Federal Practitioner

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.

One in 10 adults worldwide currently has diabetes, accounting for an estimated global health expenditure of $966 billion in U.S. dollars in 2021, according to the new International Diabetes Federation Diabetes Atlas.

The IDF Atlas, 10th edition, was published online Dec. 6, 2021.

Highlights from it were presented during two sessions at the IDF Virtual Congress 2021, covering global diabetes incidence and prevalence, mortality, and costs, as well as new sections in this edition devoted to adult-onset type 1 diabetes, childhood-onset type 2 diabetes, and the interactions between diabetes and COVID-19.

More detailed data from some of the Atlas chapters were also published Dec. 6, 2021, in separate papers in the IDF journal Diabetes Research and Clinical Practice, with more publications planned.

Information for the Atlas comes from peer-reviewed literature, unpublished reports, and national registries. This latest edition includes 219 data sources from 144 countries, with figures for other countries extrapolated.

Atlas cochair Dianna Magliano, PhD, reviewed some of the highlights. Half of those currently with diabetes, or about 240 million adults, are undiagnosed, and another 319 million have impaired fasting glucose. Over three-quarters of all adults with diabetes now live in low- and middle-income countries. And about 6.7 million deaths in 2021 can be attributed to diabetes.

The Atlas also predicts increases in these numbers over the coming decades if current trends continue.

“Our data and projections tell a sobering story. Diabetes prevalence is expected to increase globally. The number of adults with diabetes will rise from 537 million in 2021 to 786 million ... by the year 2045, an increase of 46%. Rises are expected in every region of the world, with the largest increases expected to occur in the regions of Africa, the Middle East, and Southeast Asia,” said Dr. Magliano, head of diabetes and population health at the Baker Heart and Diabetes Institute, Melbourne.

Since 2019, when the last Atlas was published, the 2021 numbers represent increases of 73.6 million more adults with diabetes including 7.8 million more undiagnosed, 2.5 million more deaths attributed to diabetes, and an additional global expenditure of $206 billion.

Increases have also occurred in the number of people with prediabetes, children with type 1 diabetes, and pregnancies affected by diabetes, Dr. Magliano reported.

“There is a strong need for effective intervention strategies and policies to stall the increase in the number of people developing diabetes across the world,” she added.
 

Projected rise in expenditures for diabetes will be ‘unsustainable’

The current $966 billion global health expenditure caused by diabetes represents a 316% increase from the $232 billion reported in 2006, according to William H. Herman, MD, professor of internal medicine and epidemiology at the University of Michigan, Ann Arbor.

By region, 43% of current diabetes-related global expenditures are in North America, 25% in the Western Pacific, and 20% in Europe, while 12% are from the regions of South and Central America, North Africa, Africa, and Southeast Asia combined, Herman said.

The direct costs of diabetes are projected to grow to $1054 billion in 2045, an increase of just 9% over 25 years. The reason for the far lower increase going forward, compared with the tripling in the 15 years prior, is because of the anticipated diabetes rise in regions of the world where per-person spending on diabetes is low, a situation Dr. Herman called “unsustainable.”

“The keys to controlling the global costs of diabetes care are diabetes prevention and providing effective care to the largest number of people at the lowest possible cost,” he said.
 

Diabetes-related mortality: Some shifts since 2019

One third of the current 6.7 million diabetes-related deaths in 2021 were in people younger than 60 years, said Elbert S. Huang, MD, professor of medicine and public health sciences at the University of Chicago.

Overall, diabetes accounted for 11.8% of total global deaths in people younger than 60 years, but that varied widely, from 24.5% in the Middle East/North Africa to just 6.9% in Southeast Asia.

The regions with the highest number of diabetes-related deaths in people younger than 60 years in 2021 were the Western Pacific and the Middle East/North Africa, a major change from just 2 years ago, when Southeast Asia and Africa saw the greatest numbers of diabetes-related deaths in working-age adults.

“These findings mirror recent reports on inadequate uptake of diabetes prevention programs as well as stagnant quality of care trends for the past decade and reemphasize the need to address noncommunicable diseases across the globe,” Dr. Huang said.
 

Diabetes and COVID-19: Other factors partly explain the increased risk

Gillian Booth, MD, summarized the current literature on COVID-19 and diabetes including a meta-analysis her group conducted of 300 studies from around the world, with 58% from high-income countries.

The risk for increased COVID-19 severity in people with diabetes could be at least partly explained by factors such as age, sex, and comorbidities, said Dr. Booth, professor in the department of medicine and the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

For example, the unadjusted pooled odds of hospitalization with COVID-19 in patients with diabetes, compared with those without diabetes, was 3.69, but dropped to 1.73 after adjustment for age, sex, and having one or more comorbidities. For COVID-19–related death, those odds ratios were 2.32 unadjusted versus 1.59 adjusted. In both cases, the values were still significant after adjustment, she emphasized.

Overall, hyperglycemia and hemoglobin A1c at admission emerged as significant independent predictors of severe outcomes.

“Further research is needed to understand the interplay between COVID-19 and diabetes and how best to address the disproportionate burden of COVID-19 among people living with diabetes,” she stressed.
 

Adult-onset type 1 diabetes: Growing recognition of the burden

Ascertainment of data for both adult-onset type 1 and type 2 diabetes in youth was subject to significant limitations.

For adult-onset type 1 diabetes, Jessica Harding, PhD, pointed to the fact that the epidemiology of adult-onset type 1 diabetes hasn’t been well characterized because of the historical focus on children, the difficulty of distinguishing it from type 2 diabetes in adults, and that many registries simply don’t include incident data across the lifespan for type 1 diabetes.

Nonetheless, she said, “there is growing recognition of the burden of adult-onset type 1,” noting that the American Diabetes Association and European Association for the Study of Diabetes just published a consensus statement addressing the topic.

A systematic review of 46 studies representing 32 countries or regions revealed that countries with the highest incidence of type 1 diabetes onset per population of 100,000 ages 20 or above were Eritrea, at 46.2, followed by Sweden and Ireland, both at 30.6, and Finland, at 0. The lowest rates were in Asian countries.

While the Nordic countries (Finland, Sweden, and Norway) are among the top for incidence of both childhood-onset (0-14 years) and adult-onset type 1 diabetes, Eritrea isn’t even among the top 10 for childhood onset.

The unusual situation in Eritrea is the subject of current study but the reasons aren’t yet clear, noted Dr. Magliano, of Emory University, Atlanta, during the question-and-answer period.

And only seven studies, 15%, used biomarkers to determine type 1 diabetes status, suggesting “there is a pressing need to improve the quality and quantity of information on adult-onset type 1 diabetes, particularly in those low- and middle-income countries,” Dr. Harding said.
 

Type 2 diabetes in youth: A call for better data

When presenting the data for childhood-onset type 2 diabetes, Andrea Luk, MD, noted: “The onset of advanced complications during the most productive time of life has significant impact on individuals, communities, and health economies.”

In 19 studies, the highest reported prevalence of type 2 diabetes in youth was in Brazil, Mexico, indigenous populations of the United States and Canada, and the Black population in the United States, with rates ranging from 160 per 100,000 to 3300 per 100,000. The lowest prevalence rates of 0.6 per 100,000 to 2.7 per 100,000 were reported in Europe. Incidence data were similar, with the highest rates from 31 per 100,000 to 94 per 100,000 and the lowest 0.1 per 100,000 to 0.8 per 100,000 per year.  

Of note, Dr. Luk pointed out that childhood obesity is an important factor but not the only one.

“Some populations that have a low prevalence of obesity, such as East Asians, reported higher incidence rates of youth-onset type 2 diabetes than populations with a greater burden of childhood obesity.”

There was variability in incidence rates for youth of similar ethnic background but from different countries. “Apart from genetic predisposition and background obesogenic environment, disparity in socioeconomic status, access to health care, and cultural practices are other contributors to differences in risk of type 2 diabetes in youth,” noted Dr. Luk, associate professor in the division of endocrinology, Department of Medicine and Therapeutics, Chinese University of Hong Kong.

She also noted that the incidence of type 2 diabetes was extremely low in prepubertal children and rises gradually during puberty, and that the incidence is higher in girls than boys but that reverses in adulthood.

Compared with adults with type 2 diabetes, youth with type 2 diabetes had a more adverse glycemic trajectory and higher rates of metformin failure.

And compared with youth with type 1 diabetes, those with type 2 diabetes had more adverse metabolic profiles and higher rates of vascular complications.

“A strong call must be made for the collection of trend data to assess global burden of type 2 diabetes in youth,” she concluded.

Dr. Luk reported serving as an advisory panel member for and/or receiving research support from Amgen, AstraZeneca, Boehringer Ingelheim, Sanofi, the Asia Diabetes Foundation, Bayer, Lee’s Pharmaceutical, MSD, Novo Nordisk, Roche, Sugardown, and Takeda. The other authors reported no relevant financial relationships.

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

One in 10 adults worldwide currently has diabetes, accounting for an estimated global health expenditure of $966 billion in U.S. dollars in 2021, according to the new International Diabetes Federation Diabetes Atlas.

The IDF Atlas, 10th edition, was published online Dec. 6, 2021.

Highlights from it were presented during two sessions at the IDF Virtual Congress 2021, covering global diabetes incidence and prevalence, mortality, and costs, as well as new sections in this edition devoted to adult-onset type 1 diabetes, childhood-onset type 2 diabetes, and the interactions between diabetes and COVID-19.

More detailed data from some of the Atlas chapters were also published Dec. 6, 2021, in separate papers in the IDF journal Diabetes Research and Clinical Practice, with more publications planned.

Information for the Atlas comes from peer-reviewed literature, unpublished reports, and national registries. This latest edition includes 219 data sources from 144 countries, with figures for other countries extrapolated.

Atlas cochair Dianna Magliano, PhD, reviewed some of the highlights. Half of those currently with diabetes, or about 240 million adults, are undiagnosed, and another 319 million have impaired fasting glucose. Over three-quarters of all adults with diabetes now live in low- and middle-income countries. And about 6.7 million deaths in 2021 can be attributed to diabetes.

The Atlas also predicts increases in these numbers over the coming decades if current trends continue.

“Our data and projections tell a sobering story. Diabetes prevalence is expected to increase globally. The number of adults with diabetes will rise from 537 million in 2021 to 786 million ... by the year 2045, an increase of 46%. Rises are expected in every region of the world, with the largest increases expected to occur in the regions of Africa, the Middle East, and Southeast Asia,” said Dr. Magliano, head of diabetes and population health at the Baker Heart and Diabetes Institute, Melbourne.

Since 2019, when the last Atlas was published, the 2021 numbers represent increases of 73.6 million more adults with diabetes including 7.8 million more undiagnosed, 2.5 million more deaths attributed to diabetes, and an additional global expenditure of $206 billion.

Increases have also occurred in the number of people with prediabetes, children with type 1 diabetes, and pregnancies affected by diabetes, Dr. Magliano reported.

“There is a strong need for effective intervention strategies and policies to stall the increase in the number of people developing diabetes across the world,” she added.
 

Projected rise in expenditures for diabetes will be ‘unsustainable’

The current $966 billion global health expenditure caused by diabetes represents a 316% increase from the $232 billion reported in 2006, according to William H. Herman, MD, professor of internal medicine and epidemiology at the University of Michigan, Ann Arbor.

By region, 43% of current diabetes-related global expenditures are in North America, 25% in the Western Pacific, and 20% in Europe, while 12% are from the regions of South and Central America, North Africa, Africa, and Southeast Asia combined, Herman said.

The direct costs of diabetes are projected to grow to $1054 billion in 2045, an increase of just 9% over 25 years. The reason for the far lower increase going forward, compared with the tripling in the 15 years prior, is because of the anticipated diabetes rise in regions of the world where per-person spending on diabetes is low, a situation Dr. Herman called “unsustainable.”

“The keys to controlling the global costs of diabetes care are diabetes prevention and providing effective care to the largest number of people at the lowest possible cost,” he said.
 

Diabetes-related mortality: Some shifts since 2019

One third of the current 6.7 million diabetes-related deaths in 2021 were in people younger than 60 years, said Elbert S. Huang, MD, professor of medicine and public health sciences at the University of Chicago.

Overall, diabetes accounted for 11.8% of total global deaths in people younger than 60 years, but that varied widely, from 24.5% in the Middle East/North Africa to just 6.9% in Southeast Asia.

The regions with the highest number of diabetes-related deaths in people younger than 60 years in 2021 were the Western Pacific and the Middle East/North Africa, a major change from just 2 years ago, when Southeast Asia and Africa saw the greatest numbers of diabetes-related deaths in working-age adults.

“These findings mirror recent reports on inadequate uptake of diabetes prevention programs as well as stagnant quality of care trends for the past decade and reemphasize the need to address noncommunicable diseases across the globe,” Dr. Huang said.
 

Diabetes and COVID-19: Other factors partly explain the increased risk

Gillian Booth, MD, summarized the current literature on COVID-19 and diabetes including a meta-analysis her group conducted of 300 studies from around the world, with 58% from high-income countries.

The risk for increased COVID-19 severity in people with diabetes could be at least partly explained by factors such as age, sex, and comorbidities, said Dr. Booth, professor in the department of medicine and the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

For example, the unadjusted pooled odds of hospitalization with COVID-19 in patients with diabetes, compared with those without diabetes, was 3.69, but dropped to 1.73 after adjustment for age, sex, and having one or more comorbidities. For COVID-19–related death, those odds ratios were 2.32 unadjusted versus 1.59 adjusted. In both cases, the values were still significant after adjustment, she emphasized.

Overall, hyperglycemia and hemoglobin A1c at admission emerged as significant independent predictors of severe outcomes.

“Further research is needed to understand the interplay between COVID-19 and diabetes and how best to address the disproportionate burden of COVID-19 among people living with diabetes,” she stressed.
 

Adult-onset type 1 diabetes: Growing recognition of the burden

Ascertainment of data for both adult-onset type 1 and type 2 diabetes in youth was subject to significant limitations.

For adult-onset type 1 diabetes, Jessica Harding, PhD, pointed to the fact that the epidemiology of adult-onset type 1 diabetes hasn’t been well characterized because of the historical focus on children, the difficulty of distinguishing it from type 2 diabetes in adults, and that many registries simply don’t include incident data across the lifespan for type 1 diabetes.

Nonetheless, she said, “there is growing recognition of the burden of adult-onset type 1,” noting that the American Diabetes Association and European Association for the Study of Diabetes just published a consensus statement addressing the topic.

A systematic review of 46 studies representing 32 countries or regions revealed that countries with the highest incidence of type 1 diabetes onset per population of 100,000 ages 20 or above were Eritrea, at 46.2, followed by Sweden and Ireland, both at 30.6, and Finland, at 0. The lowest rates were in Asian countries.

While the Nordic countries (Finland, Sweden, and Norway) are among the top for incidence of both childhood-onset (0-14 years) and adult-onset type 1 diabetes, Eritrea isn’t even among the top 10 for childhood onset.

The unusual situation in Eritrea is the subject of current study but the reasons aren’t yet clear, noted Dr. Magliano, of Emory University, Atlanta, during the question-and-answer period.

And only seven studies, 15%, used biomarkers to determine type 1 diabetes status, suggesting “there is a pressing need to improve the quality and quantity of information on adult-onset type 1 diabetes, particularly in those low- and middle-income countries,” Dr. Harding said.
 

Type 2 diabetes in youth: A call for better data

When presenting the data for childhood-onset type 2 diabetes, Andrea Luk, MD, noted: “The onset of advanced complications during the most productive time of life has significant impact on individuals, communities, and health economies.”

In 19 studies, the highest reported prevalence of type 2 diabetes in youth was in Brazil, Mexico, indigenous populations of the United States and Canada, and the Black population in the United States, with rates ranging from 160 per 100,000 to 3300 per 100,000. The lowest prevalence rates of 0.6 per 100,000 to 2.7 per 100,000 were reported in Europe. Incidence data were similar, with the highest rates from 31 per 100,000 to 94 per 100,000 and the lowest 0.1 per 100,000 to 0.8 per 100,000 per year.  

Of note, Dr. Luk pointed out that childhood obesity is an important factor but not the only one.

“Some populations that have a low prevalence of obesity, such as East Asians, reported higher incidence rates of youth-onset type 2 diabetes than populations with a greater burden of childhood obesity.”

There was variability in incidence rates for youth of similar ethnic background but from different countries. “Apart from genetic predisposition and background obesogenic environment, disparity in socioeconomic status, access to health care, and cultural practices are other contributors to differences in risk of type 2 diabetes in youth,” noted Dr. Luk, associate professor in the division of endocrinology, Department of Medicine and Therapeutics, Chinese University of Hong Kong.

She also noted that the incidence of type 2 diabetes was extremely low in prepubertal children and rises gradually during puberty, and that the incidence is higher in girls than boys but that reverses in adulthood.

Compared with adults with type 2 diabetes, youth with type 2 diabetes had a more adverse glycemic trajectory and higher rates of metformin failure.

And compared with youth with type 1 diabetes, those with type 2 diabetes had more adverse metabolic profiles and higher rates of vascular complications.

“A strong call must be made for the collection of trend data to assess global burden of type 2 diabetes in youth,” she concluded.

Dr. Luk reported serving as an advisory panel member for and/or receiving research support from Amgen, AstraZeneca, Boehringer Ingelheim, Sanofi, the Asia Diabetes Foundation, Bayer, Lee’s Pharmaceutical, MSD, Novo Nordisk, Roche, Sugardown, and Takeda. The other authors reported no relevant financial relationships.

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

One in 10 adults worldwide currently has diabetes, accounting for an estimated global health expenditure of $966 billion in U.S. dollars in 2021, according to the new International Diabetes Federation Diabetes Atlas.

The IDF Atlas, 10th edition, was published online Dec. 6, 2021.

Highlights from it were presented during two sessions at the IDF Virtual Congress 2021, covering global diabetes incidence and prevalence, mortality, and costs, as well as new sections in this edition devoted to adult-onset type 1 diabetes, childhood-onset type 2 diabetes, and the interactions between diabetes and COVID-19.

More detailed data from some of the Atlas chapters were also published Dec. 6, 2021, in separate papers in the IDF journal Diabetes Research and Clinical Practice, with more publications planned.

Information for the Atlas comes from peer-reviewed literature, unpublished reports, and national registries. This latest edition includes 219 data sources from 144 countries, with figures for other countries extrapolated.

Atlas cochair Dianna Magliano, PhD, reviewed some of the highlights. Half of those currently with diabetes, or about 240 million adults, are undiagnosed, and another 319 million have impaired fasting glucose. Over three-quarters of all adults with diabetes now live in low- and middle-income countries. And about 6.7 million deaths in 2021 can be attributed to diabetes.

The Atlas also predicts increases in these numbers over the coming decades if current trends continue.

“Our data and projections tell a sobering story. Diabetes prevalence is expected to increase globally. The number of adults with diabetes will rise from 537 million in 2021 to 786 million ... by the year 2045, an increase of 46%. Rises are expected in every region of the world, with the largest increases expected to occur in the regions of Africa, the Middle East, and Southeast Asia,” said Dr. Magliano, head of diabetes and population health at the Baker Heart and Diabetes Institute, Melbourne.

Since 2019, when the last Atlas was published, the 2021 numbers represent increases of 73.6 million more adults with diabetes including 7.8 million more undiagnosed, 2.5 million more deaths attributed to diabetes, and an additional global expenditure of $206 billion.

Increases have also occurred in the number of people with prediabetes, children with type 1 diabetes, and pregnancies affected by diabetes, Dr. Magliano reported.

“There is a strong need for effective intervention strategies and policies to stall the increase in the number of people developing diabetes across the world,” she added.
 

Projected rise in expenditures for diabetes will be ‘unsustainable’

The current $966 billion global health expenditure caused by diabetes represents a 316% increase from the $232 billion reported in 2006, according to William H. Herman, MD, professor of internal medicine and epidemiology at the University of Michigan, Ann Arbor.

By region, 43% of current diabetes-related global expenditures are in North America, 25% in the Western Pacific, and 20% in Europe, while 12% are from the regions of South and Central America, North Africa, Africa, and Southeast Asia combined, Herman said.

The direct costs of diabetes are projected to grow to $1054 billion in 2045, an increase of just 9% over 25 years. The reason for the far lower increase going forward, compared with the tripling in the 15 years prior, is because of the anticipated diabetes rise in regions of the world where per-person spending on diabetes is low, a situation Dr. Herman called “unsustainable.”

“The keys to controlling the global costs of diabetes care are diabetes prevention and providing effective care to the largest number of people at the lowest possible cost,” he said.
 

Diabetes-related mortality: Some shifts since 2019

One third of the current 6.7 million diabetes-related deaths in 2021 were in people younger than 60 years, said Elbert S. Huang, MD, professor of medicine and public health sciences at the University of Chicago.

Overall, diabetes accounted for 11.8% of total global deaths in people younger than 60 years, but that varied widely, from 24.5% in the Middle East/North Africa to just 6.9% in Southeast Asia.

The regions with the highest number of diabetes-related deaths in people younger than 60 years in 2021 were the Western Pacific and the Middle East/North Africa, a major change from just 2 years ago, when Southeast Asia and Africa saw the greatest numbers of diabetes-related deaths in working-age adults.

“These findings mirror recent reports on inadequate uptake of diabetes prevention programs as well as stagnant quality of care trends for the past decade and reemphasize the need to address noncommunicable diseases across the globe,” Dr. Huang said.
 

Diabetes and COVID-19: Other factors partly explain the increased risk

Gillian Booth, MD, summarized the current literature on COVID-19 and diabetes including a meta-analysis her group conducted of 300 studies from around the world, with 58% from high-income countries.

The risk for increased COVID-19 severity in people with diabetes could be at least partly explained by factors such as age, sex, and comorbidities, said Dr. Booth, professor in the department of medicine and the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

For example, the unadjusted pooled odds of hospitalization with COVID-19 in patients with diabetes, compared with those without diabetes, was 3.69, but dropped to 1.73 after adjustment for age, sex, and having one or more comorbidities. For COVID-19–related death, those odds ratios were 2.32 unadjusted versus 1.59 adjusted. In both cases, the values were still significant after adjustment, she emphasized.

Overall, hyperglycemia and hemoglobin A1c at admission emerged as significant independent predictors of severe outcomes.

“Further research is needed to understand the interplay between COVID-19 and diabetes and how best to address the disproportionate burden of COVID-19 among people living with diabetes,” she stressed.
 

Adult-onset type 1 diabetes: Growing recognition of the burden

Ascertainment of data for both adult-onset type 1 and type 2 diabetes in youth was subject to significant limitations.

For adult-onset type 1 diabetes, Jessica Harding, PhD, pointed to the fact that the epidemiology of adult-onset type 1 diabetes hasn’t been well characterized because of the historical focus on children, the difficulty of distinguishing it from type 2 diabetes in adults, and that many registries simply don’t include incident data across the lifespan for type 1 diabetes.

Nonetheless, she said, “there is growing recognition of the burden of adult-onset type 1,” noting that the American Diabetes Association and European Association for the Study of Diabetes just published a consensus statement addressing the topic.

A systematic review of 46 studies representing 32 countries or regions revealed that countries with the highest incidence of type 1 diabetes onset per population of 100,000 ages 20 or above were Eritrea, at 46.2, followed by Sweden and Ireland, both at 30.6, and Finland, at 0. The lowest rates were in Asian countries.

While the Nordic countries (Finland, Sweden, and Norway) are among the top for incidence of both childhood-onset (0-14 years) and adult-onset type 1 diabetes, Eritrea isn’t even among the top 10 for childhood onset.

The unusual situation in Eritrea is the subject of current study but the reasons aren’t yet clear, noted Dr. Magliano, of Emory University, Atlanta, during the question-and-answer period.

And only seven studies, 15%, used biomarkers to determine type 1 diabetes status, suggesting “there is a pressing need to improve the quality and quantity of information on adult-onset type 1 diabetes, particularly in those low- and middle-income countries,” Dr. Harding said.
 

Type 2 diabetes in youth: A call for better data

When presenting the data for childhood-onset type 2 diabetes, Andrea Luk, MD, noted: “The onset of advanced complications during the most productive time of life has significant impact on individuals, communities, and health economies.”

In 19 studies, the highest reported prevalence of type 2 diabetes in youth was in Brazil, Mexico, indigenous populations of the United States and Canada, and the Black population in the United States, with rates ranging from 160 per 100,000 to 3300 per 100,000. The lowest prevalence rates of 0.6 per 100,000 to 2.7 per 100,000 were reported in Europe. Incidence data were similar, with the highest rates from 31 per 100,000 to 94 per 100,000 and the lowest 0.1 per 100,000 to 0.8 per 100,000 per year.  

Of note, Dr. Luk pointed out that childhood obesity is an important factor but not the only one.

“Some populations that have a low prevalence of obesity, such as East Asians, reported higher incidence rates of youth-onset type 2 diabetes than populations with a greater burden of childhood obesity.”

There was variability in incidence rates for youth of similar ethnic background but from different countries. “Apart from genetic predisposition and background obesogenic environment, disparity in socioeconomic status, access to health care, and cultural practices are other contributors to differences in risk of type 2 diabetes in youth,” noted Dr. Luk, associate professor in the division of endocrinology, Department of Medicine and Therapeutics, Chinese University of Hong Kong.

She also noted that the incidence of type 2 diabetes was extremely low in prepubertal children and rises gradually during puberty, and that the incidence is higher in girls than boys but that reverses in adulthood.

Compared with adults with type 2 diabetes, youth with type 2 diabetes had a more adverse glycemic trajectory and higher rates of metformin failure.

And compared with youth with type 1 diabetes, those with type 2 diabetes had more adverse metabolic profiles and higher rates of vascular complications.

“A strong call must be made for the collection of trend data to assess global burden of type 2 diabetes in youth,” she concluded.

Dr. Luk reported serving as an advisory panel member for and/or receiving research support from Amgen, AstraZeneca, Boehringer Ingelheim, Sanofi, the Asia Diabetes Foundation, Bayer, Lee’s Pharmaceutical, MSD, Novo Nordisk, Roche, Sugardown, and Takeda. The other authors reported no relevant financial relationships.

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

The Pfizer/BioNTech booster lowers the risk for confirmed illness, severe illness, and death from COVID-19, according to two large studies from Israel published Dec. 8, 2021, in the New England Journal of Medicine.

Both studies were completed before the advent of the Omicron variant.

In one study that included data on more than 4 million patients, led by Yinon M. Bar-On, MSc, of the Weizmann Institute of Science in Rehovot, Israel, the rate of confirmed SARS-CoV-2 infection was lower in the booster group than in the nonbooster group by a factor of about 10.

This was true across all five age groups studied (range among the groups [starting with age 16], 9.0-17.2).

The risk for severe COVID-19 in the primary analysis decreased in the booster group by a factor of 17.9 (95% confidence interval, 15.1-21.2), among those aged 60 years or older. Risk for severe illness in those ages 40-59 was lower by a factor of 21.7 (95% CI, 10.6-44.2).

Among the 60 and older age group, risk for death was also reduced by a factor of 14.7 (95% CI, 10.0-21.4).

Researchers analyzed data for the period from July 30 to Oct. 10, 2021, from the Israel Ministry of Health database on 4.69 million people at least 16 years old who had received two Pfizer doses at least 5 months earlier.

In the main analysis, the researchers compared the rates of confirmed COVID-19, severe disease, and death among those who had gotten a booster at least 12 days earlier with the rates in a nonbooster group.

The authors wrote: “Booster vaccination programs may provide a way to control transmission without costly social-distancing measures and quarantines. Our findings provide evidence for the short-term effectiveness of the booster dose against the currently dominant Delta variant in persons 16 years of age or older.”
 

Death risk down by 90%

A second study, led by Ronen Arbel, PhD, with the community medical services division, Clalit Health Services (CHS), Tel Aviv, which included more than 800,000 participants, also found mortality risk was greatly reduced among those who received the booster compared with those who didn’t get the booster.

Participants aged 50 years or older who received a booster at least 5 months after a second Pfizer dose had 90% lower mortality risk because of COVID-19 than participants who did not get the booster.

The adjusted hazard ratio for death as a result of COVID-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% CI, 0.07-0.14; P < .001). Of the 843,208 eligible participants, 758,118 (90%) received the booster during the 54-day study period.

The study included all CHS members who were aged 50 years or older on the study start date and had received two Pfizer doses at least 5 months earlier. CHS covers about 52% of the Israeli population and is the largest of four health care organizations in Israel that provide mandatory health care.

The authors noted that, although the study period was only 54 days (Aug. 6–Sept. 29), during that time “the incidence of COVID-19 in Israel was one of the highest in the world.”

The authors of both original articles pointed out that the studies are limited by short time periods and that longer-term studies are needed to see how the booster shots stand up to known and future variants, such as Omicron.

None of the authors involved in both studies reported relevant financial relationships.

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

The Pfizer/BioNTech booster lowers the risk for confirmed illness, severe illness, and death from COVID-19, according to two large studies from Israel published Dec. 8, 2021, in the New England Journal of Medicine.

Both studies were completed before the advent of the Omicron variant.

In one study that included data on more than 4 million patients, led by Yinon M. Bar-On, MSc, of the Weizmann Institute of Science in Rehovot, Israel, the rate of confirmed SARS-CoV-2 infection was lower in the booster group than in the nonbooster group by a factor of about 10.

This was true across all five age groups studied (range among the groups [starting with age 16], 9.0-17.2).

The risk for severe COVID-19 in the primary analysis decreased in the booster group by a factor of 17.9 (95% confidence interval, 15.1-21.2), among those aged 60 years or older. Risk for severe illness in those ages 40-59 was lower by a factor of 21.7 (95% CI, 10.6-44.2).

Among the 60 and older age group, risk for death was also reduced by a factor of 14.7 (95% CI, 10.0-21.4).

Researchers analyzed data for the period from July 30 to Oct. 10, 2021, from the Israel Ministry of Health database on 4.69 million people at least 16 years old who had received two Pfizer doses at least 5 months earlier.

In the main analysis, the researchers compared the rates of confirmed COVID-19, severe disease, and death among those who had gotten a booster at least 12 days earlier with the rates in a nonbooster group.

The authors wrote: “Booster vaccination programs may provide a way to control transmission without costly social-distancing measures and quarantines. Our findings provide evidence for the short-term effectiveness of the booster dose against the currently dominant Delta variant in persons 16 years of age or older.”
 

Death risk down by 90%

A second study, led by Ronen Arbel, PhD, with the community medical services division, Clalit Health Services (CHS), Tel Aviv, which included more than 800,000 participants, also found mortality risk was greatly reduced among those who received the booster compared with those who didn’t get the booster.

Participants aged 50 years or older who received a booster at least 5 months after a second Pfizer dose had 90% lower mortality risk because of COVID-19 than participants who did not get the booster.

The adjusted hazard ratio for death as a result of COVID-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% CI, 0.07-0.14; P < .001). Of the 843,208 eligible participants, 758,118 (90%) received the booster during the 54-day study period.

The study included all CHS members who were aged 50 years or older on the study start date and had received two Pfizer doses at least 5 months earlier. CHS covers about 52% of the Israeli population and is the largest of four health care organizations in Israel that provide mandatory health care.

The authors noted that, although the study period was only 54 days (Aug. 6–Sept. 29), during that time “the incidence of COVID-19 in Israel was one of the highest in the world.”

The authors of both original articles pointed out that the studies are limited by short time periods and that longer-term studies are needed to see how the booster shots stand up to known and future variants, such as Omicron.

None of the authors involved in both studies reported relevant financial relationships.

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

The Pfizer/BioNTech booster lowers the risk for confirmed illness, severe illness, and death from COVID-19, according to two large studies from Israel published Dec. 8, 2021, in the New England Journal of Medicine.

Both studies were completed before the advent of the Omicron variant.

In one study that included data on more than 4 million patients, led by Yinon M. Bar-On, MSc, of the Weizmann Institute of Science in Rehovot, Israel, the rate of confirmed SARS-CoV-2 infection was lower in the booster group than in the nonbooster group by a factor of about 10.

This was true across all five age groups studied (range among the groups [starting with age 16], 9.0-17.2).

The risk for severe COVID-19 in the primary analysis decreased in the booster group by a factor of 17.9 (95% confidence interval, 15.1-21.2), among those aged 60 years or older. Risk for severe illness in those ages 40-59 was lower by a factor of 21.7 (95% CI, 10.6-44.2).

Among the 60 and older age group, risk for death was also reduced by a factor of 14.7 (95% CI, 10.0-21.4).

Researchers analyzed data for the period from July 30 to Oct. 10, 2021, from the Israel Ministry of Health database on 4.69 million people at least 16 years old who had received two Pfizer doses at least 5 months earlier.

In the main analysis, the researchers compared the rates of confirmed COVID-19, severe disease, and death among those who had gotten a booster at least 12 days earlier with the rates in a nonbooster group.

The authors wrote: “Booster vaccination programs may provide a way to control transmission without costly social-distancing measures and quarantines. Our findings provide evidence for the short-term effectiveness of the booster dose against the currently dominant Delta variant in persons 16 years of age or older.”
 

Death risk down by 90%

A second study, led by Ronen Arbel, PhD, with the community medical services division, Clalit Health Services (CHS), Tel Aviv, which included more than 800,000 participants, also found mortality risk was greatly reduced among those who received the booster compared with those who didn’t get the booster.

Participants aged 50 years or older who received a booster at least 5 months after a second Pfizer dose had 90% lower mortality risk because of COVID-19 than participants who did not get the booster.

The adjusted hazard ratio for death as a result of COVID-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% CI, 0.07-0.14; P < .001). Of the 843,208 eligible participants, 758,118 (90%) received the booster during the 54-day study period.

The study included all CHS members who were aged 50 years or older on the study start date and had received two Pfizer doses at least 5 months earlier. CHS covers about 52% of the Israeli population and is the largest of four health care organizations in Israel that provide mandatory health care.

The authors noted that, although the study period was only 54 days (Aug. 6–Sept. 29), during that time “the incidence of COVID-19 in Israel was one of the highest in the world.”

The authors of both original articles pointed out that the studies are limited by short time periods and that longer-term studies are needed to see how the booster shots stand up to known and future variants, such as Omicron.

None of the authors involved in both studies reported relevant financial relationships.

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

Starting Dec. 8, the Centers for Disease Control and Prevention recommends all clinicians talk to their sexually active adolescent and adult patients about HIV pre-exposure prophylaxis (PrEP) at least once and prescribe the prevention pills to anyone who asks for them, whether or not you understand their need for it.

“PrEP is a part of good primary care,” Demetre Daskalakis, MD, CDC’s director of the division of HIV/AIDS prevention, said in an interview. “Listening to people and what they need, as opposed to assessing what you think they need, is a seismic shift in how PrEP should be offered.”

The expanded recommendation comes as part of the 2021 update to the U.S. Public Health Service’s PrEP prescribing guidelines. It’s the third iteration since the Food and Drug Administration approved the first HIV prevention pill in 2012, and the first to include guidance on how to prescribe and monitor an injectable version of PrEP, which the FDA may approve as early as December 2021.

There are currently two pills, Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences and generic) and Descovy (emtricitabine/tenofovir alafenamide, Gilead Sciences). The pills have been found to be up to 99% effective in preventing HIV acquisition. The new injectable cabotegravir appears to be even more effective.

The broadened guidance is part of an effort from the country’s top health officials to expand PrEP prescribing from infectious disease specialists and sexual health clinics to health care professionals, including gynecologists, internal medicine physicians, and family practice clinicians. It appears to be necessary. In 2020, just 25% of the 1.2 million Americans who could benefit from PrEP were taking it, according to CDC data.

But those rates belie stark disparities in PrEP use by race and gender. The vast majority of those using PrEP are White Americans and men. About 66% of White Americans who could benefit from PrEP used it in 2020, and more than a quarter of the men who could benefit used it. By contrast, just 16% of Latinx people who could benefit had a prescription. And fewer than 1 in 10 Black Americans, who make up nearly half of those with indications for PrEP, had a prescription. The same was true for the women who could benefit.

Researchers and data from early PrEP demonstration projects have documented that clinicians are less likely to refer or prescribe the HIV prevention pills to Black people, especially the Black cisgender and transgender women and same-gender-loving men who bear the disproportionate burden of new cases in the United States, as well as fail to prescribe the medication to people who inject drugs.
 

Normalizing PrEP in primary care

When Courtney Sherman, DNP, APRN, first heard about PrEP in the early 2010s, she joked that her reaction was: “You’re ridiculous. You’re making that up. That’s not real.”

Ms. Sherman is now launching a tele-PrEP program from CAN Community Health, a nonprofit network of community health centers in southern Florida. The tele-PrEP program is meant to serve people in Florida and beyond, to increase access to the pill in areas with few health care professionals, or clinicians unwilling to prescribe it.

“When I go other places, I can’t do what I do for a living without getting some sort of bizarre comment or look,” she said. But the looks don’t just come from family, friends, or her children’s teachers. They come from colleagues, too. “What I’ve learned is that anybody – anybody – can be impacted [by HIV] and the illusion that ‘those people who live over there do things that me and my kind don’t do’ is just garbage.”

That’s the PrEP stigma that the universal PrEP counseling in the guidelines is meant to override, said Dr. Daskalakis. Going forward, he said that informing people about PrEP should be treated as normally as counseling people about smoking.

“You can change the blank: You talk to all adolescents and adults about not smoking,” he said. “This is: ‘Tell adolescents and adults about ways you can prevent HIV, and PrEP is one of them.’ ”

The guidelines also simplify for monitoring lab levels for the current daily pills, checking creatinine clearance levels twice a year in people older than age 50 and once a year in those younger than 50 taking the oral pills. Dr. Daskalakis said that should ease the burden of monitoring PrEP patients for health care professionals with busy caseloads.

It’s a move that drew praise from Shawnika Hull, PhD, assistant professor of health communications at Rutgers University, New Brunswick, N.J.. Dr. Hull’s recent data showed that clinicians who espoused more biased racial views were also less likely to prescribe PrEP to Black women who asked for it.

“Public health practitioners and scientists have been advocating for this as a strategy, as one way to address several ongoing barriers to PrEP specifically but also equity in PrEP,” said Dr. Hull. “This sort of universal provision of information is really an important strategy to try to undo some of the deeply intertwined barriers to uptake.”
 

‘Don’t grill them’

The updated guidelines keep the number and proportion of Americans who could benefit from PrEP the same: 1.2 million Americans, with nearly half of those Black. And the reasons people would qualify for PrEP remain the same: inconsistent condom use, sharing injection drug equipment, and a STI diagnosis in the last 6 months. There are also 57 jurisdictions, including seven rural states, where dating and having sex carries an increased risk of acquiring HIV because of high rates of untreated HIV in the community.

That’s why the other big change in the update is guidance to prescribe PrEP to whoever asks for it, whether the patient divulges their risk or not. Or as Dr. Daskalakis puts it: “If someone asks for PrEP, don’t grill them.”

There are lots of reasons that someone might ask for PrEP without divulging their risk behaviors, said Dr. Daskalakis, who was an infectious disease doctor in New York back in 2012 (and a member of the FDA committee) when the first pill for PrEP was approved. He said he’s seen this particularly with women who ask about it. Asking for PrEP ends up being an “ice breaker” to discussing the woman’s sexual and injection drug use history, which can then improve the kinds of tests and vaccinations clinicians suggest for her.

“So many women will open the door and say, ‘I want to do this,’ and not necessarily want to go into the details,” he said. “Now, will they go into the details later? Absolutely. That’s how you create trust and connection.”
 

A mandate and a guideline

Leisha McKinley-Beach, MPH, a member of the U.S. Women and PrEP Working Group, has been urging greater funding and mandates to expand PrEP to women since the first pill was approved. And still, Ms. McKinley-Beach said she recently met a woman who worked for a community group scheduling PrEP appointments for gay men. But the woman didn’t know that she, too, could take it. 

The American Academy of Family Physicians recommends health care professionals offer PrEP to those who can benefit. The American College of Obstetricians and Gynecologists have a 2014 committee opinion stating that PrEP “may be a useful tool for women at highest risk of HIV acquisition.”

But the ACOG opinion is not a recommendation, stating that it “should not be construed as dictating an exclusive course of treatment or procedure to be followed.” Ms. McKinley-Beach said she hopes that the new CDC guidelines will prompt ACOG and other professional organizations to issue statements to include PrEP education in all health assessments. A spokesperson for ACOG said that the organization had not seen the new CDC guidelines and had no statement on them, but pointed out that the 2014 committee opinion is one of the “highest level of documents we produce.

“We have failed for nearly a decade to raise awareness that PrEP is also a prevention strategy for women,” Ms. McKinley-Beach said in an interview. “In many ways, we’re still back in 2012 as it relates to women.”

Dr. Hull reported having done previous research funded by Gilead Sciences and having received consulting fees from Gilead Sciences in 2018. Ms. McKinley-Beach reported receiving honoraria from ViiV Healthcare. Ms. Sherman and Dr. Daskalakis disclosed no relevant financial relationships.

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

Starting Dec. 8, the Centers for Disease Control and Prevention recommends all clinicians talk to their sexually active adolescent and adult patients about HIV pre-exposure prophylaxis (PrEP) at least once and prescribe the prevention pills to anyone who asks for them, whether or not you understand their need for it.

“PrEP is a part of good primary care,” Demetre Daskalakis, MD, CDC’s director of the division of HIV/AIDS prevention, said in an interview. “Listening to people and what they need, as opposed to assessing what you think they need, is a seismic shift in how PrEP should be offered.”

The expanded recommendation comes as part of the 2021 update to the U.S. Public Health Service’s PrEP prescribing guidelines. It’s the third iteration since the Food and Drug Administration approved the first HIV prevention pill in 2012, and the first to include guidance on how to prescribe and monitor an injectable version of PrEP, which the FDA may approve as early as December 2021.

There are currently two pills, Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences and generic) and Descovy (emtricitabine/tenofovir alafenamide, Gilead Sciences). The pills have been found to be up to 99% effective in preventing HIV acquisition. The new injectable cabotegravir appears to be even more effective.

The broadened guidance is part of an effort from the country’s top health officials to expand PrEP prescribing from infectious disease specialists and sexual health clinics to health care professionals, including gynecologists, internal medicine physicians, and family practice clinicians. It appears to be necessary. In 2020, just 25% of the 1.2 million Americans who could benefit from PrEP were taking it, according to CDC data.

But those rates belie stark disparities in PrEP use by race and gender. The vast majority of those using PrEP are White Americans and men. About 66% of White Americans who could benefit from PrEP used it in 2020, and more than a quarter of the men who could benefit used it. By contrast, just 16% of Latinx people who could benefit had a prescription. And fewer than 1 in 10 Black Americans, who make up nearly half of those with indications for PrEP, had a prescription. The same was true for the women who could benefit.

Researchers and data from early PrEP demonstration projects have documented that clinicians are less likely to refer or prescribe the HIV prevention pills to Black people, especially the Black cisgender and transgender women and same-gender-loving men who bear the disproportionate burden of new cases in the United States, as well as fail to prescribe the medication to people who inject drugs.
 

Normalizing PrEP in primary care

When Courtney Sherman, DNP, APRN, first heard about PrEP in the early 2010s, she joked that her reaction was: “You’re ridiculous. You’re making that up. That’s not real.”

Ms. Sherman is now launching a tele-PrEP program from CAN Community Health, a nonprofit network of community health centers in southern Florida. The tele-PrEP program is meant to serve people in Florida and beyond, to increase access to the pill in areas with few health care professionals, or clinicians unwilling to prescribe it.

“When I go other places, I can’t do what I do for a living without getting some sort of bizarre comment or look,” she said. But the looks don’t just come from family, friends, or her children’s teachers. They come from colleagues, too. “What I’ve learned is that anybody – anybody – can be impacted [by HIV] and the illusion that ‘those people who live over there do things that me and my kind don’t do’ is just garbage.”

That’s the PrEP stigma that the universal PrEP counseling in the guidelines is meant to override, said Dr. Daskalakis. Going forward, he said that informing people about PrEP should be treated as normally as counseling people about smoking.

“You can change the blank: You talk to all adolescents and adults about not smoking,” he said. “This is: ‘Tell adolescents and adults about ways you can prevent HIV, and PrEP is one of them.’ ”

The guidelines also simplify for monitoring lab levels for the current daily pills, checking creatinine clearance levels twice a year in people older than age 50 and once a year in those younger than 50 taking the oral pills. Dr. Daskalakis said that should ease the burden of monitoring PrEP patients for health care professionals with busy caseloads.

It’s a move that drew praise from Shawnika Hull, PhD, assistant professor of health communications at Rutgers University, New Brunswick, N.J.. Dr. Hull’s recent data showed that clinicians who espoused more biased racial views were also less likely to prescribe PrEP to Black women who asked for it.

“Public health practitioners and scientists have been advocating for this as a strategy, as one way to address several ongoing barriers to PrEP specifically but also equity in PrEP,” said Dr. Hull. “This sort of universal provision of information is really an important strategy to try to undo some of the deeply intertwined barriers to uptake.”
 

‘Don’t grill them’

The updated guidelines keep the number and proportion of Americans who could benefit from PrEP the same: 1.2 million Americans, with nearly half of those Black. And the reasons people would qualify for PrEP remain the same: inconsistent condom use, sharing injection drug equipment, and a STI diagnosis in the last 6 months. There are also 57 jurisdictions, including seven rural states, where dating and having sex carries an increased risk of acquiring HIV because of high rates of untreated HIV in the community.

That’s why the other big change in the update is guidance to prescribe PrEP to whoever asks for it, whether the patient divulges their risk or not. Or as Dr. Daskalakis puts it: “If someone asks for PrEP, don’t grill them.”

There are lots of reasons that someone might ask for PrEP without divulging their risk behaviors, said Dr. Daskalakis, who was an infectious disease doctor in New York back in 2012 (and a member of the FDA committee) when the first pill for PrEP was approved. He said he’s seen this particularly with women who ask about it. Asking for PrEP ends up being an “ice breaker” to discussing the woman’s sexual and injection drug use history, which can then improve the kinds of tests and vaccinations clinicians suggest for her.

“So many women will open the door and say, ‘I want to do this,’ and not necessarily want to go into the details,” he said. “Now, will they go into the details later? Absolutely. That’s how you create trust and connection.”
 

A mandate and a guideline

Leisha McKinley-Beach, MPH, a member of the U.S. Women and PrEP Working Group, has been urging greater funding and mandates to expand PrEP to women since the first pill was approved. And still, Ms. McKinley-Beach said she recently met a woman who worked for a community group scheduling PrEP appointments for gay men. But the woman didn’t know that she, too, could take it. 

The American Academy of Family Physicians recommends health care professionals offer PrEP to those who can benefit. The American College of Obstetricians and Gynecologists have a 2014 committee opinion stating that PrEP “may be a useful tool for women at highest risk of HIV acquisition.”

But the ACOG opinion is not a recommendation, stating that it “should not be construed as dictating an exclusive course of treatment or procedure to be followed.” Ms. McKinley-Beach said she hopes that the new CDC guidelines will prompt ACOG and other professional organizations to issue statements to include PrEP education in all health assessments. A spokesperson for ACOG said that the organization had not seen the new CDC guidelines and had no statement on them, but pointed out that the 2014 committee opinion is one of the “highest level of documents we produce.

“We have failed for nearly a decade to raise awareness that PrEP is also a prevention strategy for women,” Ms. McKinley-Beach said in an interview. “In many ways, we’re still back in 2012 as it relates to women.”

Dr. Hull reported having done previous research funded by Gilead Sciences and having received consulting fees from Gilead Sciences in 2018. Ms. McKinley-Beach reported receiving honoraria from ViiV Healthcare. Ms. Sherman and Dr. Daskalakis disclosed no relevant financial relationships.

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

Starting Dec. 8, the Centers for Disease Control and Prevention recommends all clinicians talk to their sexually active adolescent and adult patients about HIV pre-exposure prophylaxis (PrEP) at least once and prescribe the prevention pills to anyone who asks for them, whether or not you understand their need for it.

“PrEP is a part of good primary care,” Demetre Daskalakis, MD, CDC’s director of the division of HIV/AIDS prevention, said in an interview. “Listening to people and what they need, as opposed to assessing what you think they need, is a seismic shift in how PrEP should be offered.”

The expanded recommendation comes as part of the 2021 update to the U.S. Public Health Service’s PrEP prescribing guidelines. It’s the third iteration since the Food and Drug Administration approved the first HIV prevention pill in 2012, and the first to include guidance on how to prescribe and monitor an injectable version of PrEP, which the FDA may approve as early as December 2021.

There are currently two pills, Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences and generic) and Descovy (emtricitabine/tenofovir alafenamide, Gilead Sciences). The pills have been found to be up to 99% effective in preventing HIV acquisition. The new injectable cabotegravir appears to be even more effective.

The broadened guidance is part of an effort from the country’s top health officials to expand PrEP prescribing from infectious disease specialists and sexual health clinics to health care professionals, including gynecologists, internal medicine physicians, and family practice clinicians. It appears to be necessary. In 2020, just 25% of the 1.2 million Americans who could benefit from PrEP were taking it, according to CDC data.

But those rates belie stark disparities in PrEP use by race and gender. The vast majority of those using PrEP are White Americans and men. About 66% of White Americans who could benefit from PrEP used it in 2020, and more than a quarter of the men who could benefit used it. By contrast, just 16% of Latinx people who could benefit had a prescription. And fewer than 1 in 10 Black Americans, who make up nearly half of those with indications for PrEP, had a prescription. The same was true for the women who could benefit.

Researchers and data from early PrEP demonstration projects have documented that clinicians are less likely to refer or prescribe the HIV prevention pills to Black people, especially the Black cisgender and transgender women and same-gender-loving men who bear the disproportionate burden of new cases in the United States, as well as fail to prescribe the medication to people who inject drugs.
 

Normalizing PrEP in primary care

When Courtney Sherman, DNP, APRN, first heard about PrEP in the early 2010s, she joked that her reaction was: “You’re ridiculous. You’re making that up. That’s not real.”

Ms. Sherman is now launching a tele-PrEP program from CAN Community Health, a nonprofit network of community health centers in southern Florida. The tele-PrEP program is meant to serve people in Florida and beyond, to increase access to the pill in areas with few health care professionals, or clinicians unwilling to prescribe it.

“When I go other places, I can’t do what I do for a living without getting some sort of bizarre comment or look,” she said. But the looks don’t just come from family, friends, or her children’s teachers. They come from colleagues, too. “What I’ve learned is that anybody – anybody – can be impacted [by HIV] and the illusion that ‘those people who live over there do things that me and my kind don’t do’ is just garbage.”

That’s the PrEP stigma that the universal PrEP counseling in the guidelines is meant to override, said Dr. Daskalakis. Going forward, he said that informing people about PrEP should be treated as normally as counseling people about smoking.

“You can change the blank: You talk to all adolescents and adults about not smoking,” he said. “This is: ‘Tell adolescents and adults about ways you can prevent HIV, and PrEP is one of them.’ ”

The guidelines also simplify for monitoring lab levels for the current daily pills, checking creatinine clearance levels twice a year in people older than age 50 and once a year in those younger than 50 taking the oral pills. Dr. Daskalakis said that should ease the burden of monitoring PrEP patients for health care professionals with busy caseloads.

It’s a move that drew praise from Shawnika Hull, PhD, assistant professor of health communications at Rutgers University, New Brunswick, N.J.. Dr. Hull’s recent data showed that clinicians who espoused more biased racial views were also less likely to prescribe PrEP to Black women who asked for it.

“Public health practitioners and scientists have been advocating for this as a strategy, as one way to address several ongoing barriers to PrEP specifically but also equity in PrEP,” said Dr. Hull. “This sort of universal provision of information is really an important strategy to try to undo some of the deeply intertwined barriers to uptake.”
 

‘Don’t grill them’

The updated guidelines keep the number and proportion of Americans who could benefit from PrEP the same: 1.2 million Americans, with nearly half of those Black. And the reasons people would qualify for PrEP remain the same: inconsistent condom use, sharing injection drug equipment, and a STI diagnosis in the last 6 months. There are also 57 jurisdictions, including seven rural states, where dating and having sex carries an increased risk of acquiring HIV because of high rates of untreated HIV in the community.

That’s why the other big change in the update is guidance to prescribe PrEP to whoever asks for it, whether the patient divulges their risk or not. Or as Dr. Daskalakis puts it: “If someone asks for PrEP, don’t grill them.”

There are lots of reasons that someone might ask for PrEP without divulging their risk behaviors, said Dr. Daskalakis, who was an infectious disease doctor in New York back in 2012 (and a member of the FDA committee) when the first pill for PrEP was approved. He said he’s seen this particularly with women who ask about it. Asking for PrEP ends up being an “ice breaker” to discussing the woman’s sexual and injection drug use history, which can then improve the kinds of tests and vaccinations clinicians suggest for her.

“So many women will open the door and say, ‘I want to do this,’ and not necessarily want to go into the details,” he said. “Now, will they go into the details later? Absolutely. That’s how you create trust and connection.”
 

A mandate and a guideline

Leisha McKinley-Beach, MPH, a member of the U.S. Women and PrEP Working Group, has been urging greater funding and mandates to expand PrEP to women since the first pill was approved. And still, Ms. McKinley-Beach said she recently met a woman who worked for a community group scheduling PrEP appointments for gay men. But the woman didn’t know that she, too, could take it. 

The American Academy of Family Physicians recommends health care professionals offer PrEP to those who can benefit. The American College of Obstetricians and Gynecologists have a 2014 committee opinion stating that PrEP “may be a useful tool for women at highest risk of HIV acquisition.”

But the ACOG opinion is not a recommendation, stating that it “should not be construed as dictating an exclusive course of treatment or procedure to be followed.” Ms. McKinley-Beach said she hopes that the new CDC guidelines will prompt ACOG and other professional organizations to issue statements to include PrEP education in all health assessments. A spokesperson for ACOG said that the organization had not seen the new CDC guidelines and had no statement on them, but pointed out that the 2014 committee opinion is one of the “highest level of documents we produce.

“We have failed for nearly a decade to raise awareness that PrEP is also a prevention strategy for women,” Ms. McKinley-Beach said in an interview. “In many ways, we’re still back in 2012 as it relates to women.”

Dr. Hull reported having done previous research funded by Gilead Sciences and having received consulting fees from Gilead Sciences in 2018. Ms. McKinley-Beach reported receiving honoraria from ViiV Healthcare. Ms. Sherman and Dr. Daskalakis disclosed no relevant financial relationships.

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