Federal Practitioner

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Vancomycin is a commonly used glycopeptide antibiotic used to treat infections caused by gram-positive organisms. Vancomycin is most often used as a parenteral agent for empiric or definitive treatment of methicillin-resistant Staphylococcus aureus (MRSA). It can also be used for the treatment of other susceptible Staphylococcus or Enterococcus species. Adverse effects of parenteral vancomycin include infusion-related reactions, ototoxicity, and nephrotoxicity.¹ Higher vancomycin trough levels have been associated with an increased risk of nephrotoxicity.^1-4 The major safety concern with vancomycin is acute kidney injury (AKI). Even mild AKI can prolong hospitalizations, increase the cost of health care, and increase morbidity.²

In March 2020, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society, and the Society of Infectious Diseases Pharmacists released a consensus statement and guidelines regarding the optimization of vancomycin dosing and monitoring for patients with suspected or definitive serious MRSA infections. Based on these guidelines, it is recommended to target an individualized area under the curve/minimum inhibitory concentration (AUC/MIC) ratio of 400 to 600 mg × h/L to maximize clinical efficacy and minimize the risk of AKI.²

Before March 2020, the vancomycin monitoring recommendation was to target trough levels of 10 to 20 mg/L. A goal trough of 15 to 20 mg/L was recommended for severe infections, including sepsis, endocarditis, hospital-acquired pneumonia, meningitis, and osteomyelitis, caused by MRSA. A goal trough of 10 to 15 mg/L was recommended for noninvasive infections, such as skin and soft tissue infections and urinary tract infections, caused by MRSA. Targeting these trough levels was thought to achieve an AUC/MIC ≥ 400 mg × h/L.⁵ Evidence has since shown that trough values may not be an optimal marker for AUC/MIC values.²

The updated vancomycin therapeutic drug monitoring (TDM) guidelines recommend that health systems transition to AUC/MIC-guided monitoring for suspected or confirmed infections caused by MRSA. There is not enough evidence to recommend AUC/MIC-guided monitoring in patients with noninvasive infections or infections caused by other microbes.²

AUC/MIC-guided monitoring can be achieved in 2 ways. The first method is collecting C_max (peak level) and C_min (trough level) serum concentrations, preferably during the same dosing interval. Ideally, C_max should be drawn 1 to 2 hours after the vancomycin infusion and C_min should be drawn at the end of the dosing interval. First-order pharmacokinetic equations are used to estimate the AUC/MIC with this method. Bayesian software pharmacokinetic modeling based on 1 or 2 vancomycin concentrations with 1 trough level also can be used for monitoring. Preferably, 2 levels would be obtained to estimate the AUC/MIC when using Bayesian modeling.²

The bactericidal activity of vancomycin was achieved with AUC/MIC ratios of ≥ 400 mg × h/L. AUC/MIC ratios of < 400 mg × h/L increase the incidence of resistant and intermediate strains of S aureus. AUC/MIC-guided monitoring assumes an MIC of 1 mg/L. When the MIC is > 1 mg/L, it is less likely that an AUC/MIC ≥ 400 mg × h/L is achievable. Regardless of the TDM method used, AUC/MIC ratios ≥ 400 mg × h/L are not achievable with conventional dosing methods if the vancomycin MIC is > 2 mg/L in patients with normal renal function. Alternative therapy is recommended to be used for these patients.²

There are multiple studies investigating the therapeutic dosing of vancomycin and the associated incidence of AKI. Previous studies have correlated vancomycin AUC/MICs of 400 mg to 600 mg × h/L with clinical effectiveness.^2,6 In 2017, Neely and colleagues looked at the therapeutic dosing of vancomycin in 252 adults with ≥ 1 vancomycin level.⁷ During this prospective trial, they evaluated patients for 1 year and targeted trough concentrations of 10 to 20 mg/L with infection-specific goal ranges of 10 to 15 mg/L and 15 to 20 mg/L for noninvasive and invasive infections, respectively. They also targeted AUC/MIC ratios ≥ 400 mg × h/L regardless of trough concentration using Bayesian estimated AUC/MICs for 2 years. They found only 19% of trough concentrations to be therapeutic compared with 70% of AUC/MICs. A secondary outcome assessed by Neely and colleagues was nephrotoxicity, which was identified in 8% of patients with trough targets and 2% of patients with AUC/MIC targets.⁸

Previous studies evaluating the use of vancomycin in the veteran population have focused on AKI incidence, general nephrotoxicity, and 30-day readmission rates.^4,7,9,10 Poston-Blahnik and colleagues investigated the rates of AKI in 200 veterans using AUC/MIC-guided vancomycin TDM.⁵ They found an AKI incidence of 42% of patients with AUC/MICs ≥ 550 mg × h/L and 2% of patients with AUC/MICs < 550 mg × h/L.⁵ Gyamlani and colleagues investigated the rates of AKI in 33,527 veterans and found that serum vancomycin trough levels ≥ 20 mg/L were associated with a higher risk of AKI.⁸ Prabaker and colleagues investigated the association between vancomycin trough levels and nephrotoxicity, defined as 0.5 mg/L or a 50% increase in serum creatinine (sCr) in 348 veterans. They found nephrotoxicity in 8.9% of patients.¹⁰ Patel and colleagues investigated the effect of AKI on 30-day readmission rates in 216 veterans.¹⁰ AKI occurred in 8.8% of patients and of those 19.4% were readmitted within 30 days.¹⁰ Current literature lacks evidence regarding the comparison of the safety and efficacy of vancomycin trough-guided vs AUC/MIC-guided TDM in the veteran population. Therefore, the objective of this study was to investigate the differences in the safety and efficacy of vancomycin TDM in the veteran population based on the different monitoring methods used.

METHODS

This study was a retrospective, single-center, quasi-experimental chart review conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS) in South Dakota. Data were collected from the Computerized Patient Record System (CPRS). The SFVAHCS transitioned from trough-guided to AUC/MIC-guided TDM in November 2020.

Patients included in this study were veterans aged ≥ 18 years with orders for parenteral vancomycin between February 1, 2020, and October 31, 2020, for the trough-guided TDM group and between December 1, 2020, and August 31, 2021, for the AUC/MIC-guided TDM group. Patients with vancomycin courses initiated during November 2020 were excluded as both TDM methods were being used at that time. Patients were excluded if their vancomycin course began before February 1, 2020, for the trough-guided TDM group or began during November 2020 for the AUC/MIC-guided TDM group. Patients were excluded if their vancomycin course extended past October 31, 2020, for the trough group or past August 31, 2021, for the AUC/MIC group. Patients on dialysis or missing C_max, C_min, or sCr levels were excluded.

This study evaluated both safety (AKI incidence) and effectiveness (time spent in therapeutic range and time to therapeutic range). The primary endpoint was presence of vancomycin-induced AKI, which was based on the most recent Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition: increased sCr of ≥ 0.3 mg/dL or by 50% from baseline sustained over 48 hours without any other explanation for the change.¹¹ A secondary endpoint was the absence or presence of AKI.

Additional secondary endpoints included the presence of the initial trough or AUC/MIC of each vancomycin course within the therapeutic range and the percentage of all trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges. The therapeutic range for AUC/MIC-guided TDM was 400 to 600 mg × h/L and 10 to 20 mg/L depending on indication for trough-guided TDM (15-20 mg/L for severe infections and 10-15 mg/L for less invasive infections). The percentage of trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges were calculated as a ratio of levels within each range to total levels taken for each patient.

For AUC/MIC-guided TDM the C_max levels were ideally drawn 1 to 2 hours after vancomycin infusion and C_min levels were ideally drawn 30 minutes before the next dose. First-order pharmacokinetic equations were used to estimate the AUC/MIC.¹² If the timing of a vancomycin level was inappropriate, actual levels were extrapolated based on the timing of the blood draw compared with the ideal C_min or C_max time. Extrapolated levels were used for both trough-guided and AUC/MIC-guided TDM groups when appropriate. Vancomycin levels were excluded if they were drawn during the vancomycin infusion.

Study participant age, sex, race, weight, baseline estimated glomerular filtration (eGFR) rate, baseline sCr, concomitant nephrotoxic medications, duration of vancomycin course, indication of vancomycin, and acuity of illness based on indication were collected. sCr levels were collected from the initial day vancomycin was ordered through 72 hours following completion of a vancomycin course to evaluate for AKI. Patients’ charts were reviewed for the use of the following nephrotoxic medications: nonsteroidal anti-inflammatories, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycosides, piperacillin/tazobactam, loop diuretics, amphotericin B, acyclovir, intravenous contrast, and nephrotoxic chemotherapy (cisplatin). The category of concomitant nephrotoxic medications was also collected including the continuation of a home nephrotoxic medication vs the initiation of a new nephrotoxic medication.

Statistical Analysis

The primary endpoint of the incidence of vancomycin-induced AKI was compared using a Fisher exact test. The secondary endpoint of the percentage of trough levels or AUC/MICs in the therapeutic, subtherapeutic, and supratherapeutic range were compared using a student t test. The secondary endpoint of first level or AUC/MIC within goal range was compared using a χ² test. Continuous baseline characteristics were reported as a mean and compared using a student t test. Nominal baseline characteristics were reported as a percentage and compared using the χ² test. P values < .05 were considered statistically significant.

RESULTS

This study included 97 patients, 43 in the AUC/MIC group and 54 in the trough group.

One (2%) patient in the AUC/MIC group and 2 (4%) patients in the trough group experienced vancomycin-induced AKI (P = .10) (Table 2).

DISCUSSION

There was no statistically significant difference between the 2 groups for the vancomycin-induced AKI (P = .10), the primary endpoint, or overall AKI (P = .29), the secondary endpoint. It should be noted that there was more overall AKI in the AUC/MIC group. Veterans in the AUC/MIC group were found to have their first AUC/MIC within the therapeutic range statistically significantly more often than the first trough level in the trough group (P = .04). The percentage of time spent within therapeutic range was statistically significantly higher in the AUC/MIC-guided TDM group (P = .02). The percentage of time spent subtherapeutic of goal range was statistically significantly higher in the trough-guided TDM group (P < .001). There was no statistically significant difference found in the percent of time spent supratherapeutic of goal range (P = .25). However, the observed percentage of time spent supratherapeutic of goal range was higher in the AUC/MIC group. These results indicate that AUC/MIC-guided TDM may be more efficacious with regard to time in therapeutic range and time to therapeutic range.

The finding of increased AKI with AUC/MIC-guided TDM does not align with previous studies.⁸ The prospective study by Neely and colleagues found that AUC/MIC-guided TDM resulted in more time in the therapeutic range as well as less nephrotoxicity compared with trough-guided TDM, although it was limited by its lack of randomization and did not account for other causes of nephrotoxicity.⁸ They found that only 19% of trough concentrations were therapeutic compared with 70% of AUC/MICs and found nephrotoxicity in 8% of trough-guided TDM patients compared with 2% of AUC/MIC-guided TDM patients.⁸

Unlike Nealy and colleagues, our study did not find lower nephrotoxicity associated with AUC/MIC-guided TDM. Multiple factors may have influenced our results. Our AUC/MIC group had significantly more newly started concomitant nephrotoxins and other nephrotoxic medications used during the vancomycin courses compared with the trough-guided group, which may have influenced AKI outcomes. It also should be noted that there was significantly more time spent subtherapeutic of the goal range and significantly less time in the goal range in the trough group compared with the AUC/MIC group. In our study, the trough-guided group had significantly more patients with acute illness compared with the AUC/MIC group (skin, soft tissue, and joint infections were similar between the groups). The group with more acutely ill patients would have been expected to have more nephrotoxicity. However, despite the acute illnesses, patients in the trough-guided group spent more time in the subtherapeutic range. This may explain the increased nephrotoxicity in the AUC/MIC group since those patients spent more time in the therapeutic range.

This study used the most recent KDIGO AKI definition: either an increase in sCr of ≥ 0.3 mg/dL or a 50% increase in sCr from baseline sustained over 48 hours without any other explanation for the change in renal function.¹¹ This AKI definition is stricter than the previous definition, which was used by earlier studies, including Neely and colleagues, to evaluate rates of vancomycin-induced AKI.^2,3 Therefore, the rates of overall AKI found in this study may be higher than in previous studies due to the definition of AKI used.

Limitations

This study was limited by its retrospective nature, lack of randomization, and small sample size. To decrease the potential for error in this study, analysis of power and a larger study sample would have been beneficial. During the COVID-19 pandemic, increased pneumonia cases may have hidden bacterial causes and caused an undercount. Nephrotoxicity may also be related to volume depletion, severe systemic illness, dehydration, or hypotension. Screening was completed via chart review for these alternative causes of nephrotoxicity in this study but may not be completely accounted for due to lack of documentation and the retrospective nature of this study.

CONCLUSIONS

This study did not find a significant difference in the rates of vancomycin-induced or overall AKI between AUC/MIC-guided and trough-guided TDM. However, this study may not have been powered to detect a significant difference in the primary endpoint. This study indicated that AUC/MIC-guided TDM of vancomycin resulted in a quicker time to the therapeutic range and a higher percentage of overall time in the therapeutic range as compared with trough-guided TDM. The results of this study indicated that trough-guided monitoring resulted in a higher percentage of time in a subtherapeutic range. This study also found that the first AUC/MIC calculated was within therapeutic range more often than the first trough level collected.

These results indicate that AUC/MIC-guided TDM may be more effective than trough-guided TDM in the veteran population. However, while AUC/MIC-guided TDM may be more effective with regards to time in therapeutic range and time to therapeutic range, this study did not indicate any safety benefit of AUC/MIC-guided over trough-guided TDM with regards to AKI incidence. Our data indicate that AUC/MIC-guided TDM increases the amount of time in the therapeutic range compared with trough-guided TDM and is not more nephrotoxic. The findings of this study support the recommendation to transition to the use of AUC/MIC-guided TDM of vancomycin in the veteran population.

Acknowledgments

This material is the result of work supported with the use of facilities and resources from the Sioux Falls Veterans Affairs Health Care System.

Vancomycin is a commonly used glycopeptide antibiotic used to treat infections caused by gram-positive organisms. Vancomycin is most often used as a parenteral agent for empiric or definitive treatment of methicillin-resistant Staphylococcus aureus (MRSA). It can also be used for the treatment of other susceptible Staphylococcus or Enterococcus species. Adverse effects of parenteral vancomycin include infusion-related reactions, ototoxicity, and nephrotoxicity.¹ Higher vancomycin trough levels have been associated with an increased risk of nephrotoxicity.^1-4 The major safety concern with vancomycin is acute kidney injury (AKI). Even mild AKI can prolong hospitalizations, increase the cost of health care, and increase morbidity.²

In March 2020, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society, and the Society of Infectious Diseases Pharmacists released a consensus statement and guidelines regarding the optimization of vancomycin dosing and monitoring for patients with suspected or definitive serious MRSA infections. Based on these guidelines, it is recommended to target an individualized area under the curve/minimum inhibitory concentration (AUC/MIC) ratio of 400 to 600 mg × h/L to maximize clinical efficacy and minimize the risk of AKI.²

Before March 2020, the vancomycin monitoring recommendation was to target trough levels of 10 to 20 mg/L. A goal trough of 15 to 20 mg/L was recommended for severe infections, including sepsis, endocarditis, hospital-acquired pneumonia, meningitis, and osteomyelitis, caused by MRSA. A goal trough of 10 to 15 mg/L was recommended for noninvasive infections, such as skin and soft tissue infections and urinary tract infections, caused by MRSA. Targeting these trough levels was thought to achieve an AUC/MIC ≥ 400 mg × h/L.⁵ Evidence has since shown that trough values may not be an optimal marker for AUC/MIC values.²

The updated vancomycin therapeutic drug monitoring (TDM) guidelines recommend that health systems transition to AUC/MIC-guided monitoring for suspected or confirmed infections caused by MRSA. There is not enough evidence to recommend AUC/MIC-guided monitoring in patients with noninvasive infections or infections caused by other microbes.²

AUC/MIC-guided monitoring can be achieved in 2 ways. The first method is collecting C_max (peak level) and C_min (trough level) serum concentrations, preferably during the same dosing interval. Ideally, C_max should be drawn 1 to 2 hours after the vancomycin infusion and C_min should be drawn at the end of the dosing interval. First-order pharmacokinetic equations are used to estimate the AUC/MIC with this method. Bayesian software pharmacokinetic modeling based on 1 or 2 vancomycin concentrations with 1 trough level also can be used for monitoring. Preferably, 2 levels would be obtained to estimate the AUC/MIC when using Bayesian modeling.²

The bactericidal activity of vancomycin was achieved with AUC/MIC ratios of ≥ 400 mg × h/L. AUC/MIC ratios of < 400 mg × h/L increase the incidence of resistant and intermediate strains of S aureus. AUC/MIC-guided monitoring assumes an MIC of 1 mg/L. When the MIC is > 1 mg/L, it is less likely that an AUC/MIC ≥ 400 mg × h/L is achievable. Regardless of the TDM method used, AUC/MIC ratios ≥ 400 mg × h/L are not achievable with conventional dosing methods if the vancomycin MIC is > 2 mg/L in patients with normal renal function. Alternative therapy is recommended to be used for these patients.²

There are multiple studies investigating the therapeutic dosing of vancomycin and the associated incidence of AKI. Previous studies have correlated vancomycin AUC/MICs of 400 mg to 600 mg × h/L with clinical effectiveness.^2,6 In 2017, Neely and colleagues looked at the therapeutic dosing of vancomycin in 252 adults with ≥ 1 vancomycin level.⁷ During this prospective trial, they evaluated patients for 1 year and targeted trough concentrations of 10 to 20 mg/L with infection-specific goal ranges of 10 to 15 mg/L and 15 to 20 mg/L for noninvasive and invasive infections, respectively. They also targeted AUC/MIC ratios ≥ 400 mg × h/L regardless of trough concentration using Bayesian estimated AUC/MICs for 2 years. They found only 19% of trough concentrations to be therapeutic compared with 70% of AUC/MICs. A secondary outcome assessed by Neely and colleagues was nephrotoxicity, which was identified in 8% of patients with trough targets and 2% of patients with AUC/MIC targets.⁸

Previous studies evaluating the use of vancomycin in the veteran population have focused on AKI incidence, general nephrotoxicity, and 30-day readmission rates.^4,7,9,10 Poston-Blahnik and colleagues investigated the rates of AKI in 200 veterans using AUC/MIC-guided vancomycin TDM.⁵ They found an AKI incidence of 42% of patients with AUC/MICs ≥ 550 mg × h/L and 2% of patients with AUC/MICs < 550 mg × h/L.⁵ Gyamlani and colleagues investigated the rates of AKI in 33,527 veterans and found that serum vancomycin trough levels ≥ 20 mg/L were associated with a higher risk of AKI.⁸ Prabaker and colleagues investigated the association between vancomycin trough levels and nephrotoxicity, defined as 0.5 mg/L or a 50% increase in serum creatinine (sCr) in 348 veterans. They found nephrotoxicity in 8.9% of patients.¹⁰ Patel and colleagues investigated the effect of AKI on 30-day readmission rates in 216 veterans.¹⁰ AKI occurred in 8.8% of patients and of those 19.4% were readmitted within 30 days.¹⁰ Current literature lacks evidence regarding the comparison of the safety and efficacy of vancomycin trough-guided vs AUC/MIC-guided TDM in the veteran population. Therefore, the objective of this study was to investigate the differences in the safety and efficacy of vancomycin TDM in the veteran population based on the different monitoring methods used.

METHODS

This study was a retrospective, single-center, quasi-experimental chart review conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS) in South Dakota. Data were collected from the Computerized Patient Record System (CPRS). The SFVAHCS transitioned from trough-guided to AUC/MIC-guided TDM in November 2020.

Patients included in this study were veterans aged ≥ 18 years with orders for parenteral vancomycin between February 1, 2020, and October 31, 2020, for the trough-guided TDM group and between December 1, 2020, and August 31, 2021, for the AUC/MIC-guided TDM group. Patients with vancomycin courses initiated during November 2020 were excluded as both TDM methods were being used at that time. Patients were excluded if their vancomycin course began before February 1, 2020, for the trough-guided TDM group or began during November 2020 for the AUC/MIC-guided TDM group. Patients were excluded if their vancomycin course extended past October 31, 2020, for the trough group or past August 31, 2021, for the AUC/MIC group. Patients on dialysis or missing C_max, C_min, or sCr levels were excluded.

This study evaluated both safety (AKI incidence) and effectiveness (time spent in therapeutic range and time to therapeutic range). The primary endpoint was presence of vancomycin-induced AKI, which was based on the most recent Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition: increased sCr of ≥ 0.3 mg/dL or by 50% from baseline sustained over 48 hours without any other explanation for the change.¹¹ A secondary endpoint was the absence or presence of AKI.

Additional secondary endpoints included the presence of the initial trough or AUC/MIC of each vancomycin course within the therapeutic range and the percentage of all trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges. The therapeutic range for AUC/MIC-guided TDM was 400 to 600 mg × h/L and 10 to 20 mg/L depending on indication for trough-guided TDM (15-20 mg/L for severe infections and 10-15 mg/L for less invasive infections). The percentage of trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges were calculated as a ratio of levels within each range to total levels taken for each patient.

For AUC/MIC-guided TDM the C_max levels were ideally drawn 1 to 2 hours after vancomycin infusion and C_min levels were ideally drawn 30 minutes before the next dose. First-order pharmacokinetic equations were used to estimate the AUC/MIC.¹² If the timing of a vancomycin level was inappropriate, actual levels were extrapolated based on the timing of the blood draw compared with the ideal C_min or C_max time. Extrapolated levels were used for both trough-guided and AUC/MIC-guided TDM groups when appropriate. Vancomycin levels were excluded if they were drawn during the vancomycin infusion.

Study participant age, sex, race, weight, baseline estimated glomerular filtration (eGFR) rate, baseline sCr, concomitant nephrotoxic medications, duration of vancomycin course, indication of vancomycin, and acuity of illness based on indication were collected. sCr levels were collected from the initial day vancomycin was ordered through 72 hours following completion of a vancomycin course to evaluate for AKI. Patients’ charts were reviewed for the use of the following nephrotoxic medications: nonsteroidal anti-inflammatories, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycosides, piperacillin/tazobactam, loop diuretics, amphotericin B, acyclovir, intravenous contrast, and nephrotoxic chemotherapy (cisplatin). The category of concomitant nephrotoxic medications was also collected including the continuation of a home nephrotoxic medication vs the initiation of a new nephrotoxic medication.

Statistical Analysis

The primary endpoint of the incidence of vancomycin-induced AKI was compared using a Fisher exact test. The secondary endpoint of the percentage of trough levels or AUC/MICs in the therapeutic, subtherapeutic, and supratherapeutic range were compared using a student t test. The secondary endpoint of first level or AUC/MIC within goal range was compared using a χ² test. Continuous baseline characteristics were reported as a mean and compared using a student t test. Nominal baseline characteristics were reported as a percentage and compared using the χ² test. P values < .05 were considered statistically significant.

RESULTS

This study included 97 patients, 43 in the AUC/MIC group and 54 in the trough group.

One (2%) patient in the AUC/MIC group and 2 (4%) patients in the trough group experienced vancomycin-induced AKI (P = .10) (Table 2).

DISCUSSION

There was no statistically significant difference between the 2 groups for the vancomycin-induced AKI (P = .10), the primary endpoint, or overall AKI (P = .29), the secondary endpoint. It should be noted that there was more overall AKI in the AUC/MIC group. Veterans in the AUC/MIC group were found to have their first AUC/MIC within the therapeutic range statistically significantly more often than the first trough level in the trough group (P = .04). The percentage of time spent within therapeutic range was statistically significantly higher in the AUC/MIC-guided TDM group (P = .02). The percentage of time spent subtherapeutic of goal range was statistically significantly higher in the trough-guided TDM group (P < .001). There was no statistically significant difference found in the percent of time spent supratherapeutic of goal range (P = .25). However, the observed percentage of time spent supratherapeutic of goal range was higher in the AUC/MIC group. These results indicate that AUC/MIC-guided TDM may be more efficacious with regard to time in therapeutic range and time to therapeutic range.

The finding of increased AKI with AUC/MIC-guided TDM does not align with previous studies.⁸ The prospective study by Neely and colleagues found that AUC/MIC-guided TDM resulted in more time in the therapeutic range as well as less nephrotoxicity compared with trough-guided TDM, although it was limited by its lack of randomization and did not account for other causes of nephrotoxicity.⁸ They found that only 19% of trough concentrations were therapeutic compared with 70% of AUC/MICs and found nephrotoxicity in 8% of trough-guided TDM patients compared with 2% of AUC/MIC-guided TDM patients.⁸

Unlike Nealy and colleagues, our study did not find lower nephrotoxicity associated with AUC/MIC-guided TDM. Multiple factors may have influenced our results. Our AUC/MIC group had significantly more newly started concomitant nephrotoxins and other nephrotoxic medications used during the vancomycin courses compared with the trough-guided group, which may have influenced AKI outcomes. It also should be noted that there was significantly more time spent subtherapeutic of the goal range and significantly less time in the goal range in the trough group compared with the AUC/MIC group. In our study, the trough-guided group had significantly more patients with acute illness compared with the AUC/MIC group (skin, soft tissue, and joint infections were similar between the groups). The group with more acutely ill patients would have been expected to have more nephrotoxicity. However, despite the acute illnesses, patients in the trough-guided group spent more time in the subtherapeutic range. This may explain the increased nephrotoxicity in the AUC/MIC group since those patients spent more time in the therapeutic range.

This study used the most recent KDIGO AKI definition: either an increase in sCr of ≥ 0.3 mg/dL or a 50% increase in sCr from baseline sustained over 48 hours without any other explanation for the change in renal function.¹¹ This AKI definition is stricter than the previous definition, which was used by earlier studies, including Neely and colleagues, to evaluate rates of vancomycin-induced AKI.^2,3 Therefore, the rates of overall AKI found in this study may be higher than in previous studies due to the definition of AKI used.

Limitations

This study was limited by its retrospective nature, lack of randomization, and small sample size. To decrease the potential for error in this study, analysis of power and a larger study sample would have been beneficial. During the COVID-19 pandemic, increased pneumonia cases may have hidden bacterial causes and caused an undercount. Nephrotoxicity may also be related to volume depletion, severe systemic illness, dehydration, or hypotension. Screening was completed via chart review for these alternative causes of nephrotoxicity in this study but may not be completely accounted for due to lack of documentation and the retrospective nature of this study.

CONCLUSIONS

This study did not find a significant difference in the rates of vancomycin-induced or overall AKI between AUC/MIC-guided and trough-guided TDM. However, this study may not have been powered to detect a significant difference in the primary endpoint. This study indicated that AUC/MIC-guided TDM of vancomycin resulted in a quicker time to the therapeutic range and a higher percentage of overall time in the therapeutic range as compared with trough-guided TDM. The results of this study indicated that trough-guided monitoring resulted in a higher percentage of time in a subtherapeutic range. This study also found that the first AUC/MIC calculated was within therapeutic range more often than the first trough level collected.

These results indicate that AUC/MIC-guided TDM may be more effective than trough-guided TDM in the veteran population. However, while AUC/MIC-guided TDM may be more effective with regards to time in therapeutic range and time to therapeutic range, this study did not indicate any safety benefit of AUC/MIC-guided over trough-guided TDM with regards to AKI incidence. Our data indicate that AUC/MIC-guided TDM increases the amount of time in the therapeutic range compared with trough-guided TDM and is not more nephrotoxic. The findings of this study support the recommendation to transition to the use of AUC/MIC-guided TDM of vancomycin in the veteran population.

Acknowledgments

This material is the result of work supported with the use of facilities and resources from the Sioux Falls Veterans Affairs Health Care System.

Vancomycin is a commonly used glycopeptide antibiotic used to treat infections caused by gram-positive organisms. Vancomycin is most often used as a parenteral agent for empiric or definitive treatment of methicillin-resistant Staphylococcus aureus (MRSA). It can also be used for the treatment of other susceptible Staphylococcus or Enterococcus species. Adverse effects of parenteral vancomycin include infusion-related reactions, ototoxicity, and nephrotoxicity.¹ Higher vancomycin trough levels have been associated with an increased risk of nephrotoxicity.^1-4 The major safety concern with vancomycin is acute kidney injury (AKI). Even mild AKI can prolong hospitalizations, increase the cost of health care, and increase morbidity.²

In March 2020, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society, and the Society of Infectious Diseases Pharmacists released a consensus statement and guidelines regarding the optimization of vancomycin dosing and monitoring for patients with suspected or definitive serious MRSA infections. Based on these guidelines, it is recommended to target an individualized area under the curve/minimum inhibitory concentration (AUC/MIC) ratio of 400 to 600 mg × h/L to maximize clinical efficacy and minimize the risk of AKI.²

Before March 2020, the vancomycin monitoring recommendation was to target trough levels of 10 to 20 mg/L. A goal trough of 15 to 20 mg/L was recommended for severe infections, including sepsis, endocarditis, hospital-acquired pneumonia, meningitis, and osteomyelitis, caused by MRSA. A goal trough of 10 to 15 mg/L was recommended for noninvasive infections, such as skin and soft tissue infections and urinary tract infections, caused by MRSA. Targeting these trough levels was thought to achieve an AUC/MIC ≥ 400 mg × h/L.⁵ Evidence has since shown that trough values may not be an optimal marker for AUC/MIC values.²

The updated vancomycin therapeutic drug monitoring (TDM) guidelines recommend that health systems transition to AUC/MIC-guided monitoring for suspected or confirmed infections caused by MRSA. There is not enough evidence to recommend AUC/MIC-guided monitoring in patients with noninvasive infections or infections caused by other microbes.²

AUC/MIC-guided monitoring can be achieved in 2 ways. The first method is collecting C_max (peak level) and C_min (trough level) serum concentrations, preferably during the same dosing interval. Ideally, C_max should be drawn 1 to 2 hours after the vancomycin infusion and C_min should be drawn at the end of the dosing interval. First-order pharmacokinetic equations are used to estimate the AUC/MIC with this method. Bayesian software pharmacokinetic modeling based on 1 or 2 vancomycin concentrations with 1 trough level also can be used for monitoring. Preferably, 2 levels would be obtained to estimate the AUC/MIC when using Bayesian modeling.²

The bactericidal activity of vancomycin was achieved with AUC/MIC ratios of ≥ 400 mg × h/L. AUC/MIC ratios of < 400 mg × h/L increase the incidence of resistant and intermediate strains of S aureus. AUC/MIC-guided monitoring assumes an MIC of 1 mg/L. When the MIC is > 1 mg/L, it is less likely that an AUC/MIC ≥ 400 mg × h/L is achievable. Regardless of the TDM method used, AUC/MIC ratios ≥ 400 mg × h/L are not achievable with conventional dosing methods if the vancomycin MIC is > 2 mg/L in patients with normal renal function. Alternative therapy is recommended to be used for these patients.²

There are multiple studies investigating the therapeutic dosing of vancomycin and the associated incidence of AKI. Previous studies have correlated vancomycin AUC/MICs of 400 mg to 600 mg × h/L with clinical effectiveness.^2,6 In 2017, Neely and colleagues looked at the therapeutic dosing of vancomycin in 252 adults with ≥ 1 vancomycin level.⁷ During this prospective trial, they evaluated patients for 1 year and targeted trough concentrations of 10 to 20 mg/L with infection-specific goal ranges of 10 to 15 mg/L and 15 to 20 mg/L for noninvasive and invasive infections, respectively. They also targeted AUC/MIC ratios ≥ 400 mg × h/L regardless of trough concentration using Bayesian estimated AUC/MICs for 2 years. They found only 19% of trough concentrations to be therapeutic compared with 70% of AUC/MICs. A secondary outcome assessed by Neely and colleagues was nephrotoxicity, which was identified in 8% of patients with trough targets and 2% of patients with AUC/MIC targets.⁸

Previous studies evaluating the use of vancomycin in the veteran population have focused on AKI incidence, general nephrotoxicity, and 30-day readmission rates.^4,7,9,10 Poston-Blahnik and colleagues investigated the rates of AKI in 200 veterans using AUC/MIC-guided vancomycin TDM.⁵ They found an AKI incidence of 42% of patients with AUC/MICs ≥ 550 mg × h/L and 2% of patients with AUC/MICs < 550 mg × h/L.⁵ Gyamlani and colleagues investigated the rates of AKI in 33,527 veterans and found that serum vancomycin trough levels ≥ 20 mg/L were associated with a higher risk of AKI.⁸ Prabaker and colleagues investigated the association between vancomycin trough levels and nephrotoxicity, defined as 0.5 mg/L or a 50% increase in serum creatinine (sCr) in 348 veterans. They found nephrotoxicity in 8.9% of patients.¹⁰ Patel and colleagues investigated the effect of AKI on 30-day readmission rates in 216 veterans.¹⁰ AKI occurred in 8.8% of patients and of those 19.4% were readmitted within 30 days.¹⁰ Current literature lacks evidence regarding the comparison of the safety and efficacy of vancomycin trough-guided vs AUC/MIC-guided TDM in the veteran population. Therefore, the objective of this study was to investigate the differences in the safety and efficacy of vancomycin TDM in the veteran population based on the different monitoring methods used.

METHODS

This study was a retrospective, single-center, quasi-experimental chart review conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS) in South Dakota. Data were collected from the Computerized Patient Record System (CPRS). The SFVAHCS transitioned from trough-guided to AUC/MIC-guided TDM in November 2020.

Patients included in this study were veterans aged ≥ 18 years with orders for parenteral vancomycin between February 1, 2020, and October 31, 2020, for the trough-guided TDM group and between December 1, 2020, and August 31, 2021, for the AUC/MIC-guided TDM group. Patients with vancomycin courses initiated during November 2020 were excluded as both TDM methods were being used at that time. Patients were excluded if their vancomycin course began before February 1, 2020, for the trough-guided TDM group or began during November 2020 for the AUC/MIC-guided TDM group. Patients were excluded if their vancomycin course extended past October 31, 2020, for the trough group or past August 31, 2021, for the AUC/MIC group. Patients on dialysis or missing C_max, C_min, or sCr levels were excluded.

This study evaluated both safety (AKI incidence) and effectiveness (time spent in therapeutic range and time to therapeutic range). The primary endpoint was presence of vancomycin-induced AKI, which was based on the most recent Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition: increased sCr of ≥ 0.3 mg/dL or by 50% from baseline sustained over 48 hours without any other explanation for the change.¹¹ A secondary endpoint was the absence or presence of AKI.

Additional secondary endpoints included the presence of the initial trough or AUC/MIC of each vancomycin course within the therapeutic range and the percentage of all trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges. The therapeutic range for AUC/MIC-guided TDM was 400 to 600 mg × h/L and 10 to 20 mg/L depending on indication for trough-guided TDM (15-20 mg/L for severe infections and 10-15 mg/L for less invasive infections). The percentage of trough levels or AUC/MICs within therapeutic, subtherapeutic, and supratherapeutic ranges were calculated as a ratio of levels within each range to total levels taken for each patient.

For AUC/MIC-guided TDM the C_max levels were ideally drawn 1 to 2 hours after vancomycin infusion and C_min levels were ideally drawn 30 minutes before the next dose. First-order pharmacokinetic equations were used to estimate the AUC/MIC.¹² If the timing of a vancomycin level was inappropriate, actual levels were extrapolated based on the timing of the blood draw compared with the ideal C_min or C_max time. Extrapolated levels were used for both trough-guided and AUC/MIC-guided TDM groups when appropriate. Vancomycin levels were excluded if they were drawn during the vancomycin infusion.

Study participant age, sex, race, weight, baseline estimated glomerular filtration (eGFR) rate, baseline sCr, concomitant nephrotoxic medications, duration of vancomycin course, indication of vancomycin, and acuity of illness based on indication were collected. sCr levels were collected from the initial day vancomycin was ordered through 72 hours following completion of a vancomycin course to evaluate for AKI. Patients’ charts were reviewed for the use of the following nephrotoxic medications: nonsteroidal anti-inflammatories, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycosides, piperacillin/tazobactam, loop diuretics, amphotericin B, acyclovir, intravenous contrast, and nephrotoxic chemotherapy (cisplatin). The category of concomitant nephrotoxic medications was also collected including the continuation of a home nephrotoxic medication vs the initiation of a new nephrotoxic medication.

Statistical Analysis

The primary endpoint of the incidence of vancomycin-induced AKI was compared using a Fisher exact test. The secondary endpoint of the percentage of trough levels or AUC/MICs in the therapeutic, subtherapeutic, and supratherapeutic range were compared using a student t test. The secondary endpoint of first level or AUC/MIC within goal range was compared using a χ² test. Continuous baseline characteristics were reported as a mean and compared using a student t test. Nominal baseline characteristics were reported as a percentage and compared using the χ² test. P values < .05 were considered statistically significant.

RESULTS

This study included 97 patients, 43 in the AUC/MIC group and 54 in the trough group.

One (2%) patient in the AUC/MIC group and 2 (4%) patients in the trough group experienced vancomycin-induced AKI (P = .10) (Table 2).

DISCUSSION

There was no statistically significant difference between the 2 groups for the vancomycin-induced AKI (P = .10), the primary endpoint, or overall AKI (P = .29), the secondary endpoint. It should be noted that there was more overall AKI in the AUC/MIC group. Veterans in the AUC/MIC group were found to have their first AUC/MIC within the therapeutic range statistically significantly more often than the first trough level in the trough group (P = .04). The percentage of time spent within therapeutic range was statistically significantly higher in the AUC/MIC-guided TDM group (P = .02). The percentage of time spent subtherapeutic of goal range was statistically significantly higher in the trough-guided TDM group (P < .001). There was no statistically significant difference found in the percent of time spent supratherapeutic of goal range (P = .25). However, the observed percentage of time spent supratherapeutic of goal range was higher in the AUC/MIC group. These results indicate that AUC/MIC-guided TDM may be more efficacious with regard to time in therapeutic range and time to therapeutic range.

The finding of increased AKI with AUC/MIC-guided TDM does not align with previous studies.⁸ The prospective study by Neely and colleagues found that AUC/MIC-guided TDM resulted in more time in the therapeutic range as well as less nephrotoxicity compared with trough-guided TDM, although it was limited by its lack of randomization and did not account for other causes of nephrotoxicity.⁸ They found that only 19% of trough concentrations were therapeutic compared with 70% of AUC/MICs and found nephrotoxicity in 8% of trough-guided TDM patients compared with 2% of AUC/MIC-guided TDM patients.⁸

Unlike Nealy and colleagues, our study did not find lower nephrotoxicity associated with AUC/MIC-guided TDM. Multiple factors may have influenced our results. Our AUC/MIC group had significantly more newly started concomitant nephrotoxins and other nephrotoxic medications used during the vancomycin courses compared with the trough-guided group, which may have influenced AKI outcomes. It also should be noted that there was significantly more time spent subtherapeutic of the goal range and significantly less time in the goal range in the trough group compared with the AUC/MIC group. In our study, the trough-guided group had significantly more patients with acute illness compared with the AUC/MIC group (skin, soft tissue, and joint infections were similar between the groups). The group with more acutely ill patients would have been expected to have more nephrotoxicity. However, despite the acute illnesses, patients in the trough-guided group spent more time in the subtherapeutic range. This may explain the increased nephrotoxicity in the AUC/MIC group since those patients spent more time in the therapeutic range.

This study used the most recent KDIGO AKI definition: either an increase in sCr of ≥ 0.3 mg/dL or a 50% increase in sCr from baseline sustained over 48 hours without any other explanation for the change in renal function.¹¹ This AKI definition is stricter than the previous definition, which was used by earlier studies, including Neely and colleagues, to evaluate rates of vancomycin-induced AKI.^2,3 Therefore, the rates of overall AKI found in this study may be higher than in previous studies due to the definition of AKI used.

Limitations

This study was limited by its retrospective nature, lack of randomization, and small sample size. To decrease the potential for error in this study, analysis of power and a larger study sample would have been beneficial. During the COVID-19 pandemic, increased pneumonia cases may have hidden bacterial causes and caused an undercount. Nephrotoxicity may also be related to volume depletion, severe systemic illness, dehydration, or hypotension. Screening was completed via chart review for these alternative causes of nephrotoxicity in this study but may not be completely accounted for due to lack of documentation and the retrospective nature of this study.

CONCLUSIONS

This study did not find a significant difference in the rates of vancomycin-induced or overall AKI between AUC/MIC-guided and trough-guided TDM. However, this study may not have been powered to detect a significant difference in the primary endpoint. This study indicated that AUC/MIC-guided TDM of vancomycin resulted in a quicker time to the therapeutic range and a higher percentage of overall time in the therapeutic range as compared with trough-guided TDM. The results of this study indicated that trough-guided monitoring resulted in a higher percentage of time in a subtherapeutic range. This study also found that the first AUC/MIC calculated was within therapeutic range more often than the first trough level collected.

These results indicate that AUC/MIC-guided TDM may be more effective than trough-guided TDM in the veteran population. However, while AUC/MIC-guided TDM may be more effective with regards to time in therapeutic range and time to therapeutic range, this study did not indicate any safety benefit of AUC/MIC-guided over trough-guided TDM with regards to AKI incidence. Our data indicate that AUC/MIC-guided TDM increases the amount of time in the therapeutic range compared with trough-guided TDM and is not more nephrotoxic. The findings of this study support the recommendation to transition to the use of AUC/MIC-guided TDM of vancomycin in the veteran population.

Acknowledgments

This material is the result of work supported with the use of facilities and resources from the Sioux Falls Veterans Affairs Health Care System.

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

It started as a mountain biking excursion with two friends. When we drove into the trailhead parking lot, we saw several emergency vehicles. Then a helicopter passed overhead. As we got on our bikes, a police officer told us there’d been an accident out on the trail and to be careful because emergency personnel were going to be bringing in the patient. So we started the ride cautiously, ready to yield to emergency medical services.

Half a mile down the trail, we encountered another police officer. He asked if we would be willing to go back to get an oxygen tank from the ambulance and carry it out to the scene. The three of us turned around, went back to the parking lot and were able to snag a tank of oxygen. We put it in a backpack and biked out again.

We found the scene about a mile down the trail. An adult male was lying on his back in the dirt after a crash. His eyes were closed and he wasn’t moving except for occasional breaths. Six emergency medical personnel huddled around him, one assisting breaths with a bag mask. I didn’t introduce myself initially. I just listened to hear what was happening.

They were debating the dose of medication to give him in order to intubate. I knew the answer to that question, so I introduced myself. They were happy to have somebody else to assist.

They already had an IV in place and quite a lot of supplies. They administered the meds and the paramedic attempted to intubate through the mouth. Within a few seconds, she pulled the intubating blade out and said, “I’m not going to be able to get this. His tongue is too big.”

I took the blade myself and kneeled at the head of the victim. I made three attempts at intubating, and each time couldn’t view the landmarks. I wasn’t sure if his tongue was too large or if there was some traumatic injury. To make it more difficult, a lot of secretions clogged the airway. The paramedics had a portable suction, which was somewhat functional, but I still couldn’t visualize the landmarks.

I started asking about alternative methods of establishing an airway. They had an i-gel, which is a supraglottic device that goes into the back of the mouth. So, we placed it. But when we attached the bag, air still wasn’t getting into the lungs.

We removed it and put the bag mask back on. Now I was worried. We were having difficulty keeping his oxygen above 90%. I examined the chest and abdomen again. I was wondering if perhaps he was having some gastric distention, which can result from prolonged bagging, but that didn’t seem to be the case.

Bagging became progressively more difficult, and the oxygen slowly trended down through the 80s. Then the 70s. Heart rate dropped below 60 beats per minute. The trajectory was obvious.

That’s when I asked if they had the tools for a surgical airway.

No one thought the question was crazy. In fact, they pulled out a scalpel from an equipment bag.

But now I had to actually do it. I knelt next to the patient, trying to palpate the front of the neck to identify the correct location to cut. I had difficulty finding the appropriate landmarks there as well. Frustrating.

I glanced at the monitor. O₂ was now in the 60s. Later the paramedic told me the heart rate was down to 30.

One of the medics looked me in the eye and said, “We’ve got to do something. The time is now.” That helped me snap out of it and act. I made my large vertical incision on the front of the victim’s neck, which of course resulted in quite a bit of bleeding.

My two friends, who were watching, later told me this was the moment the intensity of the scene really increased (it was already pretty intense for me, thanks).

Next, I made the horizontal stab incision. Then I probed with my finger, but it seems the incision hadn’t reached the trachea. I had to make the stab much deeper than I would’ve thought.

And then air bubbled out through the blood. A paramedic was ready with the ET tube in hand and she put it through the incision. We attached the bag. We had air movement into the lungs, and within minutes the oxygen came up.

Not long after, the flight paramedics from the helicopter showed up, having jogged a mile through the woods. They seemed rather surprised to find a patient with a cricothyrotomy. We filled them in on the situation. Now we had to get the patient out of the woods (literally and figuratively).

The emergency responders had a really great transport device: A litter with one big wheel underneath in the middle so we could roll the patient down the mountain bike trail over rocks relatively safely. One person’s job was to hold the tube as we went since we didn’t have suture to hold it in place.

We got back to the parking lot and loaded him into the ambulance, which drove another mile to the helicopter, which then had to take him a hundred miles to the hospital.

To be honest, I thought the prognosis was poor. I suspected he had an intercranial bleed slowly squeezing his brain (that later turned out to not be the case). Even though we had established an airway, it took us so long to get him to the ambulance.

The director of the local EMS called me that evening and said the patient had made it to the hospital. I had never been a part of anything with this intensity. I definitely lost sleep over it. Partly just from the uncertainty of not knowing what the outcome would be. But also second-guessing if I had done everything that I could have.

The story doesn’t quite end there, however.

A week later, a friend of the patient called me. He had recovered well and was going to be discharged from the hospital. He’d chosen to share the story with the media, and the local TV station was going to interview him. They had asked if I would agree to be interviewed.

After the local news story ran, it was kind of a media blitz. In came numerous media requests. But honestly, the portrayal of the story made me feel really weird. It was overly dramatized and not entirely accurate. It really didn’t sit well with me.

Friends all over the country saw the story, and here’s what they got from the coverage:

I was biking behind the patient when he crashed.

I had my own tools. Even the patient himself was told I used my own blade to make the incision.

The true story is what I just told you: A half-dozen emergency medical personnel were already there when I arrived. It was a combination of all of us – together – in the right place at the right time.

A month later, the patient and his family drove to the city where I live to take me out to lunch. It was emotional. There were plenty of tears. His wife and daughter were expressing a lot of gratitude and had some gifts for me. I was able to get his version of the story and learned some details. He had facial trauma in the past with some reconstruction. I realized that perhaps those anatomical changes affected my ability to do the intubation.

I hope to never again have to do this outside of the hospital. But I suppose I’m more prepared than ever now. I’ve reviewed my cricothyrotomy technique many times since then.

I was trained as a family doctor and did clinic and hospital medicine for several years. It was only in 2020 that I transitioned to doing emergency medicine work in a rural hospital. So, 2 years earlier, I’m not sure I would’ve been able to do what I did that day. To me, it was almost symbolic of the transition of my practice to emergency medicine.

I’m still in touch with the patient. We’ve talked about biking together. That hasn’t happened yet, but it may very well happen someday.

Jesse Coenen, MD, is an emergency medicine physician at Hayward Area Memorial Hospital in Hayward, Wisc.

A version of this article first appeared on Medscape.com.

It started as a mountain biking excursion with two friends. When we drove into the trailhead parking lot, we saw several emergency vehicles. Then a helicopter passed overhead. As we got on our bikes, a police officer told us there’d been an accident out on the trail and to be careful because emergency personnel were going to be bringing in the patient. So we started the ride cautiously, ready to yield to emergency medical services.

Half a mile down the trail, we encountered another police officer. He asked if we would be willing to go back to get an oxygen tank from the ambulance and carry it out to the scene. The three of us turned around, went back to the parking lot and were able to snag a tank of oxygen. We put it in a backpack and biked out again.

We found the scene about a mile down the trail. An adult male was lying on his back in the dirt after a crash. His eyes were closed and he wasn’t moving except for occasional breaths. Six emergency medical personnel huddled around him, one assisting breaths with a bag mask. I didn’t introduce myself initially. I just listened to hear what was happening.

They were debating the dose of medication to give him in order to intubate. I knew the answer to that question, so I introduced myself. They were happy to have somebody else to assist.

They already had an IV in place and quite a lot of supplies. They administered the meds and the paramedic attempted to intubate through the mouth. Within a few seconds, she pulled the intubating blade out and said, “I’m not going to be able to get this. His tongue is too big.”

I took the blade myself and kneeled at the head of the victim. I made three attempts at intubating, and each time couldn’t view the landmarks. I wasn’t sure if his tongue was too large or if there was some traumatic injury. To make it more difficult, a lot of secretions clogged the airway. The paramedics had a portable suction, which was somewhat functional, but I still couldn’t visualize the landmarks.

I started asking about alternative methods of establishing an airway. They had an i-gel, which is a supraglottic device that goes into the back of the mouth. So, we placed it. But when we attached the bag, air still wasn’t getting into the lungs.

We removed it and put the bag mask back on. Now I was worried. We were having difficulty keeping his oxygen above 90%. I examined the chest and abdomen again. I was wondering if perhaps he was having some gastric distention, which can result from prolonged bagging, but that didn’t seem to be the case.

Bagging became progressively more difficult, and the oxygen slowly trended down through the 80s. Then the 70s. Heart rate dropped below 60 beats per minute. The trajectory was obvious.

That’s when I asked if they had the tools for a surgical airway.

No one thought the question was crazy. In fact, they pulled out a scalpel from an equipment bag.

But now I had to actually do it. I knelt next to the patient, trying to palpate the front of the neck to identify the correct location to cut. I had difficulty finding the appropriate landmarks there as well. Frustrating.

I glanced at the monitor. O₂ was now in the 60s. Later the paramedic told me the heart rate was down to 30.

One of the medics looked me in the eye and said, “We’ve got to do something. The time is now.” That helped me snap out of it and act. I made my large vertical incision on the front of the victim’s neck, which of course resulted in quite a bit of bleeding.

My two friends, who were watching, later told me this was the moment the intensity of the scene really increased (it was already pretty intense for me, thanks).

Next, I made the horizontal stab incision. Then I probed with my finger, but it seems the incision hadn’t reached the trachea. I had to make the stab much deeper than I would’ve thought.

And then air bubbled out through the blood. A paramedic was ready with the ET tube in hand and she put it through the incision. We attached the bag. We had air movement into the lungs, and within minutes the oxygen came up.

Not long after, the flight paramedics from the helicopter showed up, having jogged a mile through the woods. They seemed rather surprised to find a patient with a cricothyrotomy. We filled them in on the situation. Now we had to get the patient out of the woods (literally and figuratively).

The emergency responders had a really great transport device: A litter with one big wheel underneath in the middle so we could roll the patient down the mountain bike trail over rocks relatively safely. One person’s job was to hold the tube as we went since we didn’t have suture to hold it in place.

We got back to the parking lot and loaded him into the ambulance, which drove another mile to the helicopter, which then had to take him a hundred miles to the hospital.

To be honest, I thought the prognosis was poor. I suspected he had an intercranial bleed slowly squeezing his brain (that later turned out to not be the case). Even though we had established an airway, it took us so long to get him to the ambulance.

The director of the local EMS called me that evening and said the patient had made it to the hospital. I had never been a part of anything with this intensity. I definitely lost sleep over it. Partly just from the uncertainty of not knowing what the outcome would be. But also second-guessing if I had done everything that I could have.

The story doesn’t quite end there, however.

A week later, a friend of the patient called me. He had recovered well and was going to be discharged from the hospital. He’d chosen to share the story with the media, and the local TV station was going to interview him. They had asked if I would agree to be interviewed.

After the local news story ran, it was kind of a media blitz. In came numerous media requests. But honestly, the portrayal of the story made me feel really weird. It was overly dramatized and not entirely accurate. It really didn’t sit well with me.

Friends all over the country saw the story, and here’s what they got from the coverage:

I was biking behind the patient when he crashed.

I had my own tools. Even the patient himself was told I used my own blade to make the incision.

The true story is what I just told you: A half-dozen emergency medical personnel were already there when I arrived. It was a combination of all of us – together – in the right place at the right time.

A month later, the patient and his family drove to the city where I live to take me out to lunch. It was emotional. There were plenty of tears. His wife and daughter were expressing a lot of gratitude and had some gifts for me. I was able to get his version of the story and learned some details. He had facial trauma in the past with some reconstruction. I realized that perhaps those anatomical changes affected my ability to do the intubation.

I hope to never again have to do this outside of the hospital. But I suppose I’m more prepared than ever now. I’ve reviewed my cricothyrotomy technique many times since then.

I was trained as a family doctor and did clinic and hospital medicine for several years. It was only in 2020 that I transitioned to doing emergency medicine work in a rural hospital. So, 2 years earlier, I’m not sure I would’ve been able to do what I did that day. To me, it was almost symbolic of the transition of my practice to emergency medicine.

I’m still in touch with the patient. We’ve talked about biking together. That hasn’t happened yet, but it may very well happen someday.

Jesse Coenen, MD, is an emergency medicine physician at Hayward Area Memorial Hospital in Hayward, Wisc.

A version of this article first appeared on Medscape.com.

It started as a mountain biking excursion with two friends. When we drove into the trailhead parking lot, we saw several emergency vehicles. Then a helicopter passed overhead. As we got on our bikes, a police officer told us there’d been an accident out on the trail and to be careful because emergency personnel were going to be bringing in the patient. So we started the ride cautiously, ready to yield to emergency medical services.

Half a mile down the trail, we encountered another police officer. He asked if we would be willing to go back to get an oxygen tank from the ambulance and carry it out to the scene. The three of us turned around, went back to the parking lot and were able to snag a tank of oxygen. We put it in a backpack and biked out again.

We found the scene about a mile down the trail. An adult male was lying on his back in the dirt after a crash. His eyes were closed and he wasn’t moving except for occasional breaths. Six emergency medical personnel huddled around him, one assisting breaths with a bag mask. I didn’t introduce myself initially. I just listened to hear what was happening.

They were debating the dose of medication to give him in order to intubate. I knew the answer to that question, so I introduced myself. They were happy to have somebody else to assist.

They already had an IV in place and quite a lot of supplies. They administered the meds and the paramedic attempted to intubate through the mouth. Within a few seconds, she pulled the intubating blade out and said, “I’m not going to be able to get this. His tongue is too big.”

I took the blade myself and kneeled at the head of the victim. I made three attempts at intubating, and each time couldn’t view the landmarks. I wasn’t sure if his tongue was too large or if there was some traumatic injury. To make it more difficult, a lot of secretions clogged the airway. The paramedics had a portable suction, which was somewhat functional, but I still couldn’t visualize the landmarks.

I started asking about alternative methods of establishing an airway. They had an i-gel, which is a supraglottic device that goes into the back of the mouth. So, we placed it. But when we attached the bag, air still wasn’t getting into the lungs.

We removed it and put the bag mask back on. Now I was worried. We were having difficulty keeping his oxygen above 90%. I examined the chest and abdomen again. I was wondering if perhaps he was having some gastric distention, which can result from prolonged bagging, but that didn’t seem to be the case.

Bagging became progressively more difficult, and the oxygen slowly trended down through the 80s. Then the 70s. Heart rate dropped below 60 beats per minute. The trajectory was obvious.

That’s when I asked if they had the tools for a surgical airway.

No one thought the question was crazy. In fact, they pulled out a scalpel from an equipment bag.

But now I had to actually do it. I knelt next to the patient, trying to palpate the front of the neck to identify the correct location to cut. I had difficulty finding the appropriate landmarks there as well. Frustrating.

I glanced at the monitor. O₂ was now in the 60s. Later the paramedic told me the heart rate was down to 30.

One of the medics looked me in the eye and said, “We’ve got to do something. The time is now.” That helped me snap out of it and act. I made my large vertical incision on the front of the victim’s neck, which of course resulted in quite a bit of bleeding.

My two friends, who were watching, later told me this was the moment the intensity of the scene really increased (it was already pretty intense for me, thanks).

Next, I made the horizontal stab incision. Then I probed with my finger, but it seems the incision hadn’t reached the trachea. I had to make the stab much deeper than I would’ve thought.

And then air bubbled out through the blood. A paramedic was ready with the ET tube in hand and she put it through the incision. We attached the bag. We had air movement into the lungs, and within minutes the oxygen came up.

Not long after, the flight paramedics from the helicopter showed up, having jogged a mile through the woods. They seemed rather surprised to find a patient with a cricothyrotomy. We filled them in on the situation. Now we had to get the patient out of the woods (literally and figuratively).

The emergency responders had a really great transport device: A litter with one big wheel underneath in the middle so we could roll the patient down the mountain bike trail over rocks relatively safely. One person’s job was to hold the tube as we went since we didn’t have suture to hold it in place.

We got back to the parking lot and loaded him into the ambulance, which drove another mile to the helicopter, which then had to take him a hundred miles to the hospital.

To be honest, I thought the prognosis was poor. I suspected he had an intercranial bleed slowly squeezing his brain (that later turned out to not be the case). Even though we had established an airway, it took us so long to get him to the ambulance.

The director of the local EMS called me that evening and said the patient had made it to the hospital. I had never been a part of anything with this intensity. I definitely lost sleep over it. Partly just from the uncertainty of not knowing what the outcome would be. But also second-guessing if I had done everything that I could have.

The story doesn’t quite end there, however.

A week later, a friend of the patient called me. He had recovered well and was going to be discharged from the hospital. He’d chosen to share the story with the media, and the local TV station was going to interview him. They had asked if I would agree to be interviewed.

After the local news story ran, it was kind of a media blitz. In came numerous media requests. But honestly, the portrayal of the story made me feel really weird. It was overly dramatized and not entirely accurate. It really didn’t sit well with me.

Friends all over the country saw the story, and here’s what they got from the coverage:

I was biking behind the patient when he crashed.

I had my own tools. Even the patient himself was told I used my own blade to make the incision.

The true story is what I just told you: A half-dozen emergency medical personnel were already there when I arrived. It was a combination of all of us – together – in the right place at the right time.

A month later, the patient and his family drove to the city where I live to take me out to lunch. It was emotional. There were plenty of tears. His wife and daughter were expressing a lot of gratitude and had some gifts for me. I was able to get his version of the story and learned some details. He had facial trauma in the past with some reconstruction. I realized that perhaps those anatomical changes affected my ability to do the intubation.

I hope to never again have to do this outside of the hospital. But I suppose I’m more prepared than ever now. I’ve reviewed my cricothyrotomy technique many times since then.

I was trained as a family doctor and did clinic and hospital medicine for several years. It was only in 2020 that I transitioned to doing emergency medicine work in a rural hospital. So, 2 years earlier, I’m not sure I would’ve been able to do what I did that day. To me, it was almost symbolic of the transition of my practice to emergency medicine.

I’m still in touch with the patient. We’ve talked about biking together. That hasn’t happened yet, but it may very well happen someday.

Jesse Coenen, MD, is an emergency medicine physician at Hayward Area Memorial Hospital in Hayward, Wisc.

A version of this article first appeared on Medscape.com.

Interventional cardiologist Jeffrey Tauth, MD, of Hot Springs, Ark., has agreed to pay $900,000 to resolve allegations that he submitted claims to Medicare for inserting medically unnecessary cardiac stents, in violation of the False Claims Act.

As part of the settlement, Dr. Tauth will enter into an integrity agreement with the U.S. Department of Health & Human Services, according to a news release from Henry Leventis, U.S. attorney for the Middle District of Tennessee.

“Health care fraud is a top priority of this office. We will aggressively pursue all those who are involved in fraud against government programs,” Mr. Leventis said.

Dr. Tauth formerly treated patients at National Park Medical Center (NPMC) in Hot Springs. The alleged false claims were submitted from September 2013 through August 2019.

The settlement with Dr. Tauth, aged 60, follows a November 2019 voluntary disclosure of the alleged false claims by Brentwood, Tenn.–based Lifepoint Health, which acquired NPMC and Hot Springs Cardiology Associates in November 2018.

NPMC and Hot Springs Cardiology entered into a settlement in October 2020 for the alleged violations and agreed to pay roughly $14.6 million, which includes over $9 million in restitution, according to the news release.

NPMC CEO Scott Smith said NPMC is “committed to maintaining high standards of integrity, legal compliance, and quality care for our patients. We regularly monitor our processes, procedures, and reporting and actively self-report concerns to regulators to ensure we are upholding these standards across our organization.”

“We are proud that our hospital took the appropriate steps to promptly self-report and finalize a settlement with the government for a swift resolution more than 2 years ago,” Mr. Smith said.

Dr. Tauth, however, maintains that the allegations made by NPMC are false.

“I am pleased to have reached a settlement agreement with the Department of Justice regarding allegations brought to them by my former employer, National Park Medical Center,” he said in a statement.

“The settlement agreement specifically states that it is not ‘an admission of liability’ by me, and I remain steadfast in my position that the allegations made by my former employer are false and without merit,” Dr. Tauth added.

He further stated that he has “chosen to enter into the settlement agreement because the legal process initiated by National Park’s allegations has been emotionally and financially damaging to me and my family in the extreme, and a settlement puts an end to the delays, uncertainties, inconveniences, and expenses of protracted litigation. Settlement is in the best interests of my family, my patients, and my medical practice.”

Dr. Tauth said he is “extremely grateful for the support I have received from my patients, medical staff, colleagues, friends, and family during this difficult time, and I look forward to providing high-quality cardiac care in the greater Hot Springs community for many years to come.”

A version of this article first appeared on Medscape.com.

Interventional cardiologist Jeffrey Tauth, MD, of Hot Springs, Ark., has agreed to pay $900,000 to resolve allegations that he submitted claims to Medicare for inserting medically unnecessary cardiac stents, in violation of the False Claims Act.

As part of the settlement, Dr. Tauth will enter into an integrity agreement with the U.S. Department of Health & Human Services, according to a news release from Henry Leventis, U.S. attorney for the Middle District of Tennessee.

“Health care fraud is a top priority of this office. We will aggressively pursue all those who are involved in fraud against government programs,” Mr. Leventis said.

Dr. Tauth formerly treated patients at National Park Medical Center (NPMC) in Hot Springs. The alleged false claims were submitted from September 2013 through August 2019.

The settlement with Dr. Tauth, aged 60, follows a November 2019 voluntary disclosure of the alleged false claims by Brentwood, Tenn.–based Lifepoint Health, which acquired NPMC and Hot Springs Cardiology Associates in November 2018.

NPMC and Hot Springs Cardiology entered into a settlement in October 2020 for the alleged violations and agreed to pay roughly $14.6 million, which includes over $9 million in restitution, according to the news release.

NPMC CEO Scott Smith said NPMC is “committed to maintaining high standards of integrity, legal compliance, and quality care for our patients. We regularly monitor our processes, procedures, and reporting and actively self-report concerns to regulators to ensure we are upholding these standards across our organization.”

“We are proud that our hospital took the appropriate steps to promptly self-report and finalize a settlement with the government for a swift resolution more than 2 years ago,” Mr. Smith said.

Dr. Tauth, however, maintains that the allegations made by NPMC are false.

“I am pleased to have reached a settlement agreement with the Department of Justice regarding allegations brought to them by my former employer, National Park Medical Center,” he said in a statement.

“The settlement agreement specifically states that it is not ‘an admission of liability’ by me, and I remain steadfast in my position that the allegations made by my former employer are false and without merit,” Dr. Tauth added.

He further stated that he has “chosen to enter into the settlement agreement because the legal process initiated by National Park’s allegations has been emotionally and financially damaging to me and my family in the extreme, and a settlement puts an end to the delays, uncertainties, inconveniences, and expenses of protracted litigation. Settlement is in the best interests of my family, my patients, and my medical practice.”

Dr. Tauth said he is “extremely grateful for the support I have received from my patients, medical staff, colleagues, friends, and family during this difficult time, and I look forward to providing high-quality cardiac care in the greater Hot Springs community for many years to come.”

A version of this article first appeared on Medscape.com.

Interventional cardiologist Jeffrey Tauth, MD, of Hot Springs, Ark., has agreed to pay $900,000 to resolve allegations that he submitted claims to Medicare for inserting medically unnecessary cardiac stents, in violation of the False Claims Act.

As part of the settlement, Dr. Tauth will enter into an integrity agreement with the U.S. Department of Health & Human Services, according to a news release from Henry Leventis, U.S. attorney for the Middle District of Tennessee.

“Health care fraud is a top priority of this office. We will aggressively pursue all those who are involved in fraud against government programs,” Mr. Leventis said.

Dr. Tauth formerly treated patients at National Park Medical Center (NPMC) in Hot Springs. The alleged false claims were submitted from September 2013 through August 2019.

The settlement with Dr. Tauth, aged 60, follows a November 2019 voluntary disclosure of the alleged false claims by Brentwood, Tenn.–based Lifepoint Health, which acquired NPMC and Hot Springs Cardiology Associates in November 2018.

NPMC and Hot Springs Cardiology entered into a settlement in October 2020 for the alleged violations and agreed to pay roughly $14.6 million, which includes over $9 million in restitution, according to the news release.

NPMC CEO Scott Smith said NPMC is “committed to maintaining high standards of integrity, legal compliance, and quality care for our patients. We regularly monitor our processes, procedures, and reporting and actively self-report concerns to regulators to ensure we are upholding these standards across our organization.”

“We are proud that our hospital took the appropriate steps to promptly self-report and finalize a settlement with the government for a swift resolution more than 2 years ago,” Mr. Smith said.

Dr. Tauth, however, maintains that the allegations made by NPMC are false.

“I am pleased to have reached a settlement agreement with the Department of Justice regarding allegations brought to them by my former employer, National Park Medical Center,” he said in a statement.

“The settlement agreement specifically states that it is not ‘an admission of liability’ by me, and I remain steadfast in my position that the allegations made by my former employer are false and without merit,” Dr. Tauth added.

He further stated that he has “chosen to enter into the settlement agreement because the legal process initiated by National Park’s allegations has been emotionally and financially damaging to me and my family in the extreme, and a settlement puts an end to the delays, uncertainties, inconveniences, and expenses of protracted litigation. Settlement is in the best interests of my family, my patients, and my medical practice.”

Dr. Tauth said he is “extremely grateful for the support I have received from my patients, medical staff, colleagues, friends, and family during this difficult time, and I look forward to providing high-quality cardiac care in the greater Hot Springs community for many years to come.”

A version of this article first appeared on Medscape.com.

Long COVID is typically characterized by anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations, with younger patients showing greatest improvements at 1 year, according to a nationwide cohort study conducted in Israel.

These findings help define long COVID, guiding providers and patients through the recovery process, Barak Mizrahi, MSc, of KI Research Institute, Kfar Malal, Israel, and colleagues reported.

“To provide efficient continuous treatment and prevent adverse events related to potential long term effects and delayed symptoms of COVID-19, determining the magnitude and severity of this phenomenon and distinguishing it from similar clinical manifestations that occur normally or following infections with other pathogens is essential,” the investigators wrote in The BMJ.

To this end, they conducted a retrospective, nationwide cohort study involving 1,913,234 people who took a polymerase chain reaction test for SARS-CoV-2 between March 1, 2020, and Oct. 1, 2021. They compared a range of long-term outcomes at different intervals post infection, and compared these trends across subgroups sorted by age, sex, and variant. Outcomes ranged broadly, including respiratory disorders, cough, arthralgia, weakness, hair loss, and others.

The investigators compared hazard ratios for each of these outcomes among patients who tested positive versus those who tested negative at three intervals after testing: 30-90 days, 30-180 days, and 180-360 days. Statistically significant differences in the risks of these outcomes between infected versus uninfected groups suggested that COVID was playing a role.

“The health outcomes that represent long COVID showed a significant increase in both early and late phases,” the investigators wrote. These outcomes included anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations. In contrast, chest pain, myalgia, arthralgia, cough, and dizziness were associated with patients who were in the early phase, but not the late phase of long COVID.

“Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnea and similar risk for other outcomes compared with unvaccinated infected patients,” the investigators noted.

For the long COVID outcomes, plots of risk differences over time showed that symptoms tended to get milder or resolve within a few months to a year. Patients 41-60 years were most likely to be impacted by long COVID outcomes, and show least improvement at 1 year, compared with other age groups.

“We believe that these findings will shed light on what is ‘long COVID’, support patients and doctors, and facilitate better and more efficient care,” Mr. Mizrahi and coauthor Maytal Bivas-Benita, PhD said in a joint written comment. “Primary care physicians (and patients) will now more clearly understand what are the symptoms that might be related to COVID and for how long they might linger. This would help physicians monitor the patients efficiently, ease their patients’ concerns and navigate a more efficient disease management.”

They suggested that the findings should hold consistent for future variants, although they could not “rule out the possibility of the emergence of new and more severe variants which will be more virulent and cause a more severe illness.”

One “major limitation” of the study, according to Monica Verduzco-Gutierrez, MD, a physiatrist and professor and chair of rehabilitation medicine at the University of Texas Health Science Center, San Antonio, is the lack of data for fatigue and dysautonomia, which are “the major presentations” that she sees in her long COVID clinic.

“The authors of the article focus on the primary damage being related to the lungs, though we know this is a systemic disease beyond the respiratory system, with endothelial dysfunction and immune dysregulation,” Dr. Verduzco-Gutierrez, who is also director of COVID recovery at the University of Texas Health Science Center, said in an interview.

Although it was reassuring to see that younger adults with long COVID trended toward improvement, she noted that patients 41-60 years “still had pretty significant symptoms” after 12 months.

“That [age group comprises] probably the majority of my patients that I’m seeing in the long COVID clinic,” Dr. Verduzco-Gutierrez said. “If you look at the whole thing, it looks better, but then when you drill down to that age group where you’re seeing patients, then it’s not.”

Dr. Verduzco-Gutierrez is so busy managing patients with long COVID that new appointments in her clinic are now delayed until May 31, so most patients will remain under the care of their primary care providers. She recommended that these physicians follow guidance from the American Academy of Physical Medicine and Rehabilitation, who offer consensus statements based on clinical characteristics, with separate recommendations for pediatric patients.

Our understanding of long COVID will continue to improve, and with it, available recommendations, she predicted, but further advances will require persistent effort.

“I think no matter what this [study] shows us, more research is needed,” Dr. Verduzco-Gutierrez said. “We can’t just forget about it, just because there is a population of people who get better. What about the ones who don’t?”

The investigators and Dr. Verduzco-Gutierrez disclosed no conflicts of interest.

Long COVID is typically characterized by anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations, with younger patients showing greatest improvements at 1 year, according to a nationwide cohort study conducted in Israel.

These findings help define long COVID, guiding providers and patients through the recovery process, Barak Mizrahi, MSc, of KI Research Institute, Kfar Malal, Israel, and colleagues reported.

“To provide efficient continuous treatment and prevent adverse events related to potential long term effects and delayed symptoms of COVID-19, determining the magnitude and severity of this phenomenon and distinguishing it from similar clinical manifestations that occur normally or following infections with other pathogens is essential,” the investigators wrote in The BMJ.

To this end, they conducted a retrospective, nationwide cohort study involving 1,913,234 people who took a polymerase chain reaction test for SARS-CoV-2 between March 1, 2020, and Oct. 1, 2021. They compared a range of long-term outcomes at different intervals post infection, and compared these trends across subgroups sorted by age, sex, and variant. Outcomes ranged broadly, including respiratory disorders, cough, arthralgia, weakness, hair loss, and others.

The investigators compared hazard ratios for each of these outcomes among patients who tested positive versus those who tested negative at three intervals after testing: 30-90 days, 30-180 days, and 180-360 days. Statistically significant differences in the risks of these outcomes between infected versus uninfected groups suggested that COVID was playing a role.

“The health outcomes that represent long COVID showed a significant increase in both early and late phases,” the investigators wrote. These outcomes included anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations. In contrast, chest pain, myalgia, arthralgia, cough, and dizziness were associated with patients who were in the early phase, but not the late phase of long COVID.

“Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnea and similar risk for other outcomes compared with unvaccinated infected patients,” the investigators noted.

For the long COVID outcomes, plots of risk differences over time showed that symptoms tended to get milder or resolve within a few months to a year. Patients 41-60 years were most likely to be impacted by long COVID outcomes, and show least improvement at 1 year, compared with other age groups.

“We believe that these findings will shed light on what is ‘long COVID’, support patients and doctors, and facilitate better and more efficient care,” Mr. Mizrahi and coauthor Maytal Bivas-Benita, PhD said in a joint written comment. “Primary care physicians (and patients) will now more clearly understand what are the symptoms that might be related to COVID and for how long they might linger. This would help physicians monitor the patients efficiently, ease their patients’ concerns and navigate a more efficient disease management.”

They suggested that the findings should hold consistent for future variants, although they could not “rule out the possibility of the emergence of new and more severe variants which will be more virulent and cause a more severe illness.”

One “major limitation” of the study, according to Monica Verduzco-Gutierrez, MD, a physiatrist and professor and chair of rehabilitation medicine at the University of Texas Health Science Center, San Antonio, is the lack of data for fatigue and dysautonomia, which are “the major presentations” that she sees in her long COVID clinic.

“The authors of the article focus on the primary damage being related to the lungs, though we know this is a systemic disease beyond the respiratory system, with endothelial dysfunction and immune dysregulation,” Dr. Verduzco-Gutierrez, who is also director of COVID recovery at the University of Texas Health Science Center, said in an interview.

Although it was reassuring to see that younger adults with long COVID trended toward improvement, she noted that patients 41-60 years “still had pretty significant symptoms” after 12 months.

“That [age group comprises] probably the majority of my patients that I’m seeing in the long COVID clinic,” Dr. Verduzco-Gutierrez said. “If you look at the whole thing, it looks better, but then when you drill down to that age group where you’re seeing patients, then it’s not.”

Dr. Verduzco-Gutierrez is so busy managing patients with long COVID that new appointments in her clinic are now delayed until May 31, so most patients will remain under the care of their primary care providers. She recommended that these physicians follow guidance from the American Academy of Physical Medicine and Rehabilitation, who offer consensus statements based on clinical characteristics, with separate recommendations for pediatric patients.

Our understanding of long COVID will continue to improve, and with it, available recommendations, she predicted, but further advances will require persistent effort.

“I think no matter what this [study] shows us, more research is needed,” Dr. Verduzco-Gutierrez said. “We can’t just forget about it, just because there is a population of people who get better. What about the ones who don’t?”

The investigators and Dr. Verduzco-Gutierrez disclosed no conflicts of interest.

Long COVID is typically characterized by anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations, with younger patients showing greatest improvements at 1 year, according to a nationwide cohort study conducted in Israel.

These findings help define long COVID, guiding providers and patients through the recovery process, Barak Mizrahi, MSc, of KI Research Institute, Kfar Malal, Israel, and colleagues reported.

“To provide efficient continuous treatment and prevent adverse events related to potential long term effects and delayed symptoms of COVID-19, determining the magnitude and severity of this phenomenon and distinguishing it from similar clinical manifestations that occur normally or following infections with other pathogens is essential,” the investigators wrote in The BMJ.

To this end, they conducted a retrospective, nationwide cohort study involving 1,913,234 people who took a polymerase chain reaction test for SARS-CoV-2 between March 1, 2020, and Oct. 1, 2021. They compared a range of long-term outcomes at different intervals post infection, and compared these trends across subgroups sorted by age, sex, and variant. Outcomes ranged broadly, including respiratory disorders, cough, arthralgia, weakness, hair loss, and others.

The investigators compared hazard ratios for each of these outcomes among patients who tested positive versus those who tested negative at three intervals after testing: 30-90 days, 30-180 days, and 180-360 days. Statistically significant differences in the risks of these outcomes between infected versus uninfected groups suggested that COVID was playing a role.

“The health outcomes that represent long COVID showed a significant increase in both early and late phases,” the investigators wrote. These outcomes included anosmia and dysgeusia, cognitive impairment, dyspnea, weakness, and palpitations. In contrast, chest pain, myalgia, arthralgia, cough, and dizziness were associated with patients who were in the early phase, but not the late phase of long COVID.

“Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnea and similar risk for other outcomes compared with unvaccinated infected patients,” the investigators noted.

For the long COVID outcomes, plots of risk differences over time showed that symptoms tended to get milder or resolve within a few months to a year. Patients 41-60 years were most likely to be impacted by long COVID outcomes, and show least improvement at 1 year, compared with other age groups.

“We believe that these findings will shed light on what is ‘long COVID’, support patients and doctors, and facilitate better and more efficient care,” Mr. Mizrahi and coauthor Maytal Bivas-Benita, PhD said in a joint written comment. “Primary care physicians (and patients) will now more clearly understand what are the symptoms that might be related to COVID and for how long they might linger. This would help physicians monitor the patients efficiently, ease their patients’ concerns and navigate a more efficient disease management.”

They suggested that the findings should hold consistent for future variants, although they could not “rule out the possibility of the emergence of new and more severe variants which will be more virulent and cause a more severe illness.”

One “major limitation” of the study, according to Monica Verduzco-Gutierrez, MD, a physiatrist and professor and chair of rehabilitation medicine at the University of Texas Health Science Center, San Antonio, is the lack of data for fatigue and dysautonomia, which are “the major presentations” that she sees in her long COVID clinic.

“The authors of the article focus on the primary damage being related to the lungs, though we know this is a systemic disease beyond the respiratory system, with endothelial dysfunction and immune dysregulation,” Dr. Verduzco-Gutierrez, who is also director of COVID recovery at the University of Texas Health Science Center, said in an interview.

Although it was reassuring to see that younger adults with long COVID trended toward improvement, she noted that patients 41-60 years “still had pretty significant symptoms” after 12 months.

“That [age group comprises] probably the majority of my patients that I’m seeing in the long COVID clinic,” Dr. Verduzco-Gutierrez said. “If you look at the whole thing, it looks better, but then when you drill down to that age group where you’re seeing patients, then it’s not.”

Dr. Verduzco-Gutierrez is so busy managing patients with long COVID that new appointments in her clinic are now delayed until May 31, so most patients will remain under the care of their primary care providers. She recommended that these physicians follow guidance from the American Academy of Physical Medicine and Rehabilitation, who offer consensus statements based on clinical characteristics, with separate recommendations for pediatric patients.

Our understanding of long COVID will continue to improve, and with it, available recommendations, she predicted, but further advances will require persistent effort.

“I think no matter what this [study] shows us, more research is needed,” Dr. Verduzco-Gutierrez said. “We can’t just forget about it, just because there is a population of people who get better. What about the ones who don’t?”

The investigators and Dr. Verduzco-Gutierrez disclosed no conflicts of interest.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports