the patient is alert, or a nonverbal scale if the patient has impaired cognition or speaks a different language. Intensity is the most common dimension evaluated in cancer pain, primarily via a numerical or visual analog scale. A numerical scale score of 0 to 10 has been found to be as effective as a visual analog scale (0 to 100 mm),^7,8 and the numerical rating scale is generally preferred as a measure of pain intensity.⁹

There are no clear guidelines for selecting one scale over another.⁷ A clinically meaningful response (ie, meaningful to patients) is at least a two-point decrease on the 10-point numerical scale or a 13-mm decrease on the 100-mm visual analog scale. A decrease in the percentage of the pain relates to global improvement better than an absolute reduction on the numerical scale.

WHAT PROBLEMS ARE ENCOUNTERED IN MANAGING CANCER PAIN?

WHAT ARE THE DIFFERENT WAYS TO MANAGE CANCER PAIN?

Pain should be treated promptly and aggressively, because if untreated it can lead to delays in healing, changes in the central nervous system (eg, sensitization, plasticity), chronic stress, family stress, depression, job loss, and even suicide.^12–14

Comprehensive pain management improves outcomes and includes the rational use of opioids and adjuvant analgesics, physical rehabilitation, cognitive behavioral (non-drug) therapies, family counseling, interventional procedures (kyphoplasty, nerve blocks, local injections, spinal analgesia), and complementary therapies such as acupuncture.¹² Adjuvant analgesics include antidepressants, anticonvulsants, and local anesthetics.

HOW DO OPIOIDS RELIEVE CANCER PAIN?

Opioids bind to receptors in tissues throughout the body, including in the central and peripheral nervous systems¹⁵ and the digestive tract. The binding of an opioid to an opioid receptor—including mu, kappa, and delta receptors and orphan receptor-like ligand-1—initiates a cascade of intracellular reactions. Due to the nature of different interactions of opioids with each of these receptors, individuals vary in their response to opioids.¹⁵

WHAT ARE THE CHARACTERISTICS OF COMMON OPIOIDS?

• Step 1. Mild pain calls for a nonopioid analgesic with or without an adjuvant (more about adjuvants below).
• Step 2. Mild or moderate pain that persists or increases calls for a weak opioid such as codeine, tramadol (Ultram), or hydrocodone, with or without a nonopioid and with or without an adjuvant.
• Step 3. Severe pain calls for a strong opioid with or without a nonopioid, and with or without an adjuvant.

Morphine, the prototypical opioid, is well studied and versatile, as it can be given orally, parenterally, rectally, or intraspinally. It is readily available in the United States and Western Europe but not in some parts of the world, such as Asia and Africa. It is also cost-effective.

Hydromorphone (Dilaudid) is similar to morphine in terms of versatility, cost, and effectiveness in pain management. An extended-release form (Exalgo) is now available in the United States.

Oxycodone is readily available in both slow-release (eg, OxyContin) and immediate-release (eg, Oxy-IR) preparations and is also cost-effective. However, there is no parenteral formulation in the United States.

Methadone is inexpensive and can be used as a long-acting or an immediate-release opioid. However, it should be used with caution in patients with a prolonged QTc interval: in general, a QTc interval of 430 to 450 msec is not a contraindication, but there is a risk of torsades de pointes when the QTc is greater than 500 msec. The physician should also look for drug interactions when prescribing methadone, which is metabolized in the liver via the cytochrome P450 3A4 system. Methadone use can also lead to respiratory depression, prolonged QTc interval, and sudden death.

Buprenorphine can be used as a third- or fourth-tier opioid for patients with both kidney and liver failure. It can be given sublingually or parenterally. It may not be readily available, may not be covered by insurance, and is expensive.

Selecting an opioid to try first

The following are some general considerations when selecting an opioid to try first:

• Does the patient have a history of organ failure? Has the patient had a therapeutic response to, or adverse effects from, a particular opioid in the past?
• Which route would best fit the patient’s needs? (Oral is always preferable.)
• How often will breakthrough dosing be required? (In general, the breakthrough dose is administered at the drug’s half-life, but it can be administered between 1 and 4 hours.)
• How much will it cost? (Consider the cost, insurance coverage, and co-pays.)

Table 2 shows different characteristics of commonly used opioids, including route of administration, onset of action, peak effect, and duration of action.¹

WHAT ARE THE EQUIANALGESIC DOSES OF COMMONLY USED OPIOIDS?

Table 3 lists equianalgesic doses and route conversions of commonly used opioids.^18–20

WHAT ARE THE PRINCIPLES BEHIND OPIOID DOSING?

Table 4 shows important strategies for opioid dosing. An in-depth discussion of specific opioid dosing strategies is beyond the scope of this article.⁵

WHAT ARE THE COMMON ADVERSE EFFECTS OF OPIOIDS?

Adverse effects are among the most common reasons for failure of opioids to relieve pain. If these effects are not anticipated and treated prophylactically, patients may avoid taking their opioid drugs or may complain that they are “allergic” to them. In reality, true allergy to any of the opioids is rare. Patients comply better if they are taught to expect that most adverse effects are either preventable or manageable.²¹ A simple strategy includes reducing the opioid dose by 25% to 50%, using different opioids (“rotation”), changing the route of administration, and directly treating adverse effects.^21,22

WHAT IS OPIOID ROTATION AND HOW IS IT DONE?

Opioid rotation involves changing to a different drug using the same administration route, with the aim of improving the analgesic response or reducing adverse effects.¹⁶ It may be useful in widening the therapeutic window, ie, establishing a more advantageous relationship between analgesia and toxicity.¹⁶ This strategy applies, for example, to patients who have an adverse reaction to morphine, and who may need rotation to fentanyl or methadone.

The major indication for switching opioids is poorly controlled pain with unacceptable adverse effects due to opioid toxicity, the rapid development of tolerance, refractory pain, or difficult pain syndromes.²⁴ A recent prospective study showed that 42% of patients underwent opioid rotation, and the two most common reasons were inadequate analgesia and severe adverse effects.²⁵ Opioid rotation resulted in relief of confusion (72%), nausea and vomiting (68%), and drowsiness (53%).²⁵

Before trying opioid rotation, review the patient’s pain syndromes and the use of an adjuvant analgesic, and assess for evidence of opioid toxicity or contributing abnormal biochemical factors such as hydration status.^24,26 Most opioids are mu-receptor agonists and may exhibit cross-tolerance, a phenomenon in which the alternative drug does not have the expected effects because of similar pharmacologic action of the first drug. Because the degree of cross-tolerance may change as opioid doses are escalated, it is advisable to proceed with caution when switching from one opioid to another in patients who are receiving very high doses. Opioid rotation generally would be ineffective if there is complete analgesic cross-tolerance between opioids.

The common equivalency conversion tables are based either on studies in patients who received low doses of opioids or on single-dose studies.^16,24 By substituting opioids and using lower doses than expected according to the equivalency conversion tables (generally a 25% to 30% decrease), it is possible in most cases to reduce or relieve the symptoms of opioid toxicity and to manage patients highly tolerant to previous opioids while improving analgesia.²⁴

Alternatives to opioid rotation are route conversion (oral to parenteral or spinal), addition of an adjuvant analgesic, and opioid dose reduction.

WHAT IS OPIOID TOXICITY AND HOW IS IT MANAGED?

Opioid overdose is commonly the result of an error in pain assessment, opioid prescribing, or dose administration. Opioid overdose classically presents as sedation or respiratory depression. The combination of coma, reduced respiratory rate, and pinpoint pupils is highly suggestive of opioid toxicity, and treatment should be initiated promptly.

This scenario, however, is the extreme example of opioid overdose, and it is rare when a patient is given the correct opioid dose titrated gradually over a period of time. The more common scenario is when a patient’s pain has finally been managed and the patient is resting comfortably with slow respirations. This would not warrant naloxone (Narcan) administration but rather close observation and monitoring of vital signs.

Naloxone has antagonist activity at all of the receptor sites.²⁷ It is important to be alert for acute opioid withdrawal in patients taking high-dose opioids for a long time.²⁷ There are no guidelines as to the route of administration and the dosing of naloxone. Table 6 summarizes the management of opioid overdose using naloxone.⁵

WHAT IS THE ROLE OF ADJUVANTS?

An adjuvant analgesic is any drug with a primary indication other than pain, but with analgesic properties in some painful conditions. Adjuvants are best used when a patient cannot obtain satisfactory pain relief from an opioid.²⁸ Antidepressants, anticonvulsants, neuroleptics, antiarrhythmics, antihistamines, N-methyl-d-aspartate (NMDA) receptor antagonists, steroids, muscle relaxants, bisphosphonates, and radiopharmaceuticals can be adjuvant agents.²⁹

Adjuvants are generally used to complement the analgesic effects of opioids to achieve optimal pain control with a minimum of adverse effects.²⁸ The following scenarios should prompt the use of adjuvants in clinical practice²⁸:

• The toxic limit of a primary pain medication has been reached.
• The therapeutic benefit of the primary pain medication has reached a plateau.
• The primary analgesic could not be used because of substance-abuse behavior, multiple organ failure, allergy, etc.
• The patient has multiple pain syndromes.
• The patient has additional symptoms unrelated to pain, eg, insomnia or depression.

Table 7 lists adjuvants with specific indications and points to remember when prescribing them.^28,29

WHAT IS THE ROLE OF NSAIDs FOR CANCER PAIN?

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established role in treating cancer-related pain, either on their own for mild pain or in combination with opioids for moderate to severe pain, leading to additive analgesia. Using NSAIDs as adjuvants is common practice in certain cancer pain syndromes, such as malignant bone pain, although there is considerable variation in response.³¹

NSAIDs have long been known to inhibit peripheral prostaglandin synthesis, but recently they have also been suggested to have a central action. The central effect is related to NMDA receptor-induced activation of the nitric oxide system.³¹

NSAIDs have ceiling effects, and there is no therapeutic advantage to increasing the dose beyond that which is recommended.

Ketorolac (Toradol), indomethacin (Indocin), and diclofenac (Voltaren) have potent analgesic activity, whereas the “oxicam” NSAIDs show predominantly anti-inflammatory effects.³⁰

No NSAID is clearly superior for a particular type of pain. Certain NSAIDs block the NMDA receptor and inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. There is a poor correlation between the analgesic effects of NSAIDs and cyclo-oxygenase inhibition. There is no evidence to support the use of selective cyclo-oxygenase-2 inhibitors for cancer pain, and these agents have no advantage over nonselective NSAIDs on the basis of limited gastrointestinal toxicity.³²

In cancer pain, NSAIDs may delay the development of tolerance and allow lower doses of opioids to be used, with fewer central nervous system side effects.^31,32 Despite the extensive use of NSAIDs, relatively few randomized studies have documented their efficacy in cancer pain compared with other chronic pain syndromes. Data on safe and effective doses from studies of nonmalignant pain may not apply to cancer pain, since cancer patients often have several serious conditions and are on multiple medications. In addition, the potential for adverse effects of NSAIDs (gastrointestinal bleeding, renal failure, thrombosis) may be greater in patients with advanced cancer.

In conclusion, NSAIDs may help if used judiciously in somatic pain and visceral pain, and perhaps even in neuropathic pain.³¹

HOW IS CANCER PAIN MANAGED IN PATIENTS WITH ORGAN FAILURE?

• Opioids that can be used in liver failure or cirrhosis: morphine, hydromorphone, methadone, levorphanol, buprenorphine.
• Opioids that can be used in renal failure: methadone, fentanyl, and buprenorphine are safest; oxycodone and hydromorphone are moderately safe; morphine is the least safe.^35,36
• Opioids that can be used in both kidney and liver failure: methadone, buprenorphine.

HOW CAN PROBLEMS RELATED TO SUBSTANCE ABUSE BE AVOIDED?

Substance abuse is less a problem in managing cancer pain than in chronic nonmalignant pain. Prescribing opioids safely is challenging, and very little has been published on substance abuse and the management of cancer pain. However, in the absence of practice guidelines, the best approach is to establish a dosing structure, control prescription refills, and monitor the patient.

Abuse is the misuse of an opioid via self-titration or altering the dosing schedule or route of administration. Patients who misuse opioids—ie, take them differently than prescribed—are not necessarily addicted.

Addiction is the abuse of a drug associated with psychological dependence, despite harm.

Diversion can occur without addiction and is done for financial gain, and this is the worst offense as it may harm others.

Pseudoaddiction is abnormal, demanding, often hostile behavior resulting from uncontrolled pain; once the pain is controlled, the behavior resolves.

Behaviors such as forging prescriptions, stealing or borrowing drugs, frequently “losing” prescriptions, and resisting changes to medication despite adverse effects are more predictive of addiction than are behaviors such as aggressive complaining about the need for more drugs, drug-hoarding, and unsanctioned dose escalations or other forms of noncompliance, as the latter three are more likely to indicate poorly controlled pain.³⁷

Predictors of opioid abuse include a family history or a personal history of alcohol or drug abuse (including prescription drugs); a history of psychiatric illness (including anxiety disorder); male sex; nonwhite race; a history of driving under the influence of alcohol or drugs; a record of drug-related convictions; lost or stolen prescriptions; and using supplemental sources to obtain opioids.³⁸ Socioeconomic status and disability level were not found to be significant predictors.³⁸

Different scales are available to predict the risk of aberrant drug behavior in patients on chronic opioid therapy. Of the many available, the Screener and Opioid Assessment for Patients With Pain and the Current Opioid Misuse Measure assess all the key factors.³⁸

After an assessment, the next step is monitoring. Unfortunately, no specific method has been validated. In one study, urine toxicology testing was more effective at identifying problems than monitoring patient behavior alone, and monitoring behavior alone would have resulted in missing about half of the patients with a problem.³⁹ The same study showed that even in the absence of aberrant drug-related behavior based on predictors, a significant number of urine toxicology screens were positive.³⁹

A negative urine screen for the patient’s opioid suggests diversion. The clinician should order a screen for the prescribed opioid because a general screen may not detect nonmorphine opioids. A general screen may detect polysubstance abuse, which is common in individuals with addiction.

Table 9 summarizes a strategy to manage opioid therapy in patients with history of substance abuse.⁴⁰

WHAT IS THE ROLE OF COMPLEMENTARY AND ALTERNATIVE THERAPIES?

Complementary and alternative medicine therapies are commonly used by cancer patients, with an average prevalence rate of 31%.^41–43 As the names suggest, they have been used both as an alternative to and as a complement to conventional medicine. Practitioners of complementary and alternative medicine emphasize its holistic, individualistic, empowering, and educational nature.

Patients do not routinely ask their physicians about these therapies,⁴⁴ and physicians often have only a limited knowledge of them.⁴⁵ Surveys of North American physicians showed that they view certain of these therapies as legitimate and effective.^46,47

The role of complementary and alternative medicine in cancer pain has been the subject of debate, as relatively little is known about adverse effects and drug interactions. Nevertheless, the American Cancer Society and the National Comprehensive Cancer Network guidelines on cancer pain recommend nonpharmacologic treatment be added for patients who report a pain score of 4 or greater on a 10-point scale after analgesic adjustment.^48,49

Most studies of complementary and alternative therapies for cancer pain are of poor quality, with significant shortcomings in methodology and study design and with no clear definition of outcomes.⁵⁰

Acupuncture is probably the most studied of these therapies, but clinical trials so far have not shown it to be an effective adjunct analgesic for cancer pain.⁵¹ A placebo-controlled, blinded randomized trial using auricular acupuncture showed a pain score decrease of 36% from baseline at 2 months compared with controls.⁵²

Studies involving cognitive therapy, supportive psychotherapy, and hypnosis showed modest benefit.^53,54 Two trials involving relaxation and imagery reduced cancer pain compared with controls.^55,56

Studies of massage therapy have shown mixed results; two studies reported a significant reduction in pain immediately after intervention, and no study found pain relief after 4 weeks.^57–60 Studies involving Reiki and touch therapy were inconclusive.^60,61

Music therapy has been used to treat patients physically, psychologically, socially, emotionally, and spiritually, with evidence still equivocal. A large prospective observational study involving 200 patients conducted by Gallagher et al⁶² showed pain was reduced by 30% after music therapy intervention. The same study showed a reduction in depression and anxiety.⁶² Music therapy could be used as a component of a multimodal approach to pain.

Herbal preparations are often used to treat cancer and symptoms by patients and naturalists. Some herbal medicines are known to cause toxicity in cancer patients. Examples are PC-SPES, mistletoe, and saw palmetto.⁶³

At this juncture, there is some evidence that some complementary and alternative therapies can relieve cancer pain, and the most promising therapy seems to be related to mind-body medicine (eg, biofeedback, relaxation techniques). But before we can legitimately integrate these therapies into the management of cancer pain, we need large randomized controlled trials to determine if they are effective in patients on chronic high-dose opioids and if they decrease the need for opioids.

Some 90% of patients with cancer experience pain during their illness.¹ The pain usually worsens as the disease progresses, and patients may experience different types of pain.

Persistent pain decreases function, appetite, and sleep, induces fear, causes depression, and generally lowers the quality of life.² Persistent pain is demoralizing and debilitating for patients and their caregivers.³

Adequate pain control is important to ensure that patients can function productively, maintain social relationships, and improve their quality of life.² Yet 86% of practicing physicians surveyed believed that most cancer patients with pain were undermedicated,² and most felt that pain management is unsuccessful in more than half of patients who seek help.³

The critical importance of pain management has been emphasized by the World Health Organization (WHO), by international and national professional organizations, and by government agencies. All practitioners who care for cancer patients need to be well educated in managing cancer pain, a key part of which is to educate patients about the process and what to expect. This results in better pain control.⁴

Although much has been written on the management of cancer pain in a referral setting, little has been published on how to manage it in primary care. In this article, we discuss common questions faced by generalists. We emphasize the use of opioids, perhaps the most challenging aspect of cancer pain management. We also discuss when consultation with a specialist in pain management or a palliative medicine specialist is especially helpful.

WHAT ARE THE DIFFERENT TYPES OF PAIN SYNDROMES?

Pain is classified in several ways^1–6:

Nociceptive vs neuropathic. Nociceptive pain comprises somatic and visceral components and is the result of continued tissue injury.⁴ Neuropathic pain is due to injury to the peripheral and central nervous systems and occurs within an area of sensory or motor deficit.

Continuous vs intermittent. Continuous pain, even if controlled, can have breakthroughs, ie, flares of pain above the controlled baseline level. Intermittent pain is a pain flare without chronic baseline pain. Intermittent pain is further divided into incident pain (ie, on movement) and end-of-dose failure (ie, pain occurring just before the next scheduled opioid dose).⁵ Pain specialists continue to debate the meaning and the use of these terms.

Malignant vs nonmalignant. Cancer pain is multifactorial,¹ being induced by the disease itself, by the treatment of cancer, and by pain unrelated to cancer or its treatment (eg, osteoarthritis or diabetic neuropathy).²

Familiarity with the causes and the types of pain, including pain related to cancer, is important, as this influences treatment decisions.

HOW IS PAIN ASSESSED?

The assessment of pain is vital in managing it.

Since pain is inherently subjective, the patient’s self-report is the gold standard.⁴ Characteristics of the pain along with a physical examination, laboratory testing, and imaging studies can define the pathophysiology of the pain and influence the decision to undertake further assessment or specific therapies.

Patients and physicians can use various scales, such as a visual analog scale, a numerical rating scale, a graphic scale, a verbal scale, a word descriptor scale, and a functional pain scale. A verbal scale can be used if the patient is alert, or a nonverbal scale if the patient has impaired cognition or speaks a different language. Intensity is the most common dimension evaluated in cancer pain, primarily via a numerical or visual analog scale. A numerical scale score of 0 to 10 has been found to be as effective as a visual analog scale (0 to 100 mm),^7,8 and the numerical rating scale is generally preferred as a measure of pain intensity.⁹

There are no clear guidelines for selecting one scale over another.⁷ A clinically meaningful response (ie, meaningful to patients) is at least a two-point decrease on the 10-point numerical scale or a 13-mm decrease on the 100-mm visual analog scale. A decrease in the percentage of the pain relates to global improvement better than an absolute reduction on the numerical scale.

WHAT PROBLEMS ARE ENCOUNTERED IN MANAGING CANCER PAIN?

WHAT ARE THE DIFFERENT WAYS TO MANAGE CANCER PAIN?

Pain should be treated promptly and aggressively, because if untreated it can lead to delays in healing, changes in the central nervous system (eg, sensitization, plasticity), chronic stress, family stress, depression, job loss, and even suicide.^12–14

Comprehensive pain management improves outcomes and includes the rational use of opioids and adjuvant analgesics, physical rehabilitation, cognitive behavioral (non-drug) therapies, family counseling, interventional procedures (kyphoplasty, nerve blocks, local injections, spinal analgesia), and complementary therapies such as acupuncture.¹² Adjuvant analgesics include antidepressants, anticonvulsants, and local anesthetics.

HOW DO OPIOIDS RELIEVE CANCER PAIN?

Opioids bind to receptors in tissues throughout the body, including in the central and peripheral nervous systems¹⁵ and the digestive tract. The binding of an opioid to an opioid receptor—including mu, kappa, and delta receptors and orphan receptor-like ligand-1—initiates a cascade of intracellular reactions. Due to the nature of different interactions of opioids with each of these receptors, individuals vary in their response to opioids.¹⁵

WHAT ARE THE CHARACTERISTICS OF COMMON OPIOIDS?

• Step 1. Mild pain calls for a nonopioid analgesic with or without an adjuvant (more about adjuvants below).
• Step 2. Mild or moderate pain that persists or increases calls for a weak opioid such as codeine, tramadol (Ultram), or hydrocodone, with or without a nonopioid and with or without an adjuvant.
• Step 3. Severe pain calls for a strong opioid with or without a nonopioid, and with or without an adjuvant.

Morphine, the prototypical opioid, is well studied and versatile, as it can be given orally, parenterally, rectally, or intraspinally. It is readily available in the United States and Western Europe but not in some parts of the world, such as Asia and Africa. It is also cost-effective.

Hydromorphone (Dilaudid) is similar to morphine in terms of versatility, cost, and effectiveness in pain management. An extended-release form (Exalgo) is now available in the United States.

Oxycodone is readily available in both slow-release (eg, OxyContin) and immediate-release (eg, Oxy-IR) preparations and is also cost-effective. However, there is no parenteral formulation in the United States.

Methadone is inexpensive and can be used as a long-acting or an immediate-release opioid. However, it should be used with caution in patients with a prolonged QTc interval: in general, a QTc interval of 430 to 450 msec is not a contraindication, but there is a risk of torsades de pointes when the QTc is greater than 500 msec. The physician should also look for drug interactions when prescribing methadone, which is metabolized in the liver via the cytochrome P450 3A4 system. Methadone use can also lead to respiratory depression, prolonged QTc interval, and sudden death.

Buprenorphine can be used as a third- or fourth-tier opioid for patients with both kidney and liver failure. It can be given sublingually or parenterally. It may not be readily available, may not be covered by insurance, and is expensive.

Selecting an opioid to try first

The following are some general considerations when selecting an opioid to try first:

• Does the patient have a history of organ failure? Has the patient had a therapeutic response to, or adverse effects from, a particular opioid in the past?
• Which route would best fit the patient’s needs? (Oral is always preferable.)
• How often will breakthrough dosing be required? (In general, the breakthrough dose is administered at the drug’s half-life, but it can be administered between 1 and 4 hours.)
• How much will it cost? (Consider the cost, insurance coverage, and co-pays.)

Table 2 shows different characteristics of commonly used opioids, including route of administration, onset of action, peak effect, and duration of action.¹

WHAT ARE THE EQUIANALGESIC DOSES OF COMMONLY USED OPIOIDS?

Table 3 lists equianalgesic doses and route conversions of commonly used opioids.^18–20

WHAT ARE THE PRINCIPLES BEHIND OPIOID DOSING?

Table 4 shows important strategies for opioid dosing. An in-depth discussion of specific opioid dosing strategies is beyond the scope of this article.⁵

WHAT ARE THE COMMON ADVERSE EFFECTS OF OPIOIDS?

Adverse effects are among the most common reasons for failure of opioids to relieve pain. If these effects are not anticipated and treated prophylactically, patients may avoid taking their opioid drugs or may complain that they are “allergic” to them. In reality, true allergy to any of the opioids is rare. Patients comply better if they are taught to expect that most adverse effects are either preventable or manageable.²¹ A simple strategy includes reducing the opioid dose by 25% to 50%, using different opioids (“rotation”), changing the route of administration, and directly treating adverse effects.^21,22

WHAT IS OPIOID ROTATION AND HOW IS IT DONE?

Opioid rotation involves changing to a different drug using the same administration route, with the aim of improving the analgesic response or reducing adverse effects.¹⁶ It may be useful in widening the therapeutic window, ie, establishing a more advantageous relationship between analgesia and toxicity.¹⁶ This strategy applies, for example, to patients who have an adverse reaction to morphine, and who may need rotation to fentanyl or methadone.

The major indication for switching opioids is poorly controlled pain with unacceptable adverse effects due to opioid toxicity, the rapid development of tolerance, refractory pain, or difficult pain syndromes.²⁴ A recent prospective study showed that 42% of patients underwent opioid rotation, and the two most common reasons were inadequate analgesia and severe adverse effects.²⁵ Opioid rotation resulted in relief of confusion (72%), nausea and vomiting (68%), and drowsiness (53%).²⁵

Before trying opioid rotation, review the patient’s pain syndromes and the use of an adjuvant analgesic, and assess for evidence of opioid toxicity or contributing abnormal biochemical factors such as hydration status.^24,26 Most opioids are mu-receptor agonists and may exhibit cross-tolerance, a phenomenon in which the alternative drug does not have the expected effects because of similar pharmacologic action of the first drug. Because the degree of cross-tolerance may change as opioid doses are escalated, it is advisable to proceed with caution when switching from one opioid to another in patients who are receiving very high doses. Opioid rotation generally would be ineffective if there is complete analgesic cross-tolerance between opioids.

The common equivalency conversion tables are based either on studies in patients who received low doses of opioids or on single-dose studies.^16,24 By substituting opioids and using lower doses than expected according to the equivalency conversion tables (generally a 25% to 30% decrease), it is possible in most cases to reduce or relieve the symptoms of opioid toxicity and to manage patients highly tolerant to previous opioids while improving analgesia.²⁴

Alternatives to opioid rotation are route conversion (oral to parenteral or spinal), addition of an adjuvant analgesic, and opioid dose reduction.

WHAT IS OPIOID TOXICITY AND HOW IS IT MANAGED?

Opioid overdose is commonly the result of an error in pain assessment, opioid prescribing, or dose administration. Opioid overdose classically presents as sedation or respiratory depression. The combination of coma, reduced respiratory rate, and pinpoint pupils is highly suggestive of opioid toxicity, and treatment should be initiated promptly.