Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

The inpatient to outpatient transition marks an abrupt paradigm shift from intensive, provider‐initiated care to self‐managed care, in which patients are primarily responsible for maintaining day‐to‐day health behaviors, following through with outpatient appointments, and negotiating medications, transport, and equipment needs. Studies indicate that medication nonadherence and medication‐related adverse events are common during the post‐discharge period, and may be related to the discontinuities associated with transitions of care.110

Given the complexity and uncertainty inherent in care transitions for patients with chronic illness, it is not surprising that poorly executed care transitions have been associated with increased risk of rehospitalizations and emergency department (ED) use.11 Patients with chronic illness are at particularly high risk for recurrent hospitalization.1114 System‐wide improvements in chronic illness care have been successful in triaging longitudinally followed, high‐risk outpatients to appropriate higher‐intensity care management interventions.1519 But the post‐discharge setting presents unique challenges for patients with chronic illness, especially those that are socioeconomically disadvantaged. External barriers, such as lack of transportation, lack of monitoring equipment, confusion about arranging follow‐up care, uncertainty about medication regimen changes, and financial constraints, represent important targets for improving care in the transition from inpatient to outpatient settings.

Transitional care has been defined as a set of actions designed to ensure the coordination and continuity of healthcare as members transfer between different locations or different levels of care.20 Most successful transitional care interventions have focused on geriatric populations or patients with congestive heart failure enrolled in health maintenance organizations, and have involved intensive nurse case management from the hospital setting through the post‐discharge period.2125 In these studies, trained nurse case managers provided critical support and patient education to improve patients' ability to self‐manage chronic illness.2629

In a resource‐poor Medicaid payment structure, the implementation of intensive care management across a broad population of patients may not be practical; alternative options for intervention dosing and implementation may be needed. Few studies have examined care needs and the impact of transitional care interventions in socioeconomically disadvantaged patients with chronic illness, though a recent study including such a population did find benefit from a pharmacist‐based intervention.30 The purpose of our study was to examine the impact of a low‐cost, post‐discharge needs assessment, as an adjunct to an existing care management program, on the risk of recurrent hospitalization in a clinically diverse cohort of chronically ill Medicaid managed care enrollees.

METHODS

RESULTS

We enrolled 97 intervention and 130 control patients. Follow‐up utilization data were available for all patients. Table 1 compares sociodemographic, utilization, and comorbidity characteristics of the 2 groups, and Table 2 summarizes patient distribution and characteristics of the hospitals from which they were discharged. The control group was significantly older and more racially diverse than the intervention group. On the other hand, the intervention group had a higher burden of illness as suggested by higher ACG scores and a higher rate of hospitalization within the previous year. Most patients had been hospitalized at large, urban hospitals.

Patients in the intervention group had a slightly lower 60‐day rehospitalization rate compared to the control group, but this difference was not statistically significant in unadjusted analyses (Table 3; 23.7% vs 29.2%, P = 0.35). This difference became significant after controlling for ACG score, prior inpatient utilization, and age: adjusted odds ratio (OR) [95% confidence interval (CI)] 0.49 [0.24‐1.00].

Nearly half the intervention patients received one or more brief‐touch interventions (48.5%), and the majority of patients (61.7%) receiving a brief‐touch intervention did not require referral to care management. Table 4 lists examples of brief‐touch interventions received by patients. More patients in the intervention group than in the control group were enrolled in the CareSupport care management program (40.2% vs 14.6%, P < 0.001), and about half (53.8%) of the intervention patients referred for care management did not receive a brief‐touch intervention. Patients enrolled in care management were slightly younger (mean age 56.7 vs 59.1 years, P = 0.16), but had a higher burden of illness (mean ACG score 0.53 vs 0.40, P = 0.006) than those not enrolled in care management.

More patients in the intervention group compared to control patients had one or more primary care visits within the year after hospital discharge (86.6% vs 72.3%, P = 0.01), and within 60 days after hospital discharge (68.0% vs 58.5%, P = 0.14), though the latter difference did not reach statistical significance. Interestingly, in an exploratory analysis, we found that hospitalization was more likely to introduce discontinuities in longitudinal primary care in control patients than in intervention patients: among patients who had had 3 or more primary care visits in the year prior to hospitalization, control patients were more likely than intervention patients to have 2 or fewer primary care visits during the year following hospitalization (33.8% vs 20.6%, P = 0.03).

Our mediation analyses suggested that neither post‐hospitalization primary care utilization within 60 days nor care management services accounted for the lower rate of recurrent hospitalization in the intervention group (Table 3). The addition of post‐hospitalization primary care utilization to the original model did not change the primary effect estimate, while controlling for care management enrollment actually increased the effect size. Finally, there was no difference in readmission rates between those receiving and not receiving brief‐touch interventions (31.8 vs 25.7%, P = 0.92).

DISCUSSION

We found that a simple, telephone‐based, transitional care intervention may be associated with lower 60‐day rehospitalization rates in a cohort of Medicaid managed care patients. We observed a reduced rate of readmissions in the intervention, a difference that became significant after adjustment for important confounders. Implicit in the design of the intervention was a recognition that patients' transitional care needs may vary, from help negotiating the post‐discharge follow‐up care process to more substantial and complex care management support needs. Our study adds to the current body of literature by examining an understudied, socioeconomically disadvantaged population in a resource‐poor health system. Importantly, our study targeted the most intensive intervention to those with the highest anticipated needs based on a simple triage scheme. Such targeted approaches may be especially important in resource‐poor settings.

Although our study was too small to characterize in detail the relative importance of specific elements of our intervention responsible for lower short‐term rehospitalization rates, the study does highlight the diversity of transitional care needs. Patients received logistic support negotiating the health system, preventive health promotion, and patient empowerment through self‐management and information access training. Nearly half the patients received a documented simple telephone‐based intervention, and many of these patients did not require referral for intensive nurse care management. On the other hand, our needs assessment did identify over one‐third of recently discharged patients as having more complex chronic disease management needs requiring assessment for ongoing nurse care management.

We were not able to identify the specific aspects of the intervention responsible for the observed reduction in recurrent hospitalization. Our mediation analysis suggests that triaging patients to a nurse care management program was not responsible for the observed reduction in recurrent hospitalizations. In fact, the analysis suggests these patients may have been more likely to require hospitalization, though our study was too small to allow strong conclusions to be drawn from a subgroup analysis. Past studies have similarly suggested that patients enrolled in care management may simply have a higher burden of disease or may have the need for hospitalization recognized more frequently.36 Readmission rates were also similar between patients who did and did not receive a brief‐touch intervention, possibly suggesting that patients with a higher level of need were appropriately selected to receive assistance.

Although our intervention appeared to increase post‐discharge follow‐up in primary care, this also did not explain the observed reduction in 60‐day rehospitalization rates. Despite differences in post‐discharge outpatient utilization patterns, there were relatively few patients in either group that had no follow‐up, and the lack of effect may simply reflect inadequate power given our small sample size. On the other hand, the lack of association between outpatient utilization and 60‐day rehospitalization rates may reflect a true lack of association between primary care follow‐up and rehospitalization as seen in some studies, though a larger Medicare study did find an association.3638

Improvements in outpatient utilization patterns, as we saw in this study, may be a laudable intermediate outcome benefit despite the lack of association with 60‐day rehospitalization rates in our study. Short‐term rehospitalization rates represent only one outcome and do not capture the expected slow, iterative benefits from chronic illness risk reduction, which may accrue over time, with stable longitudinal primary care and associated outpatient chronic illness care systems' innovations.15, 31, 39, 40

Recent studies of transitional care interventions in publicly insured adults have produced mixed results. An evaluation of Medicare demonstration projects found largely negative results, but did find 2 successful programs in which the highest‐risk patients seemed to benefit most, a finding that supports the importance of assessing risk and appropriately dosing interventions.41 Another recent study in a socioeconomically disadvantaged population suggests the utility of an alternate transitional care approach centered on a pharmacy‐based intervention.30

Ours is essentially a test‐of‐concept study, with several important limitations, which should temper widespread application of these results and suggest the need for further study. The sample size of our study was limited, and this, coupled with a slightly lower‐than‐expected event rate, limits our ability to detect potentially important effects. Our study was not a randomized trial, and we cannot discount the possibility that our results reflect the effect of residual or unmeasured confounders, especially those factors such as patient volume and care quality related to the discharging hospitals themselves. We attempted to minimize the effects of such confounders by balancing the types of hospitals included in each group, and by accounting for clustering by hospital in our statistical analysis. Important differences in baseline characteristics between the 2 groups also raise the possibility of residual confounding despite multivariate adjustment. However, the intervention group generally carried a higher burden of illness which would, if anything, have biased results towards the null. The pragmatic study design necessitated an intervention that was defined broadly and left much to the discretion of the staff delivering the intervention, rather than adherence to a strictly defined protocol. We believe this approach allows evaluation of systems innovations within limited‐resource settings, but we acknowledge the challenges this presents in applying study results to other settings. Finally, only approximately 1 in 4 intervention patients were successfully contacted and completed the post‐discharge survey within 1 week. The relatively low rate of successful telephone contact underscores the difficulty of implementing transitional care interventions dependent on post‐discharge contact in a socioeconomically disadvantaged population with unstable telephone access. Because only successfully contacted patients were included in the intervention group, selection bias is a potential issue, though again, most baseline discrepancies between the 2 groups suggest that intervention patients were more complex.

Transitions of care in uninsured and publicly insured nonelderly adults should be studied in greater depth. Outpatient access to care deficiencies may be compounded in these groups, especially as states face widespread budget crises. Future studies should examine the effects of inpatient to outpatient linkages for such patients. Also, studies should assess the impact of transitional care interventions on self‐management, quality of care, and intermediate health outcomes in the outpatient setting after hospital discharge. Future research should taxonomize the range of transitional care needs by qualitatively evaluating subgroups of patients and delineating challenges faced by each group. For example, the post‐discharge needs of marginally housed patients may be unique and could inform the development of interventions specifically targeted to this group.

In summary, we found that a simple, brief‐touch intervention and needs assessment in the post‐discharge period may be associated with reduced recurrent hospitalization rates in a cohort of chronically ill Medicaid managed care patients with diverse post‐discharge care needs, though the exact mechanisms responsible for the observed improvements are unclear. Future studies should evaluate transitional care interventions targeted to needs in a larger group of chronically ill patients.

The inpatient to outpatient transition marks an abrupt paradigm shift from intensive, provider‐initiated care to self‐managed care, in which patients are primarily responsible for maintaining day‐to‐day health behaviors, following through with outpatient appointments, and negotiating medications, transport, and equipment needs. Studies indicate that medication nonadherence and medication‐related adverse events are common during the post‐discharge period, and may be related to the discontinuities associated with transitions of care.110

Given the complexity and uncertainty inherent in care transitions for patients with chronic illness, it is not surprising that poorly executed care transitions have been associated with increased risk of rehospitalizations and emergency department (ED) use.11 Patients with chronic illness are at particularly high risk for recurrent hospitalization.1114 System‐wide improvements in chronic illness care have been successful in triaging longitudinally followed, high‐risk outpatients to appropriate higher‐intensity care management interventions.1519 But the post‐discharge setting presents unique challenges for patients with chronic illness, especially those that are socioeconomically disadvantaged. External barriers, such as lack of transportation, lack of monitoring equipment, confusion about arranging follow‐up care, uncertainty about medication regimen changes, and financial constraints, represent important targets for improving care in the transition from inpatient to outpatient settings.

Transitional care has been defined as a set of actions designed to ensure the coordination and continuity of healthcare as members transfer between different locations or different levels of care.20 Most successful transitional care interventions have focused on geriatric populations or patients with congestive heart failure enrolled in health maintenance organizations, and have involved intensive nurse case management from the hospital setting through the post‐discharge period.2125 In these studies, trained nurse case managers provided critical support and patient education to improve patients' ability to self‐manage chronic illness.2629

In a resource‐poor Medicaid payment structure, the implementation of intensive care management across a broad population of patients may not be practical; alternative options for intervention dosing and implementation may be needed. Few studies have examined care needs and the impact of transitional care interventions in socioeconomically disadvantaged patients with chronic illness, though a recent study including such a population did find benefit from a pharmacist‐based intervention.30 The purpose of our study was to examine the impact of a low‐cost, post‐discharge needs assessment, as an adjunct to an existing care management program, on the risk of recurrent hospitalization in a clinically diverse cohort of chronically ill Medicaid managed care enrollees.

METHODS

RESULTS

We enrolled 97 intervention and 130 control patients. Follow‐up utilization data were available for all patients. Table 1 compares sociodemographic, utilization, and comorbidity characteristics of the 2 groups, and Table 2 summarizes patient distribution and characteristics of the hospitals from which they were discharged. The control group was significantly older and more racially diverse than the intervention group. On the other hand, the intervention group had a higher burden of illness as suggested by higher ACG scores and a higher rate of hospitalization within the previous year. Most patients had been hospitalized at large, urban hospitals.

Patients in the intervention group had a slightly lower 60‐day rehospitalization rate compared to the control group, but this difference was not statistically significant in unadjusted analyses (Table 3; 23.7% vs 29.2%, P = 0.35). This difference became significant after controlling for ACG score, prior inpatient utilization, and age: adjusted odds ratio (OR) [95% confidence interval (CI)] 0.49 [0.24‐1.00].

Nearly half the intervention patients received one or more brief‐touch interventions (48.5%), and the majority of patients (61.7%) receiving a brief‐touch intervention did not require referral to care management. Table 4 lists examples of brief‐touch interventions received by patients. More patients in the intervention group than in the control group were enrolled in the CareSupport care management program (40.2% vs 14.6%, P < 0.001), and about half (53.8%) of the intervention patients referred for care management did not receive a brief‐touch intervention. Patients enrolled in care management were slightly younger (mean age 56.7 vs 59.1 years, P = 0.16), but had a higher burden of illness (mean ACG score 0.53 vs 0.40, P = 0.006) than those not enrolled in care management.

More patients in the intervention group compared to control patients had one or more primary care visits within the year after hospital discharge (86.6% vs 72.3%, P = 0.01), and within 60 days after hospital discharge (68.0% vs 58.5%, P = 0.14), though the latter difference did not reach statistical significance. Interestingly, in an exploratory analysis, we found that hospitalization was more likely to introduce discontinuities in longitudinal primary care in control patients than in intervention patients: among patients who had had 3 or more primary care visits in the year prior to hospitalization, control patients were more likely than intervention patients to have 2 or fewer primary care visits during the year following hospitalization (33.8% vs 20.6%, P = 0.03).

Our mediation analyses suggested that neither post‐hospitalization primary care utilization within 60 days nor care management services accounted for the lower rate of recurrent hospitalization in the intervention group (Table 3). The addition of post‐hospitalization primary care utilization to the original model did not change the primary effect estimate, while controlling for care management enrollment actually increased the effect size. Finally, there was no difference in readmission rates between those receiving and not receiving brief‐touch interventions (31.8 vs 25.7%, P = 0.92).

DISCUSSION

We found that a simple, telephone‐based, transitional care intervention may be associated with lower 60‐day rehospitalization rates in a cohort of Medicaid managed care patients. We observed a reduced rate of readmissions in the intervention, a difference that became significant after adjustment for important confounders. Implicit in the design of the intervention was a recognition that patients' transitional care needs may vary, from help negotiating the post‐discharge follow‐up care process to more substantial and complex care management support needs. Our study adds to the current body of literature by examining an understudied, socioeconomically disadvantaged population in a resource‐poor health system. Importantly, our study targeted the most intensive intervention to those with the highest anticipated needs based on a simple triage scheme. Such targeted approaches may be especially important in resource‐poor settings.

Although our study was too small to characterize in detail the relative importance of specific elements of our intervention responsible for lower short‐term rehospitalization rates, the study does highlight the diversity of transitional care needs. Patients received logistic support negotiating the health system, preventive health promotion, and patient empowerment through self‐management and information access training. Nearly half the patients received a documented simple telephone‐based intervention, and many of these patients did not require referral for intensive nurse care management. On the other hand, our needs assessment did identify over one‐third of recently discharged patients as having more complex chronic disease management needs requiring assessment for ongoing nurse care management.

We were not able to identify the specific aspects of the intervention responsible for the observed reduction in recurrent hospitalization. Our mediation analysis suggests that triaging patients to a nurse care management program was not responsible for the observed reduction in recurrent hospitalizations. In fact, the analysis suggests these patients may have been more likely to require hospitalization, though our study was too small to allow strong conclusions to be drawn from a subgroup analysis. Past studies have similarly suggested that patients enrolled in care management may simply have a higher burden of disease or may have the need for hospitalization recognized more frequently.36 Readmission rates were also similar between patients who did and did not receive a brief‐touch intervention, possibly suggesting that patients with a higher level of need were appropriately selected to receive assistance.

Although our intervention appeared to increase post‐discharge follow‐up in primary care, this also did not explain the observed reduction in 60‐day rehospitalization rates. Despite differences in post‐discharge outpatient utilization patterns, there were relatively few patients in either group that had no follow‐up, and the lack of effect may simply reflect inadequate power given our small sample size. On the other hand, the lack of association between outpatient utilization and 60‐day rehospitalization rates may reflect a true lack of association between primary care follow‐up and rehospitalization as seen in some studies, though a larger Medicare study did find an association.3638

Improvements in outpatient utilization patterns, as we saw in this study, may be a laudable intermediate outcome benefit despite the lack of association with 60‐day rehospitalization rates in our study. Short‐term rehospitalization rates represent only one outcome and do not capture the expected slow, iterative benefits from chronic illness risk reduction, which may accrue over time, with stable longitudinal primary care and associated outpatient chronic illness care systems' innovations.15, 31, 39, 40

Recent studies of transitional care interventions in publicly insured adults have produced mixed results. An evaluation of Medicare demonstration projects found largely negative results, but did find 2 successful programs in which the highest‐risk patients seemed to benefit most, a finding that supports the importance of assessing risk and appropriately dosing interventions.41 Another recent study in a socioeconomically disadvantaged population suggests the utility of an alternate transitional care approach centered on a pharmacy‐based intervention.30

Ours is essentially a test‐of‐concept study, with several important limitations, which should temper widespread application of these results and suggest the need for further study. The sample size of our study was limited, and this, coupled with a slightly lower‐than‐expected event rate, limits our ability to detect potentially important effects. Our study was not a randomized trial, and we cannot discount the possibility that our results reflect the effect of residual or unmeasured confounders, especially those factors such as patient volume and care quality related to the discharging hospitals themselves. We attempted to minimize the effects of such confounders by balancing the types of hospitals included in each group, and by accounting for clustering by hospital in our statistical analysis. Important differences in baseline characteristics between the 2 groups also raise the possibility of residual confounding despite multivariate adjustment. However, the intervention group generally carried a higher burden of illness which would, if anything, have biased results towards the null. The pragmatic study design necessitated an intervention that was defined broadly and left much to the discretion of the staff delivering the intervention, rather than adherence to a strictly defined protocol. We believe this approach allows evaluation of systems innovations within limited‐resource settings, but we acknowledge the challenges this presents in applying study results to other settings. Finally, only approximately 1 in 4 intervention patients were successfully contacted and completed the post‐discharge survey within 1 week. The relatively low rate of successful telephone contact underscores the difficulty of implementing transitional care interventions dependent on post‐discharge contact in a socioeconomically disadvantaged population with unstable telephone access. Because only successfully contacted patients were included in the intervention group, selection bias is a potential issue, though again, most baseline discrepancies between the 2 groups suggest that intervention patients were more complex.

Transitions of care in uninsured and publicly insured nonelderly adults should be studied in greater depth. Outpatient access to care deficiencies may be compounded in these groups, especially as states face widespread budget crises. Future studies should examine the effects of inpatient to outpatient linkages for such patients. Also, studies should assess the impact of transitional care interventions on self‐management, quality of care, and intermediate health outcomes in the outpatient setting after hospital discharge. Future research should taxonomize the range of transitional care needs by qualitatively evaluating subgroups of patients and delineating challenges faced by each group. For example, the post‐discharge needs of marginally housed patients may be unique and could inform the development of interventions specifically targeted to this group.

In summary, we found that a simple, brief‐touch intervention and needs assessment in the post‐discharge period may be associated with reduced recurrent hospitalization rates in a cohort of chronically ill Medicaid managed care patients with diverse post‐discharge care needs, though the exact mechanisms responsible for the observed improvements are unclear. Future studies should evaluate transitional care interventions targeted to needs in a larger group of chronically ill patients.

The inpatient to outpatient transition marks an abrupt paradigm shift from intensive, provider‐initiated care to self‐managed care, in which patients are primarily responsible for maintaining day‐to‐day health behaviors, following through with outpatient appointments, and negotiating medications, transport, and equipment needs. Studies indicate that medication nonadherence and medication‐related adverse events are common during the post‐discharge period, and may be related to the discontinuities associated with transitions of care.110

Given the complexity and uncertainty inherent in care transitions for patients with chronic illness, it is not surprising that poorly executed care transitions have been associated with increased risk of rehospitalizations and emergency department (ED) use.11 Patients with chronic illness are at particularly high risk for recurrent hospitalization.1114 System‐wide improvements in chronic illness care have been successful in triaging longitudinally followed, high‐risk outpatients to appropriate higher‐intensity care management interventions.1519 But the post‐discharge setting presents unique challenges for patients with chronic illness, especially those that are socioeconomically disadvantaged. External barriers, such as lack of transportation, lack of monitoring equipment, confusion about arranging follow‐up care, uncertainty about medication regimen changes, and financial constraints, represent important targets for improving care in the transition from inpatient to outpatient settings.

Transitional care has been defined as a set of actions designed to ensure the coordination and continuity of healthcare as members transfer between different locations or different levels of care.20 Most successful transitional care interventions have focused on geriatric populations or patients with congestive heart failure enrolled in health maintenance organizations, and have involved intensive nurse case management from the hospital setting through the post‐discharge period.2125 In these studies, trained nurse case managers provided critical support and patient education to improve patients' ability to self‐manage chronic illness.2629

In a resource‐poor Medicaid payment structure, the implementation of intensive care management across a broad population of patients may not be practical; alternative options for intervention dosing and implementation may be needed. Few studies have examined care needs and the impact of transitional care interventions in socioeconomically disadvantaged patients with chronic illness, though a recent study including such a population did find benefit from a pharmacist‐based intervention.30 The purpose of our study was to examine the impact of a low‐cost, post‐discharge needs assessment, as an adjunct to an existing care management program, on the risk of recurrent hospitalization in a clinically diverse cohort of chronically ill Medicaid managed care enrollees.

METHODS

RESULTS

We enrolled 97 intervention and 130 control patients. Follow‐up utilization data were available for all patients. Table 1 compares sociodemographic, utilization, and comorbidity characteristics of the 2 groups, and Table 2 summarizes patient distribution and characteristics of the hospitals from which they were discharged. The control group was significantly older and more racially diverse than the intervention group. On the other hand, the intervention group had a higher burden of illness as suggested by higher ACG scores and a higher rate of hospitalization within the previous year. Most patients had been hospitalized at large, urban hospitals.

Patients in the intervention group had a slightly lower 60‐day rehospitalization rate compared to the control group, but this difference was not statistically significant in unadjusted analyses (Table 3; 23.7% vs 29.2%, P = 0.35). This difference became significant after controlling for ACG score, prior inpatient utilization, and age: adjusted odds ratio (OR) [95% confidence interval (CI)] 0.49 [0.24‐1.00].

Nearly half the intervention patients received one or more brief‐touch interventions (48.5%), and the majority of patients (61.7%) receiving a brief‐touch intervention did not require referral to care management. Table 4 lists examples of brief‐touch interventions received by patients. More patients in the intervention group than in the control group were enrolled in the CareSupport care management program (40.2% vs 14.6%, P < 0.001), and about half (53.8%) of the intervention patients referred for care management did not receive a brief‐touch intervention. Patients enrolled in care management were slightly younger (mean age 56.7 vs 59.1 years, P = 0.16), but had a higher burden of illness (mean ACG score 0.53 vs 0.40, P = 0.006) than those not enrolled in care management.

More patients in the intervention group compared to control patients had one or more primary care visits within the year after hospital discharge (86.6% vs 72.3%, P = 0.01), and within 60 days after hospital discharge (68.0% vs 58.5%, P = 0.14), though the latter difference did not reach statistical significance. Interestingly, in an exploratory analysis, we found that hospitalization was more likely to introduce discontinuities in longitudinal primary care in control patients than in intervention patients: among patients who had had 3 or more primary care visits in the year prior to hospitalization, control patients were more likely than intervention patients to have 2 or fewer primary care visits during the year following hospitalization (33.8% vs 20.6%, P = 0.03).

Our mediation analyses suggested that neither post‐hospitalization primary care utilization within 60 days nor care management services accounted for the lower rate of recurrent hospitalization in the intervention group (Table 3). The addition of post‐hospitalization primary care utilization to the original model did not change the primary effect estimate, while controlling for care management enrollment actually increased the effect size. Finally, there was no difference in readmission rates between those receiving and not receiving brief‐touch interventions (31.8 vs 25.7%, P = 0.92).

DISCUSSION

We found that a simple, telephone‐based, transitional care intervention may be associated with lower 60‐day rehospitalization rates in a cohort of Medicaid managed care patients. We observed a reduced rate of readmissions in the intervention, a difference that became significant after adjustment for important confounders. Implicit in the design of the intervention was a recognition that patients' transitional care needs may vary, from help negotiating the post‐discharge follow‐up care process to more substantial and complex care management support needs. Our study adds to the current body of literature by examining an understudied, socioeconomically disadvantaged population in a resource‐poor health system. Importantly, our study targeted the most intensive intervention to those with the highest anticipated needs based on a simple triage scheme. Such targeted approaches may be especially important in resource‐poor settings.

Although our study was too small to characterize in detail the relative importance of specific elements of our intervention responsible for lower short‐term rehospitalization rates, the study does highlight the diversity of transitional care needs. Patients received logistic support negotiating the health system, preventive health promotion, and patient empowerment through self‐management and information access training. Nearly half the patients received a documented simple telephone‐based intervention, and many of these patients did not require referral for intensive nurse care management. On the other hand, our needs assessment did identify over one‐third of recently discharged patients as having more complex chronic disease management needs requiring assessment for ongoing nurse care management.

We were not able to identify the specific aspects of the intervention responsible for the observed reduction in recurrent hospitalization. Our mediation analysis suggests that triaging patients to a nurse care management program was not responsible for the observed reduction in recurrent hospitalizations. In fact, the analysis suggests these patients may have been more likely to require hospitalization, though our study was too small to allow strong conclusions to be drawn from a subgroup analysis. Past studies have similarly suggested that patients enrolled in care management may simply have a higher burden of disease or may have the need for hospitalization recognized more frequently.36 Readmission rates were also similar between patients who did and did not receive a brief‐touch intervention, possibly suggesting that patients with a higher level of need were appropriately selected to receive assistance.

Although our intervention appeared to increase post‐discharge follow‐up in primary care, this also did not explain the observed reduction in 60‐day rehospitalization rates. Despite differences in post‐discharge outpatient utilization patterns, there were relatively few patients in either group that had no follow‐up, and the lack of effect may simply reflect inadequate power given our small sample size. On the other hand, the lack of association between outpatient utilization and 60‐day rehospitalization rates may reflect a true lack of association between primary care follow‐up and rehospitalization as seen in some studies, though a larger Medicare study did find an association.3638

Improvements in outpatient utilization patterns, as we saw in this study, may be a laudable intermediate outcome benefit despite the lack of association with 60‐day rehospitalization rates in our study. Short‐term rehospitalization rates represent only one outcome and do not capture the expected slow, iterative benefits from chronic illness risk reduction, which may accrue over time, with stable longitudinal primary care and associated outpatient chronic illness care systems' innovations.15, 31, 39, 40

Recent studies of transitional care interventions in publicly insured adults have produced mixed results. An evaluation of Medicare demonstration projects found largely negative results, but did find 2 successful programs in which the highest‐risk patients seemed to benefit most, a finding that supports the importance of assessing risk and appropriately dosing interventions.41 Another recent study in a socioeconomically disadvantaged population suggests the utility of an alternate transitional care approach centered on a pharmacy‐based intervention.30

Ours is essentially a test‐of‐concept study, with several important limitations, which should temper widespread application of these results and suggest the need for further study. The sample size of our study was limited, and this, coupled with a slightly lower‐than‐expected event rate, limits our ability to detect potentially important effects. Our study was not a randomized trial, and we cannot discount the possibility that our results reflect the effect of residual or unmeasured confounders, especially those factors such as patient volume and care quality related to the discharging hospitals themselves. We attempted to minimize the effects of such confounders by balancing the types of hospitals included in each group, and by accounting for clustering by hospital in our statistical analysis. Important differences in baseline characteristics between the 2 groups also raise the possibility of residual confounding despite multivariate adjustment. However, the intervention group generally carried a higher burden of illness which would, if anything, have biased results towards the null. The pragmatic study design necessitated an intervention that was defined broadly and left much to the discretion of the staff delivering the intervention, rather than adherence to a strictly defined protocol. We believe this approach allows evaluation of systems innovations within limited‐resource settings, but we acknowledge the challenges this presents in applying study results to other settings. Finally, only approximately 1 in 4 intervention patients were successfully contacted and completed the post‐discharge survey within 1 week. The relatively low rate of successful telephone contact underscores the difficulty of implementing transitional care interventions dependent on post‐discharge contact in a socioeconomically disadvantaged population with unstable telephone access. Because only successfully contacted patients were included in the intervention group, selection bias is a potential issue, though again, most baseline discrepancies between the 2 groups suggest that intervention patients were more complex.

Transitions of care in uninsured and publicly insured nonelderly adults should be studied in greater depth. Outpatient access to care deficiencies may be compounded in these groups, especially as states face widespread budget crises. Future studies should examine the effects of inpatient to outpatient linkages for such patients. Also, studies should assess the impact of transitional care interventions on self‐management, quality of care, and intermediate health outcomes in the outpatient setting after hospital discharge. Future research should taxonomize the range of transitional care needs by qualitatively evaluating subgroups of patients and delineating challenges faced by each group. For example, the post‐discharge needs of marginally housed patients may be unique and could inform the development of interventions specifically targeted to this group.

In summary, we found that a simple, brief‐touch intervention and needs assessment in the post‐discharge period may be associated with reduced recurrent hospitalization rates in a cohort of chronically ill Medicaid managed care patients with diverse post‐discharge care needs, though the exact mechanisms responsible for the observed improvements are unclear. Future studies should evaluate transitional care interventions targeted to needs in a larger group of chronically ill patients.

Hyperkalemia is a common condition in hospitalized patients and can be fatal if left untreated.1 The incidence of hyperkalemia in hospitalized patients is 1‐10%.2 Hyperkalemia develops secondary to decreased renal excretion of potassium, increased potassium intake, or redistribution of potassium into the extracellular fluid. Patients with renal dysfunction, especially acute kidney injury (AKI) or end‐stage renal disease (ESRD), are especially predisposed to hyperkalemia. Drug therapy (particularly inhibitors of the renin‐angiotensin‐aldosterone system, calcineurin inhibitors, potassium sparing diuretics, and heparin) may also predispose patients to elevated potassium levels.2 High extracellular potassium adversely affects the resting membrane potential of the myocardial cell. This results in a slowing of ventricular conduction, and may precipitate ventricular fibrillation or asystole.3, 4 Due to this high risk of cardiac complications, the American Heart Association recommends treatment when potassium levels are 6.0 mEq/L.5

A threefold approach to the treatment of hyperkalemia is currently adopted by clinicians: (1) stabilizing the cardiac membranes using intravenous (IV) calcium; (2) redistribution of potassium using IV insulin and nebulized albuterol (in the setting of metabolic acidosis, IV sodium bicarbonate will also help to shift potassium into cells); and (3) elimination of potassium from the body via hemodialysis or Na‐K exchange resin binders.2

The use of insulin is incorporated into most acute hyperkalemia stabilization treatment regimens and, with or without concomitant dextrose, can predispose patients to develop hypoglycemia. Dosing recommendations for insulin and dextrose for hyperkalemia vary among clinical references but commonly include 10 units of regular insulin IV and 25‐50 gm of IV dextrose.6, 7 Hypoglycemia following insulin and dextrose administration has received limited documentation.810 Furthermore, several factors account for an increased frequency of hypoglycemia in patients with end‐stage renal disease, a group also predisposed to hyperkalemia.11 This study assesses the incidence of hypoglycemia in hospitalized patients after acute stabilization treatment of hyperkalemia with insulin.

METHODS

A retrospective search of the electronic records of a large university‐based tertiary care hospital was conducted from June 1, 2009 to December 1, 2009. Adult hospitalized patients met our study inclusion criteria if they received IV insulin as part of an acute hyperkalemia stabilization treatment regimen and their potassium level was 6 mmol/L or greater. A medical record search was performed by applying the following search criteria: 5‐10 units of intravenous insulin administered within 6 hours of a collected potassium level which was reported as 6 mmol/L or greater. Patients were excluded if they did not have a reported blood glucose level measured within 6 hours of insulin administration. Patient demographic data was collected including: patient's age, sex, weight, and presence of diabetes or renal dysfunction. AKI was defined as an acute rise in serum creatinine of >0.5 mg/dl within a 7‐day period during hospitalization. Hypoglycemia and severe hypoglycemia were defined as blood glucose levels of <70 mg/dl and <40 mg/dl, respectively, consistent with the current medical literature. Hypoglycemic patients were grouped into hypoglycemic and severely hypoglycemic subsets based on their blood glucose levels. Information on patients' hypoglycemic symptoms was recorded when documented in the medical record. All administered doses of insulin and dextrose were documented by reviewing the medication administration record for each patient. Blood glucose levels were obtained by both point‐of‐care finger stick bedside measurements and blood draws taken for laboratory analysis. The incidence of patients who became hypoglycemic following a hyperkalemic treatment was then assessed.

RESULTS

Our retrospective computer data search identified 250 hyperkalemic patients (with potassium levels 6 mmol/L) who received intravenous regular insulin within 6 hours of the potassium level measurement during the 6‐month study period. Thirty patients (12%) met study criteria but were excluded because they did not have a blood glucose level documented within 6 hours of insulin administration. One patient, who qualified for the study from the electronic data, was excluded because of an erroneous potassium level secondary to a hemolyzed blood sample. Nineteen (8.7%) of the remaining 219 study patients were identified as hypoglycemic (blood glucose <70 mg/dl). Five patients (2.3%) were classified as having severe hypoglycemia (blood glucose <40 mg/dl). The distribution of hypoglycemic events among the various insulin/dextrose regimens are shown in Table 1. Fifty‐eight percent and 40% of the blood glucose <70 mg/dl and <40 mg/dl events, respectively, occurred following the commonly employed 10 units of regular insulin by intravenous push (IVP) and 25 gm of dextrose 50% IVP treatment regimen.

The average body weight of patients with a blood glucose <40 mg/dl was significantly less than those patients having blood sugars in the 41‐69 mg/dl range (55.8 kg vs 92.0 kg, P <0.05) or patients with blood sugars >70 mg/dl (55.8 kg vs 87.4 kg, P <0.05). Table 2 lists patient characteristics by blood glucose cohort, with the 200 patient >70 mg/dl group represented by a random subset of 70 patients.

The average pretreatment blood glucose level for this cohort of 19 patients was 127 mg/dl with a blood glucose range of 59‐298 mg/dl. One patient was identified as hypoglycemic prior to treatment. Five hypoglycemic patients were identified as diabetic. One of these patients had an A1C level >13%, and 3 patients had levels <7%. Distribution of the potassium levels within the cohort were as follows: 6.0‐6.4 mmol/L: 12 patients (67%); 6.5‐6.9 mmol/L: 1 patient (5%); and 7 mmol/L or greater: 6 patients (28%). Seven patients had stat electrocardiograms ordered at the time of their hyperkalemia, and 3 patients had repeat potassium levels which verified their hyperkalemia. Fifteen (79%) of the hypoglycemic patients had acute kidney injury or were end‐stage renal disease patients on hemodialysis at the time of treatment.

Hypoglycemia was demonstrated at a median time of 3 hours post‐insulin administration. Documentation of the patients' hypoglycemia symptoms and the treatment of the hypoglycemic events were very poor. Only 3 patients had documentation of their hypoglycemia in the notes section of the electronic chart. The documentation included common symptoms of hypoglycemia in 2 patients, and was limited to the type of hypoglycemic treatment in the third patient. Seven patients had dextrose IV documented in the medication administration record, and 1 patient was treated with cranberry juice. No documentation of treatment was found in the remaining 58% of patients.

Eight of the 19 hypoglycemic patients were treated in an intensive care unit while receiving treatment for hyperkalemia. Of the 5 patients with severe hypoglycemia, 3 were treated in an intensive care unit and 2 of these patients died the day following treatment. One of the deaths resulted from a cardiac arrest with pulseless electrical activity while the patient was on dialysis. One patient with severe hypoglycemia was transferred to the medical intensive care unit but was discharged to home 4 days later. One additional patient, with chronic myeloid leukemia and a blood glucose level between 40 and 70 mg/dl died on the day of his admission.

DISCUSSION

Studies often do not agree on whether hypoglycemia is a complication resulting from standard insulin/glucose treatments for hyperkalemia. A previous study by Kim12 evaluated a combination regimen of insulin/glucose with bicarbonate for the treatment of hyperkalemia in 8 end‐stage renal disease patients. In this study, a solution of 8.4% bicarbonate (120 cc of bicarbonate and 80 ml of normal saline) was infused at a rate of 2 mmol/min. In addition, patients simultaneously received 550 ml of 20% glucose containing 50 units of regular insulin infused at a rate of 5 mU/kg/min. The study reported that the potassium level was lowered from 6.2 to 5.2 mEq/L in 1 hour without any patients experiencing hypoglycemia. The ratio of insulin to glucose was approximately 11 units/25 gm. However, in a similar study by Allon and Copkney,9 asymptomatic hypoglycemia was reported in 75% of patients following the administration of 10 units of regular insulin and 25 gm of dextrose for hyperkalemia in patients with renal failure. The study demonstrated baseline plasma glucose levels of 85‐92 mg/dl in patients prior to the insulin and dextrose therapy. Transient hyperglycemia developed 15 minutes post‐therapy, resolved within 30 minutes, and then progressed toward significant hypoglycemia at 60 minutes with blood glucose levels declining into the 45‐56 mg/dl range. The study also demonstrated that the hypoglycemia secondary to the insulin/dextrose regimen was attenuated by the concomitant use of inhaled albuterol.

Management of acute hyperkalemia stabilization lacks a standardized treatment regimen. Often a shot‐gun approach employing multiple therapeutic modalities is prescribed concomitantly, and intravenous insulin and dextrose are commonly included in these treatment regimens. Hyperkalemia treatment regimens are often prescribed based on local treatment patterns or from online references including Pepid6 and UpToDate.7 In addition, reference manuals such as the Washington Manual of Medical Therapeutics13 also provide therapeutic guidelines. However, these sources often do not agree on a standard treatment. In terms of a combined insulin and glucose therapy for hyperkalemia, the practice at our hospital is to administer, 10 units of regular insulin IVP with 50 ml (25 gm) of dextrose 50% IVP. UpToDate7 suggests 10 units of regular insulin IVP with 25 gm of dextrose 50% IVP, followed by dextrose 10% infusion by intravenous piggyback (IVPB) at 50‐75 ml/hr with careful monitoring. Pepid6 recommends 10 units of regular insulin IVP and 25 gm of dextrose 50% IVP, whereas the Washington Manual of Medical Therapeutics13 suggests 10‐20 units of regular insulin and 25‐50 gm of glucose administered intravenously.

Our study demonstrated a hypoglycemia frequency of 8.7% (<70 mg/dl) which occurred over a range of 5‐10 units of regular insulin and 0‐50 gm of dextrose 50%. However, this frequency may underestimate the true hypoglycemic incidence, as our study excluded patients without posttreatment blood glucose levels, and we were unable to control for patient self‐treatment or nurse‐assisted treatment of hypoglycemia with dietary sources of glucose (juice, crackers, etc). Despite these limitations, a hypoglycemic incidence of 8.7% is extremely high and constitutes an unacceptably high iatrogenic risk for complications. Data from the critical care literature suggests that hypoglycemia is an independent marker of mortality.14 Fifty‐eight percent of our total hypoglycemic events developed after patients received the commonly cited regimen of 10 units of regular insulin IVP and 25 gm of 50% dextrose IVP. One of our patients developed hypoglycemia despite a regimen of 10 units of regular insulin with 50 gm of 50% dextrose. This variability of patient response suggests that no single algorithm will prevent all hypoglycemic events, therefore, careful patient assessment and blood glucose monitoring should be routinely employed.

The decision regarding the order of dextrose and insulin administration can be influenced by clinical factors. Dextrose administration should generally precede insulin administration.15 In the setting of insulin and aldosterone deficiency (ie, a patient with type 1 diabetes and type IV renal tubular acidosis), dextrose administration prior to insulin administration could exacerbate the patient's hyperkalemia. In this circumstance, insulin administration should precede dextrose administration, with dextrose dosing predicated on the patient's estimated glycemic requirements and glucose monitoring. However, in patients with isolated insulin or aldosterone deficiency, the initial administration of dextrose does not predispose to further hyperkalemia.16

Hypoglycemia risk can be minimized by increasing the dextrose component in most insulin/dextrose hyperkalemia treatment regimens. The dextrose may be administered as 100 ml of 50% dextrose IVP or 50 ml of 50% dextrose IVPB, followed by 250 ml of D10 IVPB over 1 hour. The latter regimen may be preferred for patients at higher risk of hypoglycemia, although the added volume of fluid may not be appropriate for all patients. It must be recognized that this regimen may result in short‐term hyperglycemia, and patients should be closely monitored. It is reasonable, prior to treatment, to obtain a baseline blood glucose level and to obtain a 1‐hour and 3‐hour posttreatment blood glucose level.

While an electronic hospital record provides convenient access to a large number of patients and allows cross‐referencing of various laboratory values and prescribed medications, the ability to develop persuasive conclusions from the generated data may be significantly limited by inadequate or missing documentation of patient's pretreatment symptoms and response to therapy. The documentation of treatment response in the acute stabilization of hyperkalemia of our patients lacked specificity and standardization. Similarly, documentation of hypoglycemia and subsequent treatment response is not standardized at our institution. This lack of patient data limits our ability to gauge the level of harm experienced by our patients or evaluate the timeliness and appropriateness of their hypoglycemic treatment. Therefore, documentation of hypoglycemic symptoms and treatment will be the subject of future performance improvement initiatives and study at our institution. Further, studies need to be pursued utilizing standardized charting templates to facilitate and guide appropriate treatment assessment and follow‐up documentation. This will also assist in evaluating the treatment options addressed in this article. In addition, evaluation of bolus therapy with 50% dextrose versus therapies using D10 infusions in combination with insulin for hyperkalemia treatment in emergency room patients will be pursued. Despite these limitations, any policy which can limit harm from potential hypoglycemia deserves institutional attention and study.

Iatrogenic hypoglycemia as a result of treatment for hyperkalemia is a common occurrence, is largely unrecognized, and can have adverse outcomes. In our present study, 8.7% of patients became hypoglycemic following insulin treatment for hyperkalemia. Hyperkalemia occurs disproportionately in patients with acute kidney injury or end‐stage renal function. Moreover, the risk of severe hypoglycemia escalates in patients with lower body weight, and careful surveillance is needed in these cases.

Hyperkalemia is a common condition in hospitalized patients and can be fatal if left untreated.1 The incidence of hyperkalemia in hospitalized patients is 1‐10%.2 Hyperkalemia develops secondary to decreased renal excretion of potassium, increased potassium intake, or redistribution of potassium into the extracellular fluid. Patients with renal dysfunction, especially acute kidney injury (AKI) or end‐stage renal disease (ESRD), are especially predisposed to hyperkalemia. Drug therapy (particularly inhibitors of the renin‐angiotensin‐aldosterone system, calcineurin inhibitors, potassium sparing diuretics, and heparin) may also predispose patients to elevated potassium levels.2 High extracellular potassium adversely affects the resting membrane potential of the myocardial cell. This results in a slowing of ventricular conduction, and may precipitate ventricular fibrillation or asystole.3, 4 Due to this high risk of cardiac complications, the American Heart Association recommends treatment when potassium levels are 6.0 mEq/L.5

A threefold approach to the treatment of hyperkalemia is currently adopted by clinicians: (1) stabilizing the cardiac membranes using intravenous (IV) calcium; (2) redistribution of potassium using IV insulin and nebulized albuterol (in the setting of metabolic acidosis, IV sodium bicarbonate will also help to shift potassium into cells); and (3) elimination of potassium from the body via hemodialysis or Na‐K exchange resin binders.2

The use of insulin is incorporated into most acute hyperkalemia stabilization treatment regimens and, with or without concomitant dextrose, can predispose patients to develop hypoglycemia. Dosing recommendations for insulin and dextrose for hyperkalemia vary among clinical references but commonly include 10 units of regular insulin IV and 25‐50 gm of IV dextrose.6, 7 Hypoglycemia following insulin and dextrose administration has received limited documentation.810 Furthermore, several factors account for an increased frequency of hypoglycemia in patients with end‐stage renal disease, a group also predisposed to hyperkalemia.11 This study assesses the incidence of hypoglycemia in hospitalized patients after acute stabilization treatment of hyperkalemia with insulin.

METHODS

A retrospective search of the electronic records of a large university‐based tertiary care hospital was conducted from June 1, 2009 to December 1, 2009. Adult hospitalized patients met our study inclusion criteria if they received IV insulin as part of an acute hyperkalemia stabilization treatment regimen and their potassium level was 6 mmol/L or greater. A medical record search was performed by applying the following search criteria: 5‐10 units of intravenous insulin administered within 6 hours of a collected potassium level which was reported as 6 mmol/L or greater. Patients were excluded if they did not have a reported blood glucose level measured within 6 hours of insulin administration. Patient demographic data was collected including: patient's age, sex, weight, and presence of diabetes or renal dysfunction. AKI was defined as an acute rise in serum creatinine of >0.5 mg/dl within a 7‐day period during hospitalization. Hypoglycemia and severe hypoglycemia were defined as blood glucose levels of <70 mg/dl and <40 mg/dl, respectively, consistent with the current medical literature. Hypoglycemic patients were grouped into hypoglycemic and severely hypoglycemic subsets based on their blood glucose levels. Information on patients' hypoglycemic symptoms was recorded when documented in the medical record. All administered doses of insulin and dextrose were documented by reviewing the medication administration record for each patient. Blood glucose levels were obtained by both point‐of‐care finger stick bedside measurements and blood draws taken for laboratory analysis. The incidence of patients who became hypoglycemic following a hyperkalemic treatment was then assessed.

RESULTS

Our retrospective computer data search identified 250 hyperkalemic patients (with potassium levels 6 mmol/L) who received intravenous regular insulin within 6 hours of the potassium level measurement during the 6‐month study period. Thirty patients (12%) met study criteria but were excluded because they did not have a blood glucose level documented within 6 hours of insulin administration. One patient, who qualified for the study from the electronic data, was excluded because of an erroneous potassium level secondary to a hemolyzed blood sample. Nineteen (8.7%) of the remaining 219 study patients were identified as hypoglycemic (blood glucose <70 mg/dl). Five patients (2.3%) were classified as having severe hypoglycemia (blood glucose <40 mg/dl). The distribution of hypoglycemic events among the various insulin/dextrose regimens are shown in Table 1. Fifty‐eight percent and 40% of the blood glucose <70 mg/dl and <40 mg/dl events, respectively, occurred following the commonly employed 10 units of regular insulin by intravenous push (IVP) and 25 gm of dextrose 50% IVP treatment regimen.

The average body weight of patients with a blood glucose <40 mg/dl was significantly less than those patients having blood sugars in the 41‐69 mg/dl range (55.8 kg vs 92.0 kg, P <0.05) or patients with blood sugars >70 mg/dl (55.8 kg vs 87.4 kg, P <0.05). Table 2 lists patient characteristics by blood glucose cohort, with the 200 patient >70 mg/dl group represented by a random subset of 70 patients.

The average pretreatment blood glucose level for this cohort of 19 patients was 127 mg/dl with a blood glucose range of 59‐298 mg/dl. One patient was identified as hypoglycemic prior to treatment. Five hypoglycemic patients were identified as diabetic. One of these patients had an A1C level >13%, and 3 patients had levels <7%. Distribution of the potassium levels within the cohort were as follows: 6.0‐6.4 mmol/L: 12 patients (67%); 6.5‐6.9 mmol/L: 1 patient (5%); and 7 mmol/L or greater: 6 patients (28%). Seven patients had stat electrocardiograms ordered at the time of their hyperkalemia, and 3 patients had repeat potassium levels which verified their hyperkalemia. Fifteen (79%) of the hypoglycemic patients had acute kidney injury or were end‐stage renal disease patients on hemodialysis at the time of treatment.

Hypoglycemia was demonstrated at a median time of 3 hours post‐insulin administration. Documentation of the patients' hypoglycemia symptoms and the treatment of the hypoglycemic events were very poor. Only 3 patients had documentation of their hypoglycemia in the notes section of the electronic chart. The documentation included common symptoms of hypoglycemia in 2 patients, and was limited to the type of hypoglycemic treatment in the third patient. Seven patients had dextrose IV documented in the medication administration record, and 1 patient was treated with cranberry juice. No documentation of treatment was found in the remaining 58% of patients.

Eight of the 19 hypoglycemic patients were treated in an intensive care unit while receiving treatment for hyperkalemia. Of the 5 patients with severe hypoglycemia, 3 were treated in an intensive care unit and 2 of these patients died the day following treatment. One of the deaths resulted from a cardiac arrest with pulseless electrical activity while the patient was on dialysis. One patient with severe hypoglycemia was transferred to the medical intensive care unit but was discharged to home 4 days later. One additional patient, with chronic myeloid leukemia and a blood glucose level between 40 and 70 mg/dl died on the day of his admission.

DISCUSSION

Studies often do not agree on whether hypoglycemia is a complication resulting from standard insulin/glucose treatments for hyperkalemia. A previous study by Kim12 evaluated a combination regimen of insulin/glucose with bicarbonate for the treatment of hyperkalemia in 8 end‐stage renal disease patients. In this study, a solution of 8.4% bicarbonate (120 cc of bicarbonate and 80 ml of normal saline) was infused at a rate of 2 mmol/min. In addition, patients simultaneously received 550 ml of 20% glucose containing 50 units of regular insulin infused at a rate of 5 mU/kg/min. The study reported that the potassium level was lowered from 6.2 to 5.2 mEq/L in 1 hour without any patients experiencing hypoglycemia. The ratio of insulin to glucose was approximately 11 units/25 gm. However, in a similar study by Allon and Copkney,9 asymptomatic hypoglycemia was reported in 75% of patients following the administration of 10 units of regular insulin and 25 gm of dextrose for hyperkalemia in patients with renal failure. The study demonstrated baseline plasma glucose levels of 85‐92 mg/dl in patients prior to the insulin and dextrose therapy. Transient hyperglycemia developed 15 minutes post‐therapy, resolved within 30 minutes, and then progressed toward significant hypoglycemia at 60 minutes with blood glucose levels declining into the 45‐56 mg/dl range. The study also demonstrated that the hypoglycemia secondary to the insulin/dextrose regimen was attenuated by the concomitant use of inhaled albuterol.

Management of acute hyperkalemia stabilization lacks a standardized treatment regimen. Often a shot‐gun approach employing multiple therapeutic modalities is prescribed concomitantly, and intravenous insulin and dextrose are commonly included in these treatment regimens. Hyperkalemia treatment regimens are often prescribed based on local treatment patterns or from online references including Pepid6 and UpToDate.7 In addition, reference manuals such as the Washington Manual of Medical Therapeutics13 also provide therapeutic guidelines. However, these sources often do not agree on a standard treatment. In terms of a combined insulin and glucose therapy for hyperkalemia, the practice at our hospital is to administer, 10 units of regular insulin IVP with 50 ml (25 gm) of dextrose 50% IVP. UpToDate7 suggests 10 units of regular insulin IVP with 25 gm of dextrose 50% IVP, followed by dextrose 10% infusion by intravenous piggyback (IVPB) at 50‐75 ml/hr with careful monitoring. Pepid6 recommends 10 units of regular insulin IVP and 25 gm of dextrose 50% IVP, whereas the Washington Manual of Medical Therapeutics13 suggests 10‐20 units of regular insulin and 25‐50 gm of glucose administered intravenously.

Our study demonstrated a hypoglycemia frequency of 8.7% (<70 mg/dl) which occurred over a range of 5‐10 units of regular insulin and 0‐50 gm of dextrose 50%. However, this frequency may underestimate the true hypoglycemic incidence, as our study excluded patients without posttreatment blood glucose levels, and we were unable to control for patient self‐treatment or nurse‐assisted treatment of hypoglycemia with dietary sources of glucose (juice, crackers, etc). Despite these limitations, a hypoglycemic incidence of 8.7% is extremely high and constitutes an unacceptably high iatrogenic risk for complications. Data from the critical care literature suggests that hypoglycemia is an independent marker of mortality.14 Fifty‐eight percent of our total hypoglycemic events developed after patients received the commonly cited regimen of 10 units of regular insulin IVP and 25 gm of 50% dextrose IVP. One of our patients developed hypoglycemia despite a regimen of 10 units of regular insulin with 50 gm of 50% dextrose. This variability of patient response suggests that no single algorithm will prevent all hypoglycemic events, therefore, careful patient assessment and blood glucose monitoring should be routinely employed.

The decision regarding the order of dextrose and insulin administration can be influenced by clinical factors. Dextrose administration should generally precede insulin administration.15 In the setting of insulin and aldosterone deficiency (ie, a patient with type 1 diabetes and type IV renal tubular acidosis), dextrose administration prior to insulin administration could exacerbate the patient's hyperkalemia. In this circumstance, insulin administration should precede dextrose administration, with dextrose dosing predicated on the patient's estimated glycemic requirements and glucose monitoring. However, in patients with isolated insulin or aldosterone deficiency, the initial administration of dextrose does not predispose to further hyperkalemia.16

Hypoglycemia risk can be minimized by increasing the dextrose component in most insulin/dextrose hyperkalemia treatment regimens. The dextrose may be administered as 100 ml of 50% dextrose IVP or 50 ml of 50% dextrose IVPB, followed by 250 ml of D10 IVPB over 1 hour. The latter regimen may be preferred for patients at higher risk of hypoglycemia, although the added volume of fluid may not be appropriate for all patients. It must be recognized that this regimen may result in short‐term hyperglycemia, and patients should be closely monitored. It is reasonable, prior to treatment, to obtain a baseline blood glucose level and to obtain a 1‐hour and 3‐hour posttreatment blood glucose level.

While an electronic hospital record provides convenient access to a large number of patients and allows cross‐referencing of various laboratory values and prescribed medications, the ability to develop persuasive conclusions from the generated data may be significantly limited by inadequate or missing documentation of patient's pretreatment symptoms and response to therapy. The documentation of treatment response in the acute stabilization of hyperkalemia of our patients lacked specificity and standardization. Similarly, documentation of hypoglycemia and subsequent treatment response is not standardized at our institution. This lack of patient data limits our ability to gauge the level of harm experienced by our patients or evaluate the timeliness and appropriateness of their hypoglycemic treatment. Therefore, documentation of hypoglycemic symptoms and treatment will be the subject of future performance improvement initiatives and study at our institution. Further, studies need to be pursued utilizing standardized charting templates to facilitate and guide appropriate treatment assessment and follow‐up documentation. This will also assist in evaluating the treatment options addressed in this article. In addition, evaluation of bolus therapy with 50% dextrose versus therapies using D10 infusions in combination with insulin for hyperkalemia treatment in emergency room patients will be pursued. Despite these limitations, any policy which can limit harm from potential hypoglycemia deserves institutional attention and study.

Iatrogenic hypoglycemia as a result of treatment for hyperkalemia is a common occurrence, is largely unrecognized, and can have adverse outcomes. In our present study, 8.7% of patients became hypoglycemic following insulin treatment for hyperkalemia. Hyperkalemia occurs disproportionately in patients with acute kidney injury or end‐stage renal function. Moreover, the risk of severe hypoglycemia escalates in patients with lower body weight, and careful surveillance is needed in these cases.

Hyperkalemia is a common condition in hospitalized patients and can be fatal if left untreated.1 The incidence of hyperkalemia in hospitalized patients is 1‐10%.2 Hyperkalemia develops secondary to decreased renal excretion of potassium, increased potassium intake, or redistribution of potassium into the extracellular fluid. Patients with renal dysfunction, especially acute kidney injury (AKI) or end‐stage renal disease (ESRD), are especially predisposed to hyperkalemia. Drug therapy (particularly inhibitors of the renin‐angiotensin‐aldosterone system, calcineurin inhibitors, potassium sparing diuretics, and heparin) may also predispose patients to elevated potassium levels.2 High extracellular potassium adversely affects the resting membrane potential of the myocardial cell. This results in a slowing of ventricular conduction, and may precipitate ventricular fibrillation or asystole.3, 4 Due to this high risk of cardiac complications, the American Heart Association recommends treatment when potassium levels are 6.0 mEq/L.5

A threefold approach to the treatment of hyperkalemia is currently adopted by clinicians: (1) stabilizing the cardiac membranes using intravenous (IV) calcium; (2) redistribution of potassium using IV insulin and nebulized albuterol (in the setting of metabolic acidosis, IV sodium bicarbonate will also help to shift potassium into cells); and (3) elimination of potassium from the body via hemodialysis or Na‐K exchange resin binders.2

The use of insulin is incorporated into most acute hyperkalemia stabilization treatment regimens and, with or without concomitant dextrose, can predispose patients to develop hypoglycemia. Dosing recommendations for insulin and dextrose for hyperkalemia vary among clinical references but commonly include 10 units of regular insulin IV and 25‐50 gm of IV dextrose.6, 7 Hypoglycemia following insulin and dextrose administration has received limited documentation.810 Furthermore, several factors account for an increased frequency of hypoglycemia in patients with end‐stage renal disease, a group also predisposed to hyperkalemia.11 This study assesses the incidence of hypoglycemia in hospitalized patients after acute stabilization treatment of hyperkalemia with insulin.

METHODS

A retrospective search of the electronic records of a large university‐based tertiary care hospital was conducted from June 1, 2009 to December 1, 2009. Adult hospitalized patients met our study inclusion criteria if they received IV insulin as part of an acute hyperkalemia stabilization treatment regimen and their potassium level was 6 mmol/L or greater. A medical record search was performed by applying the following search criteria: 5‐10 units of intravenous insulin administered within 6 hours of a collected potassium level which was reported as 6 mmol/L or greater. Patients were excluded if they did not have a reported blood glucose level measured within 6 hours of insulin administration. Patient demographic data was collected including: patient's age, sex, weight, and presence of diabetes or renal dysfunction. AKI was defined as an acute rise in serum creatinine of >0.5 mg/dl within a 7‐day period during hospitalization. Hypoglycemia and severe hypoglycemia were defined as blood glucose levels of <70 mg/dl and <40 mg/dl, respectively, consistent with the current medical literature. Hypoglycemic patients were grouped into hypoglycemic and severely hypoglycemic subsets based on their blood glucose levels. Information on patients' hypoglycemic symptoms was recorded when documented in the medical record. All administered doses of insulin and dextrose were documented by reviewing the medication administration record for each patient. Blood glucose levels were obtained by both point‐of‐care finger stick bedside measurements and blood draws taken for laboratory analysis. The incidence of patients who became hypoglycemic following a hyperkalemic treatment was then assessed.

RESULTS

Our retrospective computer data search identified 250 hyperkalemic patients (with potassium levels 6 mmol/L) who received intravenous regular insulin within 6 hours of the potassium level measurement during the 6‐month study period. Thirty patients (12%) met study criteria but were excluded because they did not have a blood glucose level documented within 6 hours of insulin administration. One patient, who qualified for the study from the electronic data, was excluded because of an erroneous potassium level secondary to a hemolyzed blood sample. Nineteen (8.7%) of the remaining 219 study patients were identified as hypoglycemic (blood glucose <70 mg/dl). Five patients (2.3%) were classified as having severe hypoglycemia (blood glucose <40 mg/dl). The distribution of hypoglycemic events among the various insulin/dextrose regimens are shown in Table 1. Fifty‐eight percent and 40% of the blood glucose <70 mg/dl and <40 mg/dl events, respectively, occurred following the commonly employed 10 units of regular insulin by intravenous push (IVP) and 25 gm of dextrose 50% IVP treatment regimen.

The average body weight of patients with a blood glucose <40 mg/dl was significantly less than those patients having blood sugars in the 41‐69 mg/dl range (55.8 kg vs 92.0 kg, P <0.05) or patients with blood sugars >70 mg/dl (55.8 kg vs 87.4 kg, P <0.05). Table 2 lists patient characteristics by blood glucose cohort, with the 200 patient >70 mg/dl group represented by a random subset of 70 patients.

The average pretreatment blood glucose level for this cohort of 19 patients was 127 mg/dl with a blood glucose range of 59‐298 mg/dl. One patient was identified as hypoglycemic prior to treatment. Five hypoglycemic patients were identified as diabetic. One of these patients had an A1C level >13%, and 3 patients had levels <7%. Distribution of the potassium levels within the cohort were as follows: 6.0‐6.4 mmol/L: 12 patients (67%); 6.5‐6.9 mmol/L: 1 patient (5%); and 7 mmol/L or greater: 6 patients (28%). Seven patients had stat electrocardiograms ordered at the time of their hyperkalemia, and 3 patients had repeat potassium levels which verified their hyperkalemia. Fifteen (79%) of the hypoglycemic patients had acute kidney injury or were end‐stage renal disease patients on hemodialysis at the time of treatment.

Hypoglycemia was demonstrated at a median time of 3 hours post‐insulin administration. Documentation of the patients' hypoglycemia symptoms and the treatment of the hypoglycemic events were very poor. Only 3 patients had documentation of their hypoglycemia in the notes section of the electronic chart. The documentation included common symptoms of hypoglycemia in 2 patients, and was limited to the type of hypoglycemic treatment in the third patient. Seven patients had dextrose IV documented in the medication administration record, and 1 patient was treated with cranberry juice. No documentation of treatment was found in the remaining 58% of patients.

Eight of the 19 hypoglycemic patients were treated in an intensive care unit while receiving treatment for hyperkalemia. Of the 5 patients with severe hypoglycemia, 3 were treated in an intensive care unit and 2 of these patients died the day following treatment. One of the deaths resulted from a cardiac arrest with pulseless electrical activity while the patient was on dialysis. One patient with severe hypoglycemia was transferred to the medical intensive care unit but was discharged to home 4 days later. One additional patient, with chronic myeloid leukemia and a blood glucose level between 40 and 70 mg/dl died on the day of his admission.

DISCUSSION

Studies often do not agree on whether hypoglycemia is a complication resulting from standard insulin/glucose treatments for hyperkalemia. A previous study by Kim12 evaluated a combination regimen of insulin/glucose with bicarbonate for the treatment of hyperkalemia in 8 end‐stage renal disease patients. In this study, a solution of 8.4% bicarbonate (120 cc of bicarbonate and 80 ml of normal saline) was infused at a rate of 2 mmol/min. In addition, patients simultaneously received 550 ml of 20% glucose containing 50 units of regular insulin infused at a rate of 5 mU/kg/min. The study reported that the potassium level was lowered from 6.2 to 5.2 mEq/L in 1 hour without any patients experiencing hypoglycemia. The ratio of insulin to glucose was approximately 11 units/25 gm. However, in a similar study by Allon and Copkney,9 asymptomatic hypoglycemia was reported in 75% of patients following the administration of 10 units of regular insulin and 25 gm of dextrose for hyperkalemia in patients with renal failure. The study demonstrated baseline plasma glucose levels of 85‐92 mg/dl in patients prior to the insulin and dextrose therapy. Transient hyperglycemia developed 15 minutes post‐therapy, resolved within 30 minutes, and then progressed toward significant hypoglycemia at 60 minutes with blood glucose levels declining into the 45‐56 mg/dl range. The study also demonstrated that the hypoglycemia secondary to the insulin/dextrose regimen was attenuated by the concomitant use of inhaled albuterol.

Management of acute hyperkalemia stabilization lacks a standardized treatment regimen. Often a shot‐gun approach employing multiple therapeutic modalities is prescribed concomitantly, and intravenous insulin and dextrose are commonly included in these treatment regimens. Hyperkalemia treatment regimens are often prescribed based on local treatment patterns or from online references including Pepid6 and UpToDate.7 In addition, reference manuals such as the Washington Manual of Medical Therapeutics13 also provide therapeutic guidelines. However, these sources often do not agree on a standard treatment. In terms of a combined insulin and glucose therapy for hyperkalemia, the practice at our hospital is to administer, 10 units of regular insulin IVP with 50 ml (25 gm) of dextrose 50% IVP. UpToDate7 suggests 10 units of regular insulin IVP with 25 gm of dextrose 50% IVP, followed by dextrose 10% infusion by intravenous piggyback (IVPB) at 50‐75 ml/hr with careful monitoring. Pepid6 recommends 10 units of regular insulin IVP and 25 gm of dextrose 50% IVP, whereas the Washington Manual of Medical Therapeutics13 suggests 10‐20 units of regular insulin and 25‐50 gm of glucose administered intravenously.

Our study demonstrated a hypoglycemia frequency of 8.7% (<70 mg/dl) which occurred over a range of 5‐10 units of regular insulin and 0‐50 gm of dextrose 50%. However, this frequency may underestimate the true hypoglycemic incidence, as our study excluded patients without posttreatment blood glucose levels, and we were unable to control for patient self‐treatment or nurse‐assisted treatment of hypoglycemia with dietary sources of glucose (juice, crackers, etc). Despite these limitations, a hypoglycemic incidence of 8.7% is extremely high and constitutes an unacceptably high iatrogenic risk for complications. Data from the critical care literature suggests that hypoglycemia is an independent marker of mortality.14 Fifty‐eight percent of our total hypoglycemic events developed after patients received the commonly cited regimen of 10 units of regular insulin IVP and 25 gm of 50% dextrose IVP. One of our patients developed hypoglycemia despite a regimen of 10 units of regular insulin with 50 gm of 50% dextrose. This variability of patient response suggests that no single algorithm will prevent all hypoglycemic events, therefore, careful patient assessment and blood glucose monitoring should be routinely employed.

The decision regarding the order of dextrose and insulin administration can be influenced by clinical factors. Dextrose administration should generally precede insulin administration.15 In the setting of insulin and aldosterone deficiency (ie, a patient with type 1 diabetes and type IV renal tubular acidosis), dextrose administration prior to insulin administration could exacerbate the patient's hyperkalemia. In this circumstance, insulin administration should precede dextrose administration, with dextrose dosing predicated on the patient's estimated glycemic requirements and glucose monitoring. However, in patients with isolated insulin or aldosterone deficiency, the initial administration of dextrose does not predispose to further hyperkalemia.16

Hypoglycemia risk can be minimized by increasing the dextrose component in most insulin/dextrose hyperkalemia treatment regimens. The dextrose may be administered as 100 ml of 50% dextrose IVP or 50 ml of 50% dextrose IVPB, followed by 250 ml of D10 IVPB over 1 hour. The latter regimen may be preferred for patients at higher risk of hypoglycemia, although the added volume of fluid may not be appropriate for all patients. It must be recognized that this regimen may result in short‐term hyperglycemia, and patients should be closely monitored. It is reasonable, prior to treatment, to obtain a baseline blood glucose level and to obtain a 1‐hour and 3‐hour posttreatment blood glucose level.

While an electronic hospital record provides convenient access to a large number of patients and allows cross‐referencing of various laboratory values and prescribed medications, the ability to develop persuasive conclusions from the generated data may be significantly limited by inadequate or missing documentation of patient's pretreatment symptoms and response to therapy. The documentation of treatment response in the acute stabilization of hyperkalemia of our patients lacked specificity and standardization. Similarly, documentation of hypoglycemia and subsequent treatment response is not standardized at our institution. This lack of patient data limits our ability to gauge the level of harm experienced by our patients or evaluate the timeliness and appropriateness of their hypoglycemic treatment. Therefore, documentation of hypoglycemic symptoms and treatment will be the subject of future performance improvement initiatives and study at our institution. Further, studies need to be pursued utilizing standardized charting templates to facilitate and guide appropriate treatment assessment and follow‐up documentation. This will also assist in evaluating the treatment options addressed in this article. In addition, evaluation of bolus therapy with 50% dextrose versus therapies using D10 infusions in combination with insulin for hyperkalemia treatment in emergency room patients will be pursued. Despite these limitations, any policy which can limit harm from potential hypoglycemia deserves institutional attention and study.

Iatrogenic hypoglycemia as a result of treatment for hyperkalemia is a common occurrence, is largely unrecognized, and can have adverse outcomes. In our present study, 8.7% of patients became hypoglycemic following insulin treatment for hyperkalemia. Hyperkalemia occurs disproportionately in patients with acute kidney injury or end‐stage renal function. Moreover, the risk of severe hypoglycemia escalates in patients with lower body weight, and careful surveillance is needed in these cases.

Hospice provides a wide range of palliative and supportive services to patients and families facing a life‐limiting illness which include specialized medical care, aggressive pain and symptom management, and emotional and spiritual support. Hospice has been shown to benefit both patients and families by improving satisfaction and pain management, reducing medical costs and unmet needs, and decreasing family member's concerns,14 yet services are underutilized. In over 25 years of the Medicare hospice benefit, the median length of hospice stay has remained approximately 20‐22 days. This is consistent with the National Hospice and Palliative Care Organization (NHPCO) 2009 report which reveals that approximately 41.6% of all deaths in the United States occurred under the care of a hospice program, with more than half of the patients having a length of hospice service less than 21.1 days. The short length of stay is significant, because bereaved families commonly report that more time in hospice would have been beneficial.5

Medicare has 2 requirements for hospice eligibility: 1) the patient must understand that his/her illness is life‐limiting and be willing to forego curative therapy; and 2) two physicians must declare that the patient has 6 months or less to live. Hospice agencies often rely on NHPCO published worksheets (designed to identify patients with a prognosis of less than 6 months) to assist in determining if a patient meets the Medicare requirements. Even when a patient might meet Medicare requirements for hospice, many do not receive hospice services prior to their death. Physicians, patients, and families all present different barriers to hospice referrals which include: physician difficulty with accurate prognostication, physician grief and feelings of inadequacy, lack of knowledge about hospice and the referral process, and decreased communication between decision‐makers.69 A majority of the barriers to hospice referral may be overcome with education and normalization of hospice as an appropriate and effective medical intervention.

It is not known how often clinicians recognize that a patient is hospice eligible, nor is it known how often discussion of hospice occurs with appropriate patients or families. Studies in nursing homes and among advanced cancer patients demonstrate that physicians do not recognize hospice‐eligible patients and, as a consequence, hospice is not mentioned as a treatment option; however, when physicians are informed that a patient is hospice eligible and a hospice informational visit is provided, the physician is more likely to refer and the patient is much more likely to utilize hospice services.7, 10, 11 Earlier access to hospice improves care, helps ensure medically appropriate services are received, helps ensure death occurs in the preferred location, and is preferred by caregivers.12 In order to consider hospice, the treating physician needs to recognize and accept that the patient is dying. The goal of this study was to determine the percentage of patients who met guidelines for hospice admission, and had a documented discussion regarding hospice appropriateness in the medical record during a penultimate admission, defined as the hospital admission which preceded death.

METHODS

Study Selection and Population

This study was approved by the University of Iowa Institutional Review Board. A summer research medical student (K.F.), who was closely supervised by the principle investigator, reviewed the electronic medical record of all adult inpatient deaths at The University of Iowa Hospitals and Clinics (UIHC) in 2009 (Figure 1). Traumatic deaths were excluded. For each eligible patient, K.F. recorded age, sex, race, and date of death. For those patients who had a hospitalization in the previous 12 months, K.F. reviewed all physician and social work notes from both the penultimate and terminal admissions, and recorded primary and secondary diagnoses from both admissions, hospice enrollment at the time of either admission, evidence of a hospice discussion, occurrence of a palliative care consult during either admission, number of subspecialist referrals during the penultimate admission, length of stay, and total hospital costs for each admission.

Figure 1

RESULTS