The ulnar collateral ligament (UCL) is the primary restraint to valgus stress between 20° and 125° of motion.^1-5 Overhead athletes, most commonly baseball pitchers, are at risk of developing UCL insufficiency, and dysfunction presents as pain with loss of velocity and control. Some injuries may present acutely while throwing, but many patients, when questioned, report a preceding period of either pain or loss of velocity and control.

Authors have documented a significant rise in elbow injuries in young athletes, especially pitchers.⁶ Extended seasons, higher pitch counts, year-round pitching, pitching while fatigued, and pitching for multiple teams are risk factors for elbow injuries.⁷ Pitchers in the southern United States are more likely to undergo UCL reconstruction than those from the northern states.⁸ Pitchers who also play catcher are at a higher risk due to more total throws than those who pitch and play other positions or pitch only. Throwers with higher velocity are more likely to pitch in showcases, pitch for multiple teams, and pitch with pain and fatigue, and these are all risk factors.⁶ Also, in one study of youth baseball injuries, individuals in the injured group were found to be taller and heavier than those in the uninjured group.⁶ Pitch counts, rest from pitching during the off-season, adequate rest, and ensuring pain-free pitching can lessen the risk of injury.⁶ As expected with the rise in throwing injuries, the rise in medial elbow procedures has risen.⁹

While throwing, stress across the medial elbow has been measured to be nearly 300 N. A maximum varus force during pitching was measured to be 64 N-m at 95° ± 14°.¹⁰ Morrey and An⁴ determined that the UCL generated 54% of the varus force at 90° of flexion. During active pitching, this value is likely reduced due to simultaneous muscle contraction, but if one assumes the UCL bears 54% of the maximal load, the UCL must be able to withstand 34 N-m. The UCL can withstand a maximum valgus torque between 22.7 and 34 N-m^11-13; therefore, during pitching, the UCL is at or above its failure load. After thousands of cycles over many years, one can imagine how the UCL might be injured.

Multiple techniques have been proposed in the surgical treatment of UCL injuries. Jobe¹⁴ pioneered UCL reconstruction in 1974 in Tommy John, a Major League Baseball pitcher. John returned to pitch successfully, and both the UCL and the reconstruction are commonly called by his name. Jobe¹⁴ reported his technique in 1986, and it has remained, with a few modifications, the primary method for reconstruction of the UCL (Figure 1).

Evaluation

A standard evaluation with physical examination and imaging is completed in all throwers with elbow pain. In our prior study,¹⁶ we found that 100% of patients experienced pain during athletic activity and that 96% of throwers complained of pain during late cocking and acceleration phases of the throwing motion. Nearly half reported an acute onset of pain, while 53% were unable to identify a single inciting event. Seventy-five percent of the acute injuries were during competition. Delayed diagnosis was very common, with an average time to diagnosis after onset of symptoms of 6.4 months. Neurologic symptoms were seen in 23% of athletes, most of which were ulnar nerve paresthesias during throwing.¹⁶

Physical examination includes inspection for swelling, hand intrinsic atrophy, neurovascular examination, range of motion, shoulder examination, and elbow stress examination. Range of motion at presentation averaged 5° to 135° with 85° of supination and pronation.¹⁶ All patients need neurologic evaluation for ulnar nerve dysfunction. Tinel test of the cubital tunnel was positive in 21%.¹⁶ Significant ulnar nerve dysfunction, including hand weakness, is much less common but must be well examined and documented. The shoulder must also be evaluated for loss of rotation, which can lead to increased stress on the elbow. An evaluation of mechanics may point out flaws in technique, which may be contributing to elbow stress. The UCL stress examination includes static stress at 30° of flexion, the milking test at 90°, and the moving valgus stress test. The presence of pain directly over the UCL or laxity compared to the uninvolved side is suggestive of UCL injury.

Radiographic evaluation is completed in all patients with concern for UCL injury. Standard x-rays of the elbow, including anteroposterior, medial, and lateral obliques, axial olecranon, and lateral views, are obtained to evaluate bony abnormalities. Fifty-seven percent of our series showed some abnormality, most commonly olecranon osteophyte formation or ectopic calcification within the UCL substance. Stress radiography rarely changed the treatment course and is somewhat difficult to interpret because of the reports documenting normal increased medial elbow opening in the dominant arm of throwing athletes.²¹ Magnetic resonance imaging (MRI) is obtained very commonly in this patient population, and intra-articular contrast is crucial. Partial, undersurface tears are common, and a contrasted study better demonstrates undersurface tears or avulsions. The T-sign as described by Timmerman and colleagues²² using computed tomography (CT) arthrography shows partial undersurface detachment, which can be difficult to see without intra-articular contrast.²² This finding is very well visualized on MRI arthrogram as well (Figure 3).

Nonoperative Management

Nonoperative treatment is recommended for 3 months prior to performing reconstruction. Patients are given complete rest from throwing, but rehabilitation is initiated immediately. Rehabilitation exercises and nonsteroidal anti-inflammatory medications are prescribed, and activities that place valgus stress across the elbow are avoided. After resolution of symptoms, an interval throwing program is initiated, and the athlete is gradually returned to sport. Unfortunately, due to season-specific schedules and time-sensitive demands in high-level throwers, operative treatment is often chosen without an extended period of conservative treatment.

Platelet-rich plasma (PRP) therapy has recently been shown to improve healing rates and promote healing in partial UCL tears,²³ and as orthobiologics are advanced, they will likely play a larger role in the treatment of UCL injuries.

Surgical Technique

At our institution, UCL reconstruction is performed with the modified Jobe technique as described by Azar and colleagues.¹⁷ Arthroscopy prior to reconstruction was routinely performed at our institution until we recognized that arthroscopy rarely changed the preoperative plan.¹⁶ Currently, the presence of anterior pathology such as loose bodies or osteochondral defect is our only indication for arthroscopy before reconstruction.

Ipsilateral palmaris autograft is our current graft of choice. This must be examined preoperatively because 16% of patients have unilateral absence and 9% have bilateral absence.²⁴ In revision cases or in patients with insufficient or absent palmaris, contralateral palmaris followed by contralateral gracilis tendon is used. The contralateral gracilis is chosen because of ease of setup and position of the surgeon during the harvest. Gracilis tendon is also used in cases with bony involvement of the ligament based on the results from Dugas and colleagues.²⁵ Toe extensors, plantaris, and patellar tendon grafts have also been used. One recent study showed that neither graft choice nor diameter affected resistance to valgus stress, and that all reconstruction types restored strength at 60° to 120° of flexion.²⁶

Ulnar nerve transposition is performed in all cases regardless of the presence of preoperative nerve symptoms. A complete decompression is completed proximally to the Arcade of Struthers and distally to the deep portion of the flexor carpi ulnaris. A single fascial sling of medial intermuscular septum originating from the epicondylar attachment is used to stabilize the nerve without compression. At wound closure, the deep fascia on the posterior skin flap is also sewn into the cubital tunnel to prevent the nerve from subluxating back into the groove. A single suture is placed distally closing the muscle fascia to prevent propagation of the fascial incision, which can lead to herniation. Transposition is necessary because of the ulnar nerve exposure required in the modified Jobe technique to allow elevation of the deep flexor muscle mass for ligament exposure.

The reconstruction is completed as described by Jobe¹⁴ but with a few modifications as described by Azar and colleagues¹⁷ and slight adaptations implemented since that time. The flexor-pronator mass is retracted laterally instead of detachment or splitting as described by Thompson and colleagues.²⁷ A subcutaneous rather than a submuscular ulnar nerve transposition is used.

The patient is positioned supine using an arm board. If gracilis tendon is chosen, the contralateral leg is prepped and draped simultaneously. A tourniquet is inflated after exsanguination. A medial approach is performed, and the medial antebrachial nerve is located and protected. The ulnar nerve is then located in the cubital tunnel and mobilized. The neurolysis extends to the deep portion of the flexor carpi ulnaris distally and proximally to the Arcade of Struthers, and the nerve is retracted with a vessel loop. The flexor muscle mass is not elevated from the medial epicondyle; rather, it is retracted anteriorly by small Hohmann retractors. The dissection is carried down to the UCL and found at its attachments to the medial epicondyle and sublime tubercle. If no tear is seen on the superficial surface of the ligament, a longitudinal incision is made through the ligament. Undersurface tears, partial tears, and avulsions can then be identified (Figure 4).

Postoperative Rehabilitation

A standardized postoperative 4-phase rehabilitation program for ulnar collateral reconstruction is followed as described by Wilk and colleagues.^28-30 The first phase begins immediately after surgery and continues for 4 weeks. During surgery, the patient’s elbow is placed in a compression dressing with a posterior splint to immobilize the elbow in 90° of flexion with wrist motion for 1 week to allow initial healing. Full range of motion of the elbow joint is restored by the end of the fifth to sixth week after surgery.

During phase II (weeks 4-10), a progressive isotonic strengthening program is initiated. Exercises are focused on scapular, rotator cuff, deltoid, and arm musculature. Shoulder range of motion and stretching exercises are performed during this phase and the Thrower’s Ten exercise program is initiated. Any adaptations or strength deficits are addressed during this phase.

During the advanced strengthening phase (phase III), from weeks 10 to 16, a sport-specific exercise/rehabilitation program is initiated. During this phase, stretching and flexibility exercises are performed to enhance strength, power, and endurance. During this phase the patient is placed on the advanced Thrower’s Ten program. Isotonic strengthening exercises are progressed, and at week 12, the athlete is allowed to begin an isotonic lifting program, including bench press, seated rowing, latissimus dorsi pull downs, triceps push downs, and biceps curls. In addition, the athlete performs specific exercises to emphasize sport-specific movements. At week 12, overhead athletes begin a 2-hand plyometric throwing program, and at 14 weeks, a 1-hand plyometric throwing program. Furthermore, endurance exercises, core stability, and leg strengthening are emphasized during phase III. Phase IV, the return to activity phase (week 16 and beyond), is characterized by the initiation of an interval throwing program. The patient is instructed to continue his stretching and strengthening program. An interval throwing program off the mound is gradually initiated at 5 to 6 months postoperative and a gradual return to competition is initiated for pitchers at 9 months and for position players 6 to 7 months postoperative.

Discussion

Results after ulnar collateral reconstruction have been good. In our series of 743 patients, 83% returned to the same or higher level at an average of 11.6 months.¹⁶ There was a 4% major complication rate and 16% minor complication rate. Major complications included medial epicondyle fracture (0.5%), significant ulnar nerve dysfunction (1 patient), rupture of graft (1%), and graft site infection. Sixteen percent of patients had ulnar nerve dysfunction, and 82% of these resolved within 6 weeks. All but 1 patient’s paresthesias resolved within 1 year.¹⁶ The 10-year follow-up of this group of patients included 256 patients and was reported by Osbahr and colleagues³¹ in 2014. Retirement from baseball was due to reasons other than the elbow in 86%, and 98% were still able to throw on at least a recreational level. The overall longevity was 3.6 years, with 2.9 years at pre-injury level or higher. Statistically, pitchers performed at a higher level after reconstruction.³¹

A recent review by Erickson and colleagues⁹ showed an overall 82% excellent and 8% good result when evaluating different techniques, including the American Sports Medicine Institute (ASMI) modification of Jobe’s technique, docking technique, and Jobe’s technique. With an overall complication rate of 10% (75% of which was transient ulnar neuritis), the procedure was deemed overall a safe surgical option. Collegiate athletes had the highest return to sport (95%) compared with high school athletes (89%) and professional athletes (86%). The docking technique had the highest rate of return to play (97%) compared with ASMI technique (93%) and Jobe technique (66%).⁹ Results after repair have not been as good as reconstruction, as reported in 2 studies.^16,32 Savoie and colleagues,¹⁵ however, reported 93% good/excellent results after primary UCL repair alone.

Another recent review of outcomes showed an overall return to same or higher level was best with docking or modified docking techniques (90.4% and 91.3%, respectively).¹⁹ Overall return with modified Jobe technique was 77%.¹⁹ O’Brien and colleagues²⁰ performed a review of 33 patients with either modified Jobe or docking technique that showed 81% return to same or higher level with modified Jobe vs 92% with docking technique. The Kerlan-Jobe Orthopaedic Clinic scores were higher in the modified Jobe group (79 vs 74) and the docking technique group returned to play nearly 1 month sooner (12.4 months vs 11.8 months).²⁰ However, comparing different techniques in a heterogenous patient population over 40 years is difficult. Many of the modified Jobe technique cases were performed in the early evolution of the rehabilitation and return-to-play programs. We believe that the current modified Jobe technique has results equal to any other variation.

Despite good results with reconstructions, the recovery is lengthy and most pitchers cannot fully return to competition level for 12 to 18 months. Extensive research has been performed in exploring alternatives to the traditional reconstruction. Advancements in orthobiologics and development of new surgical options seem to provide an alternative to reconstruction, and may allow faster return to competition with less morbidity.

PRP has been at the forefront of orthopedic research for the last 2 decades, mostly focused in tendon and bone healing. Due to the release of many inflammatory mediators, PRP is theorized to initiate a healing response with growth factors that can direct healing towards normal tissue.³³ Two main types of PRP are reported based on the presence or absence of leukocytes. PRP has been studied in many applications, but only one clinical study on the UCL has been published to date. Podesta and colleagues²³ injected PRP into the elbow of 34 baseball players with MRI-confirmed partial UCL tear. The athletes then underwent a rehabilitation program, which limited stress across the UCL. Type 1A PRP was used (leukocyte-rich, unactivated, 5x or greater platelet concentration³³). Athletes were allowed to return to sport based on symptoms and examination findings. Eighty-eight percent returned to same level of play without complaints at average 70 week follow-up, and average return to play ranged from 10 to 15 weeks.²³ No specific data were given on the 16 pitchers in the group, but with such a high rate of return, PRP needs to be further evaluated in the treatment of UCL injuries.

Another recent study from Dugas and colleagues¹⁸ presented primary UCL repair using a tape augment (InternalBrace, Arthrex). Nine matched cadaver elbows underwent UCL sectioning and then either modified Jobe reconstruction or primary repair of the UCL with placement of the InternalBrace. The biomechanical data showed the repair with internal brace to have slightly less gap, more stiffness, and higher failure strength, although these findings were not statistically significant.¹⁸ This bone-preserving technique with less exposure and healing of the native ligament may be another step towards good results with a quicker return to throwing.

Conclusion

UCL injuries can be disabling in throwers. Reconstruction has afforded throwers a high rate of return to preinjury function or better, and several techniques have been presented that produce acceptable results. Overall complication rates range from 10% to 15%, and the majority of complications are transient ulnar neuropraxias. Orthobiologics and repair with augmentation have more recently offered additional options that may improve success of nonoperative treatment or allow less-invasive surgical treatment. Increased involvement in youth sports and early specialization is driving injury rates in young athletes. The orthopedic community must continue to look for better ways to prevent these injuries and investigate better methods to return athletes to high-level competition.

Am J Orthop. 2016;45(7):E534-E540. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

The ulnar collateral ligament (UCL) is the primary restraint to valgus stress between 20° and 125° of motion.^1-5 Overhead athletes, most commonly baseball pitchers, are at risk of developing UCL insufficiency, and dysfunction presents as pain with loss of velocity and control. Some injuries may present acutely while throwing, but many patients, when questioned, report a preceding period of either pain or loss of velocity and control.

Authors have documented a significant rise in elbow injuries in young athletes, especially pitchers.⁶ Extended seasons, higher pitch counts, year-round pitching, pitching while fatigued, and pitching for multiple teams are risk factors for elbow injuries.⁷ Pitchers in the southern United States are more likely to undergo UCL reconstruction than those from the northern states.⁸ Pitchers who also play catcher are at a higher risk due to more total throws than those who pitch and play other positions or pitch only. Throwers with higher velocity are more likely to pitch in showcases, pitch for multiple teams, and pitch with pain and fatigue, and these are all risk factors.⁶ Also, in one study of youth baseball injuries, individuals in the injured group were found to be taller and heavier than those in the uninjured group.⁶ Pitch counts, rest from pitching during the off-season, adequate rest, and ensuring pain-free pitching can lessen the risk of injury.⁶ As expected with the rise in throwing injuries, the rise in medial elbow procedures has risen.⁹

While throwing, stress across the medial elbow has been measured to be nearly 300 N. A maximum varus force during pitching was measured to be 64 N-m at 95° ± 14°.¹⁰ Morrey and An⁴ determined that the UCL generated 54% of the varus force at 90° of flexion. During active pitching, this value is likely reduced due to simultaneous muscle contraction, but if one assumes the UCL bears 54% of the maximal load, the UCL must be able to withstand 34 N-m. The UCL can withstand a maximum valgus torque between 22.7 and 34 N-m^11-13; therefore, during pitching, the UCL is at or above its failure load. After thousands of cycles over many years, one can imagine how the UCL might be injured.

Multiple techniques have been proposed in the surgical treatment of UCL injuries. Jobe¹⁴ pioneered UCL reconstruction in 1974 in Tommy John, a Major League Baseball pitcher. John returned to pitch successfully, and both the UCL and the reconstruction are commonly called by his name. Jobe¹⁴ reported his technique in 1986, and it has remained, with a few modifications, the primary method for reconstruction of the UCL (Figure 1).

Evaluation

A standard evaluation with physical examination and imaging is completed in all throwers with elbow pain. In our prior study,¹⁶ we found that 100% of patients experienced pain during athletic activity and that 96% of throwers complained of pain during late cocking and acceleration phases of the throwing motion. Nearly half reported an acute onset of pain, while 53% were unable to identify a single inciting event. Seventy-five percent of the acute injuries were during competition. Delayed diagnosis was very common, with an average time to diagnosis after onset of symptoms of 6.4 months. Neurologic symptoms were seen in 23% of athletes, most of which were ulnar nerve paresthesias during throwing.¹⁶

Physical examination includes inspection for swelling, hand intrinsic atrophy, neurovascular examination, range of motion, shoulder examination, and elbow stress examination. Range of motion at presentation averaged 5° to 135° with 85° of supination and pronation.¹⁶ All patients need neurologic evaluation for ulnar nerve dysfunction. Tinel test of the cubital tunnel was positive in 21%.¹⁶ Significant ulnar nerve dysfunction, including hand weakness, is much less common but must be well examined and documented. The shoulder must also be evaluated for loss of rotation, which can lead to increased stress on the elbow. An evaluation of mechanics may point out flaws in technique, which may be contributing to elbow stress. The UCL stress examination includes static stress at 30° of flexion, the milking test at 90°, and the moving valgus stress test. The presence of pain directly over the UCL or laxity compared to the uninvolved side is suggestive of UCL injury.

Radiographic evaluation is completed in all patients with concern for UCL injury. Standard x-rays of the elbow, including anteroposterior, medial, and lateral obliques, axial olecranon, and lateral views, are obtained to evaluate bony abnormalities. Fifty-seven percent of our series showed some abnormality, most commonly olecranon osteophyte formation or ectopic calcification within the UCL substance. Stress radiography rarely changed the treatment course and is somewhat difficult to interpret because of the reports documenting normal increased medial elbow opening in the dominant arm of throwing athletes.²¹ Magnetic resonance imaging (MRI) is obtained very commonly in this patient population, and intra-articular contrast is crucial. Partial, undersurface tears are common, and a contrasted study better demonstrates undersurface tears or avulsions. The T-sign as described by Timmerman and colleagues²² using computed tomography (CT) arthrography shows partial undersurface detachment, which can be difficult to see without intra-articular contrast.²² This finding is very well visualized on MRI arthrogram as well (Figure 3).

Nonoperative Management

Nonoperative treatment is recommended for 3 months prior to performing reconstruction. Patients are given complete rest from throwing, but rehabilitation is initiated immediately. Rehabilitation exercises and nonsteroidal anti-inflammatory medications are prescribed, and activities that place valgus stress across the elbow are avoided. After resolution of symptoms, an interval throwing program is initiated, and the athlete is gradually returned to sport. Unfortunately, due to season-specific schedules and time-sensitive demands in high-level throwers, operative treatment is often chosen without an extended period of conservative treatment.

Platelet-rich plasma (PRP) therapy has recently been shown to improve healing rates and promote healing in partial UCL tears,²³ and as orthobiologics are advanced, they will likely play a larger role in the treatment of UCL injuries.

Surgical Technique

At our institution, UCL reconstruction is performed with the modified Jobe technique as described by Azar and colleagues.¹⁷ Arthroscopy prior to reconstruction was routinely performed at our institution until we recognized that arthroscopy rarely changed the preoperative plan.¹⁶ Currently, the presence of anterior pathology such as loose bodies or osteochondral defect is our only indication for arthroscopy before reconstruction.

Ipsilateral palmaris autograft is our current graft of choice. This must be examined preoperatively because 16% of patients have unilateral absence and 9% have bilateral absence.²⁴ In revision cases or in patients with insufficient or absent palmaris, contralateral palmaris followed by contralateral gracilis tendon is used. The contralateral gracilis is chosen because of ease of setup and position of the surgeon during the harvest. Gracilis tendon is also used in cases with bony involvement of the ligament based on the results from Dugas and colleagues.²⁵ Toe extensors, plantaris, and patellar tendon grafts have also been used. One recent study showed that neither graft choice nor diameter affected resistance to valgus stress, and that all reconstruction types restored strength at 60° to 120° of flexion.²⁶

Ulnar nerve transposition is performed in all cases regardless of the presence of preoperative nerve symptoms. A complete decompression is completed proximally to the Arcade of Struthers and distally to the deep portion of the flexor carpi ulnaris. A single fascial sling of medial intermuscular septum originating from the epicondylar attachment is used to stabilize the nerve without compression. At wound closure, the deep fascia on the posterior skin flap is also sewn into the cubital tunnel to prevent the nerve from subluxating back into the groove. A single suture is placed distally closing the muscle fascia to prevent propagation of the fascial incision, which can lead to herniation. Transposition is necessary because of the ulnar nerve exposure required in the modified Jobe technique to allow elevation of the deep flexor muscle mass for ligament exposure.

The reconstruction is completed as described by Jobe¹⁴ but with a few modifications as described by Azar and colleagues¹⁷ and slight adaptations implemented since that time. The flexor-pronator mass is retracted laterally instead of detachment or splitting as described by Thompson and colleagues.²⁷ A subcutaneous rather than a submuscular ulnar nerve transposition is used.

The patient is positioned supine using an arm board. If gracilis tendon is chosen, the contralateral leg is prepped and draped simultaneously. A tourniquet is inflated after exsanguination. A medial approach is performed, and the medial antebrachial nerve is located and protected. The ulnar nerve is then located in the cubital tunnel and mobilized. The neurolysis extends to the deep portion of the flexor carpi ulnaris distally and proximally to the Arcade of Struthers, and the nerve is retracted with a vessel loop. The flexor muscle mass is not elevated from the medial epicondyle; rather, it is retracted anteriorly by small Hohmann retractors. The dissection is carried down to the UCL and found at its attachments to the medial epicondyle and sublime tubercle. If no tear is seen on the superficial surface of the ligament, a longitudinal incision is made through the ligament. Undersurface tears, partial tears, and avulsions can then be identified (Figure 4).

Postoperative Rehabilitation

A standardized postoperative 4-phase rehabilitation program for ulnar collateral reconstruction is followed as described by Wilk and colleagues.^28-30 The first phase begins immediately after surgery and continues for 4 weeks. During surgery, the patient’s elbow is placed in a compression dressing with a posterior splint to immobilize the elbow in 90° of flexion with wrist motion for 1 week to allow initial healing. Full range of motion of the elbow joint is restored by the end of the fifth to sixth week after surgery.

During phase II (weeks 4-10), a progressive isotonic strengthening program is initiated. Exercises are focused on scapular, rotator cuff, deltoid, and arm musculature. Shoulder range of motion and stretching exercises are performed during this phase and the Thrower’s Ten exercise program is initiated. Any adaptations or strength deficits are addressed during this phase.

During the advanced strengthening phase (phase III), from weeks 10 to 16, a sport-specific exercise/rehabilitation program is initiated. During this phase, stretching and flexibility exercises are performed to enhance strength, power, and endurance. During this phase the patient is placed on the advanced Thrower’s Ten program. Isotonic strengthening exercises are progressed, and at week 12, the athlete is allowed to begin an isotonic lifting program, including bench press, seated rowing, latissimus dorsi pull downs, triceps push downs, and biceps curls. In addition, the athlete performs specific exercises to emphasize sport-specific movements. At week 12, overhead athletes begin a 2-hand plyometric throwing program, and at 14 weeks, a 1-hand plyometric throwing program. Furthermore, endurance exercises, core stability, and leg strengthening are emphasized during phase III. Phase IV, the return to activity phase (week 16 and beyond), is characterized by the initiation of an interval throwing program. The patient is instructed to continue his stretching and strengthening program. An interval throwing program off the mound is gradually initiated at 5 to 6 months postoperative and a gradual return to competition is initiated for pitchers at 9 months and for position players 6 to 7 months postoperative.

Discussion

Results after ulnar collateral reconstruction have been good. In our series of 743 patients, 83% returned to the same or higher level at an average of 11.6 months.¹⁶ There was a 4% major complication rate and 16% minor complication rate. Major complications included medial epicondyle fracture (0.5%), significant ulnar nerve dysfunction (1 patient), rupture of graft (1%), and graft site infection. Sixteen percent of patients had ulnar nerve dysfunction, and 82% of these resolved within 6 weeks. All but 1 patient’s paresthesias resolved within 1 year.¹⁶ The 10-year follow-up of this group of patients included 256 patients and was reported by Osbahr and colleagues³¹ in 2014. Retirement from baseball was due to reasons other than the elbow in 86%, and 98% were still able to throw on at least a recreational level. The overall longevity was 3.6 years, with 2.9 years at pre-injury level or higher. Statistically, pitchers performed at a higher level after reconstruction.³¹

A recent review by Erickson and colleagues⁹ showed an overall 82% excellent and 8% good result when evaluating different techniques, including the American Sports Medicine Institute (ASMI) modification of Jobe’s technique, docking technique, and Jobe’s technique. With an overall complication rate of 10% (75% of which was transient ulnar neuritis), the procedure was deemed overall a safe surgical option. Collegiate athletes had the highest return to sport (95%) compared with high school athletes (89%) and professional athletes (86%). The docking technique had the highest rate of return to play (97%) compared with ASMI technique (93%) and Jobe technique (66%).⁹ Results after repair have not been as good as reconstruction, as reported in 2 studies.^16,32 Savoie and colleagues,¹⁵ however, reported 93% good/excellent results after primary UCL repair alone.

Another recent review of outcomes showed an overall return to same or higher level was best with docking or modified docking techniques (90.4% and 91.3%, respectively).¹⁹ Overall return with modified Jobe technique was 77%.¹⁹ O’Brien and colleagues²⁰ performed a review of 33 patients with either modified Jobe or docking technique that showed 81% return to same or higher level with modified Jobe vs 92% with docking technique. The Kerlan-Jobe Orthopaedic Clinic scores were higher in the modified Jobe group (79 vs 74) and the docking technique group returned to play nearly 1 month sooner (12.4 months vs 11.8 months).²⁰ However, comparing different techniques in a heterogenous patient population over 40 years is difficult. Many of the modified Jobe technique cases were performed in the early evolution of the rehabilitation and return-to-play programs. We believe that the current modified Jobe technique has results equal to any other variation.

Despite good results with reconstructions, the recovery is lengthy and most pitchers cannot fully return to competition level for 12 to 18 months. Extensive research has been performed in exploring alternatives to the traditional reconstruction. Advancements in orthobiologics and development of new surgical options seem to provide an alternative to reconstruction, and may allow faster return to competition with less morbidity.

PRP has been at the forefront of orthopedic research for the last 2 decades, mostly focused in tendon and bone healing. Due to the release of many inflammatory mediators, PRP is theorized to initiate a healing response with growth factors that can direct healing towards normal tissue.³³ Two main types of PRP are reported based on the presence or absence of leukocytes. PRP has been studied in many applications, but only one clinical study on the UCL has been published to date. Podesta and colleagues²³ injected PRP into the elbow of 34 baseball players with MRI-confirmed partial UCL tear. The athletes then underwent a rehabilitation program, which limited stress across the UCL. Type 1A PRP was used (leukocyte-rich, unactivated, 5x or greater platelet concentration³³). Athletes were allowed to return to sport based on symptoms and examination findings. Eighty-eight percent returned to same level of play without complaints at average 70 week follow-up, and average return to play ranged from 10 to 15 weeks.²³ No specific data were given on the 16 pitchers in the group, but with such a high rate of return, PRP needs to be further evaluated in the treatment of UCL injuries.

Another recent study from Dugas and colleagues¹⁸ presented primary UCL repair using a tape augment (InternalBrace, Arthrex). Nine matched cadaver elbows underwent UCL sectioning and then either modified Jobe reconstruction or primary repair of the UCL with placement of the InternalBrace. The biomechanical data showed the repair with internal brace to have slightly less gap, more stiffness, and higher failure strength, although these findings were not statistically significant.¹⁸ This bone-preserving technique with less exposure and healing of the native ligament may be another step towards good results with a quicker return to throwing.

Conclusion

UCL injuries can be disabling in throwers. Reconstruction has afforded throwers a high rate of return to preinjury function or better, and several techniques have been presented that produce acceptable results. Overall complication rates range from 10% to 15%, and the majority of complications are transient ulnar neuropraxias. Orthobiologics and repair with augmentation have more recently offered additional options that may improve success of nonoperative treatment or allow less-invasive surgical treatment. Increased involvement in youth sports and early specialization is driving injury rates in young athletes. The orthopedic community must continue to look for better ways to prevent these injuries and investigate better methods to return athletes to high-level competition.

Am J Orthop. 2016;45(7):E534-E540. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

The ulnar collateral ligament (UCL) is the primary restraint to valgus stress between 20° and 125° of motion.^1-5 Overhead athletes, most commonly baseball pitchers, are at risk of developing UCL insufficiency, and dysfunction presents as pain with loss of velocity and control. Some injuries may present acutely while throwing, but many patients, when questioned, report a preceding period of either pain or loss of velocity and control.

Authors have documented a significant rise in elbow injuries in young athletes, especially pitchers.⁶ Extended seasons, higher pitch counts, year-round pitching, pitching while fatigued, and pitching for multiple teams are risk factors for elbow injuries.⁷ Pitchers in the southern United States are more likely to undergo UCL reconstruction than those from the northern states.⁸ Pitchers who also play catcher are at a higher risk due to more total throws than those who pitch and play other positions or pitch only. Throwers with higher velocity are more likely to pitch in showcases, pitch for multiple teams, and pitch with pain and fatigue, and these are all risk factors.⁶ Also, in one study of youth baseball injuries, individuals in the injured group were found to be taller and heavier than those in the uninjured group.⁶ Pitch counts, rest from pitching during the off-season, adequate rest, and ensuring pain-free pitching can lessen the risk of injury.⁶ As expected with the rise in throwing injuries, the rise in medial elbow procedures has risen.⁹

While throwing, stress across the medial elbow has been measured to be nearly 300 N. A maximum varus force during pitching was measured to be 64 N-m at 95° ± 14°.¹⁰ Morrey and An⁴ determined that the UCL generated 54% of the varus force at 90° of flexion. During active pitching, this value is likely reduced due to simultaneous muscle contraction, but if one assumes the UCL bears 54% of the maximal load, the UCL must be able to withstand 34 N-m. The UCL can withstand a maximum valgus torque between 22.7 and 34 N-m^11-13; therefore, during pitching, the UCL is at or above its failure load. After thousands of cycles over many years, one can imagine how the UCL might be injured.

Multiple techniques have been proposed in the surgical treatment of UCL injuries. Jobe¹⁴ pioneered UCL reconstruction in 1974 in Tommy John, a Major League Baseball pitcher. John returned to pitch successfully, and both the UCL and the reconstruction are commonly called by his name. Jobe¹⁴ reported his technique in 1986, and it has remained, with a few modifications, the primary method for reconstruction of the UCL (Figure 1).

Evaluation

A standard evaluation with physical examination and imaging is completed in all throwers with elbow pain. In our prior study,¹⁶ we found that 100% of patients experienced pain during athletic activity and that 96% of throwers complained of pain during late cocking and acceleration phases of the throwing motion. Nearly half reported an acute onset of pain, while 53% were unable to identify a single inciting event. Seventy-five percent of the acute injuries were during competition. Delayed diagnosis was very common, with an average time to diagnosis after onset of symptoms of 6.4 months. Neurologic symptoms were seen in 23% of athletes, most of which were ulnar nerve paresthesias during throwing.¹⁶

Physical examination includes inspection for swelling, hand intrinsic atrophy, neurovascular examination, range of motion, shoulder examination, and elbow stress examination. Range of motion at presentation averaged 5° to 135° with 85° of supination and pronation.¹⁶ All patients need neurologic evaluation for ulnar nerve dysfunction. Tinel test of the cubital tunnel was positive in 21%.¹⁶ Significant ulnar nerve dysfunction, including hand weakness, is much less common but must be well examined and documented. The shoulder must also be evaluated for loss of rotation, which can lead to increased stress on the elbow. An evaluation of mechanics may point out flaws in technique, which may be contributing to elbow stress. The UCL stress examination includes static stress at 30° of flexion, the milking test at 90°, and the moving valgus stress test. The presence of pain directly over the UCL or laxity compared to the uninvolved side is suggestive of UCL injury.

Radiographic evaluation is completed in all patients with concern for UCL injury. Standard x-rays of the elbow, including anteroposterior, medial, and lateral obliques, axial olecranon, and lateral views, are obtained to evaluate bony abnormalities. Fifty-seven percent of our series showed some abnormality, most commonly olecranon osteophyte formation or ectopic calcification within the UCL substance. Stress radiography rarely changed the treatment course and is somewhat difficult to interpret because of the reports documenting normal increased medial elbow opening in the dominant arm of throwing athletes.²¹ Magnetic resonance imaging (MRI) is obtained very commonly in this patient population, and intra-articular contrast is crucial. Partial, undersurface tears are common, and a contrasted study better demonstrates undersurface tears or avulsions. The T-sign as described by Timmerman and colleagues²² using computed tomography (CT) arthrography shows partial undersurface detachment, which can be difficult to see without intra-articular contrast.²² This finding is very well visualized on MRI arthrogram as well (Figure 3).

Nonoperative Management

Nonoperative treatment is recommended for 3 months prior to performing reconstruction. Patients are given complete rest from throwing, but rehabilitation is initiated immediately. Rehabilitation exercises and nonsteroidal anti-inflammatory medications are prescribed, and activities that place valgus stress across the elbow are avoided. After resolution of symptoms, an interval throwing program is initiated, and the athlete is gradually returned to sport. Unfortunately, due to season-specific schedules and time-sensitive demands in high-level throwers, operative treatment is often chosen without an extended period of conservative treatment.

Platelet-rich plasma (PRP) therapy has recently been shown to improve healing rates and promote healing in partial UCL tears,²³ and as orthobiologics are advanced, they will likely play a larger role in the treatment of UCL injuries.

Surgical Technique

At our institution, UCL reconstruction is performed with the modified Jobe technique as described by Azar and colleagues.¹⁷ Arthroscopy prior to reconstruction was routinely performed at our institution until we recognized that arthroscopy rarely changed the preoperative plan.¹⁶ Currently, the presence of anterior pathology such as loose bodies or osteochondral defect is our only indication for arthroscopy before reconstruction.

Ipsilateral palmaris autograft is our current graft of choice. This must be examined preoperatively because 16% of patients have unilateral absence and 9% have bilateral absence.²⁴ In revision cases or in patients with insufficient or absent palmaris, contralateral palmaris followed by contralateral gracilis tendon is used. The contralateral gracilis is chosen because of ease of setup and position of the surgeon during the harvest. Gracilis tendon is also used in cases with bony involvement of the ligament based on the results from Dugas and colleagues.²⁵ Toe extensors, plantaris, and patellar tendon grafts have also been used. One recent study showed that neither graft choice nor diameter affected resistance to valgus stress, and that all reconstruction types restored strength at 60° to 120° of flexion.²⁶

Ulnar nerve transposition is performed in all cases regardless of the presence of preoperative nerve symptoms. A complete decompression is completed proximally to the Arcade of Struthers and distally to the deep portion of the flexor carpi ulnaris. A single fascial sling of medial intermuscular septum originating from the epicondylar attachment is used to stabilize the nerve without compression. At wound closure, the deep fascia on the posterior skin flap is also sewn into the cubital tunnel to prevent the nerve from subluxating back into the groove. A single suture is placed distally closing the muscle fascia to prevent propagation of the fascial incision, which can lead to herniation. Transposition is necessary because of the ulnar nerve exposure required in the modified Jobe technique to allow elevation of the deep flexor muscle mass for ligament exposure.

The reconstruction is completed as described by Jobe¹⁴ but with a few modifications as described by Azar and colleagues¹⁷ and slight adaptations implemented since that time. The flexor-pronator mass is retracted laterally instead of detachment or splitting as described by Thompson and colleagues.²⁷ A subcutaneous rather than a submuscular ulnar nerve transposition is used.

The patient is positioned supine using an arm board. If gracilis tendon is chosen, the contralateral leg is prepped and draped simultaneously. A tourniquet is inflated after exsanguination. A medial approach is performed, and the medial antebrachial nerve is located and protected. The ulnar nerve is then located in the cubital tunnel and mobilized. The neurolysis extends to the deep portion of the flexor carpi ulnaris distally and proximally to the Arcade of Struthers, and the nerve is retracted with a vessel loop. The flexor muscle mass is not elevated from the medial epicondyle; rather, it is retracted anteriorly by small Hohmann retractors. The dissection is carried down to the UCL and found at its attachments to the medial epicondyle and sublime tubercle. If no tear is seen on the superficial surface of the ligament, a longitudinal incision is made through the ligament. Undersurface tears, partial tears, and avulsions can then be identified (Figure 4).

Postoperative Rehabilitation

A standardized postoperative 4-phase rehabilitation program for ulnar collateral reconstruction is followed as described by Wilk and colleagues.^28-30 The first phase begins immediately after surgery and continues for 4 weeks. During surgery, the patient’s elbow is placed in a compression dressing with a posterior splint to immobilize the elbow in 90° of flexion with wrist motion for 1 week to allow initial healing. Full range of motion of the elbow joint is restored by the end of the fifth to sixth week after surgery.

During phase II (weeks 4-10), a progressive isotonic strengthening program is initiated. Exercises are focused on scapular, rotator cuff, deltoid, and arm musculature. Shoulder range of motion and stretching exercises are performed during this phase and the Thrower’s Ten exercise program is initiated. Any adaptations or strength deficits are addressed during this phase.

During the advanced strengthening phase (phase III), from weeks 10 to 16, a sport-specific exercise/rehabilitation program is initiated. During this phase, stretching and flexibility exercises are performed to enhance strength, power, and endurance. During this phase the patient is placed on the advanced Thrower’s Ten program. Isotonic strengthening exercises are progressed, and at week 12, the athlete is allowed to begin an isotonic lifting program, including bench press, seated rowing, latissimus dorsi pull downs, triceps push downs, and biceps curls. In addition, the athlete performs specific exercises to emphasize sport-specific movements. At week 12, overhead athletes begin a 2-hand plyometric throwing program, and at 14 weeks, a 1-hand plyometric throwing program. Furthermore, endurance exercises, core stability, and leg strengthening are emphasized during phase III. Phase IV, the return to activity phase (week 16 and beyond), is characterized by the initiation of an interval throwing program. The patient is instructed to continue his stretching and strengthening program. An interval throwing program off the mound is gradually initiated at 5 to 6 months postoperative and a gradual return to competition is initiated for pitchers at 9 months and for position players 6 to 7 months postoperative.

Discussion

Results after ulnar collateral reconstruction have been good. In our series of 743 patients, 83% returned to the same or higher level at an average of 11.6 months.¹⁶ There was a 4% major complication rate and 16% minor complication rate. Major complications included medial epicondyle fracture (0.5%), significant ulnar nerve dysfunction (1 patient), rupture of graft (1%), and graft site infection. Sixteen percent of patients had ulnar nerve dysfunction, and 82% of these resolved within 6 weeks. All but 1 patient’s paresthesias resolved within 1 year.¹⁶ The 10-year follow-up of this group of patients included 256 patients and was reported by Osbahr and colleagues³¹ in 2014. Retirement from baseball was due to reasons other than the elbow in 86%, and 98% were still able to throw on at least a recreational level. The overall longevity was 3.6 years, with 2.9 years at pre-injury level or higher. Statistically, pitchers performed at a higher level after reconstruction.³¹

A recent review by Erickson and colleagues⁹ showed an overall 82% excellent and 8% good result when evaluating different techniques, including the American Sports Medicine Institute (ASMI) modification of Jobe’s technique, docking technique, and Jobe’s technique. With an overall complication rate of 10% (75% of which was transient ulnar neuritis), the procedure was deemed overall a safe surgical option. Collegiate athletes had the highest return to sport (95%) compared with high school athletes (89%) and professional athletes (86%). The docking technique had the highest rate of return to play (97%) compared with ASMI technique (93%) and Jobe technique (66%).⁹ Results after repair have not been as good as reconstruction, as reported in 2 studies.^16,32 Savoie and colleagues,¹⁵ however, reported 93% good/excellent results after primary UCL repair alone.

Another recent review of outcomes showed an overall return to same or higher level was best with docking or modified docking techniques (90.4% and 91.3%, respectively).¹⁹ Overall return with modified Jobe technique was 77%.¹⁹ O’Brien and colleagues²⁰ performed a review of 33 patients with either modified Jobe or docking technique that showed 81% return to same or higher level with modified Jobe vs 92% with docking technique. The Kerlan-Jobe Orthopaedic Clinic scores were higher in the modified Jobe group (79 vs 74) and the docking technique group returned to play nearly 1 month sooner (12.4 months vs 11.8 months).²⁰ However, comparing different techniques in a heterogenous patient population over 40 years is difficult. Many of the modified Jobe technique cases were performed in the early evolution of the rehabilitation and return-to-play programs. We believe that the current modified Jobe technique has results equal to any other variation.

Despite good results with reconstructions, the recovery is lengthy and most pitchers cannot fully return to competition level for 12 to 18 months. Extensive research has been performed in exploring alternatives to the traditional reconstruction. Advancements in orthobiologics and development of new surgical options seem to provide an alternative to reconstruction, and may allow faster return to competition with less morbidity.

PRP has been at the forefront of orthopedic research for the last 2 decades, mostly focused in tendon and bone healing. Due to the release of many inflammatory mediators, PRP is theorized to initiate a healing response with growth factors that can direct healing towards normal tissue.³³ Two main types of PRP are reported based on the presence or absence of leukocytes. PRP has been studied in many applications, but only one clinical study on the UCL has been published to date. Podesta and colleagues²³ injected PRP into the elbow of 34 baseball players with MRI-confirmed partial UCL tear. The athletes then underwent a rehabilitation program, which limited stress across the UCL. Type 1A PRP was used (leukocyte-rich, unactivated, 5x or greater platelet concentration³³). Athletes were allowed to return to sport based on symptoms and examination findings. Eighty-eight percent returned to same level of play without complaints at average 70 week follow-up, and average return to play ranged from 10 to 15 weeks.²³ No specific data were given on the 16 pitchers in the group, but with such a high rate of return, PRP needs to be further evaluated in the treatment of UCL injuries.

Another recent study from Dugas and colleagues¹⁸ presented primary UCL repair using a tape augment (InternalBrace, Arthrex). Nine matched cadaver elbows underwent UCL sectioning and then either modified Jobe reconstruction or primary repair of the UCL with placement of the InternalBrace. The biomechanical data showed the repair with internal brace to have slightly less gap, more stiffness, and higher failure strength, although these findings were not statistically significant.¹⁸ This bone-preserving technique with less exposure and healing of the native ligament may be another step towards good results with a quicker return to throwing.

Conclusion

UCL injuries can be disabling in throwers. Reconstruction has afforded throwers a high rate of return to preinjury function or better, and several techniques have been presented that produce acceptable results. Overall complication rates range from 10% to 15%, and the majority of complications are transient ulnar neuropraxias. Orthobiologics and repair with augmentation have more recently offered additional options that may improve success of nonoperative treatment or allow less-invasive surgical treatment. Increased involvement in youth sports and early specialization is driving injury rates in young athletes. The orthopedic community must continue to look for better ways to prevent these injuries and investigate better methods to return athletes to high-level competition.

Am J Orthop. 2016;45(7):E534-E540. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

“Still Down: What to Do When Antidepressants Fail” by Dean F. MacKinnon, MD, is a compact little book that recently was released by Johns Hopkins University Press. The title, “Still Down,” says it all. At 152 pages, the book is short, but not because it isn’t jammed full of information, but because – like the title – the writing is succinct and straight to the point; there’s no flowery detail, and Dr. MacKinnon doesn’t parse words. He tells the reader up front what his mission is, how the book is organized, and who his audience is. He’s an organized writer who captures the reader while getting his point across.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has known Dr. MacKinnon for many years.

“Still Down: What to Do When Antidepressants Fail” by Dean F. MacKinnon, MD, is a compact little book that recently was released by Johns Hopkins University Press. The title, “Still Down,” says it all. At 152 pages, the book is short, but not because it isn’t jammed full of information, but because – like the title – the writing is succinct and straight to the point; there’s no flowery detail, and Dr. MacKinnon doesn’t parse words. He tells the reader up front what his mission is, how the book is organized, and who his audience is. He’s an organized writer who captures the reader while getting his point across.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has known Dr. MacKinnon for many years.

“Still Down: What to Do When Antidepressants Fail” by Dean F. MacKinnon, MD, is a compact little book that recently was released by Johns Hopkins University Press. The title, “Still Down,” says it all. At 152 pages, the book is short, but not because it isn’t jammed full of information, but because – like the title – the writing is succinct and straight to the point; there’s no flowery detail, and Dr. MacKinnon doesn’t parse words. He tells the reader up front what his mission is, how the book is organized, and who his audience is. He’s an organized writer who captures the reader while getting his point across.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has known Dr. MacKinnon for many years.

U.S.-based researchers have isolated replicative Zika virus RNA from the brain tissue of infants with microcephaly, and the placenta and fetal tissues from women suspected of being infected with Zika virus during pregnancy.

In a paper published online in Emerging Infectious Diseases, Julu Bhatnagar, PhD, of the Infectious Diseases Pathology Branch at the Center for Emerging and Zoonotic Infectious Diseases in Atlanta, and her coauthors reported a case series in 52 patients – 8 infants with microcephaly who died and 44 women thought to have been infected with Zika virus during pregnancy – using Zika virus reverse transcription PCR and in situ hybridization assay to detect the virus.

copyright Devonyu/Thinkstock

[email protected]

On Twitter @idpractitioner

U.S.-based researchers have isolated replicative Zika virus RNA from the brain tissue of infants with microcephaly, and the placenta and fetal tissues from women suspected of being infected with Zika virus during pregnancy.

In a paper published online in Emerging Infectious Diseases, Julu Bhatnagar, PhD, of the Infectious Diseases Pathology Branch at the Center for Emerging and Zoonotic Infectious Diseases in Atlanta, and her coauthors reported a case series in 52 patients – 8 infants with microcephaly who died and 44 women thought to have been infected with Zika virus during pregnancy – using Zika virus reverse transcription PCR and in situ hybridization assay to detect the virus.

copyright Devonyu/Thinkstock

[email protected]

On Twitter @idpractitioner

U.S.-based researchers have isolated replicative Zika virus RNA from the brain tissue of infants with microcephaly, and the placenta and fetal tissues from women suspected of being infected with Zika virus during pregnancy.

In a paper published online in Emerging Infectious Diseases, Julu Bhatnagar, PhD, of the Infectious Diseases Pathology Branch at the Center for Emerging and Zoonotic Infectious Diseases in Atlanta, and her coauthors reported a case series in 52 patients – 8 infants with microcephaly who died and 44 women thought to have been infected with Zika virus during pregnancy – using Zika virus reverse transcription PCR and in situ hybridization assay to detect the virus.

copyright Devonyu/Thinkstock

[email protected]

On Twitter @idpractitioner

Supplement Editor:
Maan A. Fares, MD

Contents

Cardiovascular disease: Innovations in devices and techniques
Maan A. Fares

Transcatheter mitral valve replacement: A frontier in cardiac intervention
Amar Krishnaswamy, Stephanie Mick, Jose Navia, A. Marc Gillinov, E. Murrat Tuzcu, and Samir R. Kapadia

Bioresorbable stents: The future of Interventional cardiology?
Stephen G. Ellis and Haris Riaz

Leadless cardiac pacing: What primary care providers and non-EP cardiologists should know
Erich L. Kiehl and Daniel J. Cantillon

PCSK9 inhibition: A promise fulfilled?
Khendi White, Chaitra Mohan, and Michael Rocco

Fibromuscular dysplasia: Advances in understanding and management
Ellen K. Brinza and Heather L. Gornik

Supplement Editor:
Maan A. Fares, MD

Contents

Cardiovascular disease: Innovations in devices and techniques
Maan A. Fares

Transcatheter mitral valve replacement: A frontier in cardiac intervention
Amar Krishnaswamy, Stephanie Mick, Jose Navia, A. Marc Gillinov, E. Murrat Tuzcu, and Samir R. Kapadia

Bioresorbable stents: The future of Interventional cardiology?
Stephen G. Ellis and Haris Riaz

Leadless cardiac pacing: What primary care providers and non-EP cardiologists should know
Erich L. Kiehl and Daniel J. Cantillon

PCSK9 inhibition: A promise fulfilled?
Khendi White, Chaitra Mohan, and Michael Rocco

Fibromuscular dysplasia: Advances in understanding and management
Ellen K. Brinza and Heather L. Gornik

Supplement Editor:
Maan A. Fares, MD

Contents

Cardiovascular disease: Innovations in devices and techniques
Maan A. Fares

Transcatheter mitral valve replacement: A frontier in cardiac intervention
Amar Krishnaswamy, Stephanie Mick, Jose Navia, A. Marc Gillinov, E. Murrat Tuzcu, and Samir R. Kapadia

Bioresorbable stents: The future of Interventional cardiology?
Stephen G. Ellis and Haris Riaz

Leadless cardiac pacing: What primary care providers and non-EP cardiologists should know
Erich L. Kiehl and Daniel J. Cantillon

PCSK9 inhibition: A promise fulfilled?
Khendi White, Chaitra Mohan, and Michael Rocco

Fibromuscular dysplasia: Advances in understanding and management
Ellen K. Brinza and Heather L. Gornik

ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.

“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”

The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.

Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”

Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).

The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.

Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”

Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.

Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”

“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”

So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).

Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.

To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”

The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”

Safety profile

So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”

Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”

In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.

“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”

Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”

One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”

“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”

“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.

ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.

“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”

The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.

Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”

Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).

The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.

Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”

Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.

Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”

“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”

So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).

Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.

To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”

The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”

Safety profile

So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”

Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”

In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.

“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”

Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”

One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”

“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”

“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.

ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.

“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”

The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.

Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”

Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).

The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.

Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”

Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.

Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”

“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”

So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).

Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.

To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”

The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”

Safety profile

So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”

Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”

In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.

“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”

Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”

One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”

“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”

“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.

Hospital-acquired pneumonia (HAP) is pneumonia that presents at least 48 hours after admission to the hospital. In contrast, ventilator-associated pneumonia (VAP), is pneumonia that clinically presents 48 hours after endotracheal intubation. Together, these are some of the most common hospital-acquired infections in the United States and pose a considerable burden on hospitals nationwide.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recently updated their management guidelines for HAP and VAP with a goal of striking a balance between providing appropriate early antibiotic coverage and avoiding unnecessary treatment that can lead to adverse effects such as Clostridium difficile infections and development of antibiotic resistance.¹ This update eliminated the concept of Healthcare Associated Pneumonia (HCAP), often used for patients in skilled care facilities, because newer evidence has shown that patients who had met these criteria did not have a higher incidence of multidrug resistant pathogens; rather, they have microbial etiologies and sensitivities that are similar to adults with community acquired pneumonia (CAP).

Hospital-acquired pneumonia

MRSA should be covered with use of either vancomycin or linezolid in these cases.

Use two antipseudomonal antibiotics in HAP if the patient has these risk factors:

Pseudomonas risk factors:

• IV antibiotic treatment within 90 days

• Structural lung disease increasing the risk of gram-negative infection (bronchiectasis, cystic fibrosis)

• High-quality gram stain from respiratory specimen showing predominant and numerous gram-negative bacilli

High risk of mortality:

• Septic shock

• Need for ventilator support

Ventilator-associated pneumonia

General management of VAP is similar to HAP in that empiric treatment should be tailored to the local distribution and susceptibilities of pathogens based on each hospital’s antibiogram. All regimens should cover for S. aureus, P. aeruginosa, and other gram-negative bacilli based on the risk of mortality associated with the need for ventilator support. MSSA should be covered for VAP unless the patient has methicillin-resistant risk factors (see below).

MRSA should be covered for VAP if:

• Patient has had IV antibiotic use within past 90 days

• Hospital unit has greater than 10%-20% of S. aureus isolates are MRSA or MRSA prevalence unknown

Only one antipseudomonal agent should be used unless there are one of the following characteristics present, as described below.

Use two antipseudomonal agents in VAP if:

• Prior IV antibiotic use within 90 days

• Septic shock at time of VAP

• Acute respiratory distress syndrome preceding VAP

• 5 or more days of hospitalization prior to the occurrence of VAP

• Acute renal replacement therapy prior to VAP onset

• Greater than 10% of gram-negative isolates are resistant to an agent being considered for monotherapy

• Local antibiotic susceptibility rates unknown

In both HAP and VAP, antibiotics should be de-escalated to those with a narrower spectrum after initial empiric therapy, ideally within 72 hours and based on sputum or blood culture results. The guidelines support obtaining noninvasive sputum cultures in patients with VAP (endotracheal aspirates) and HAP (spontaneous expectoration, induced sputum, or nasotracheal suctioning in a patient who is unable to cooperate to produce a sputum sample). Patients who are improving clinically may be switched to appropriate oral therapy based on the susceptibility of an identified organism. Another key change is that of the standard duration of therapy. Previously, patients were treated for up to 2-3 weeks with antibiotics. The new IDSA/ATS guidelines recommend that patients should be treated with 7 days of antibiotics rather than a longer course.

The bottom line

Empiric therapy for HAP and VAP should be tailored to each hospital’s local pathogen distribution and antimicrobial susceptibilities, as detailed in an antibiogram. In HAP and VAP, empiric antibiotics should cover for S. aureus, but it only needs to target MRSA if risk factors are present, prevalence is greater than 20% or unknown, and – if HAP – a high risk of mortality. P. aeruginosa and other gram-negative bacilli should also be covered in empiric regimens. Dual antipseudomonal antibiotics is only recommended to be used in HAP if there are specific pseudomonal risk factors or a high risk of mortality. They should be used in VAP if there are multidrug-resistant risk factors present or there is a high/unknown prevalence of resistant organisms. All antibiotic regimens should be deescalated rather than maintained, and both HAP and VAP patients ought to be treated for 7 days.

References

1. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):557-82.

2. Beardsley JR, Williamson JC, Johnson JW, Ohl CA, Karchmer TB, Bowton DL. Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest. 2006 Sep;130(3):787-93.

Dr. Botti is a second-year resident in the family medicine residency program department of family and community medicine at Jefferson Medical College, Philadelphia. Dr. Mills is assistant residency program director and assistant professor in the department of family and community medicine and department of physiology at Jefferson Medical College, Philadelphia. Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia.

Hospital-acquired pneumonia (HAP) is pneumonia that presents at least 48 hours after admission to the hospital. In contrast, ventilator-associated pneumonia (VAP), is pneumonia that clinically presents 48 hours after endotracheal intubation. Together, these are some of the most common hospital-acquired infections in the United States and pose a considerable burden on hospitals nationwide.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recently updated their management guidelines for HAP and VAP with a goal of striking a balance between providing appropriate early antibiotic coverage and avoiding unnecessary treatment that can lead to adverse effects such as Clostridium difficile infections and development of antibiotic resistance.¹ This update eliminated the concept of Healthcare Associated Pneumonia (HCAP), often used for patients in skilled care facilities, because newer evidence has shown that patients who had met these criteria did not have a higher incidence of multidrug resistant pathogens; rather, they have microbial etiologies and sensitivities that are similar to adults with community acquired pneumonia (CAP).

Hospital-acquired pneumonia

MRSA should be covered with use of either vancomycin or linezolid in these cases.

Use two antipseudomonal antibiotics in HAP if the patient has these risk factors:

Pseudomonas risk factors:

• IV antibiotic treatment within 90 days

• Structural lung disease increasing the risk of gram-negative infection (bronchiectasis, cystic fibrosis)

• High-quality gram stain from respiratory specimen showing predominant and numerous gram-negative bacilli

High risk of mortality:

• Septic shock

• Need for ventilator support

Ventilator-associated pneumonia

General management of VAP is similar to HAP in that empiric treatment should be tailored to the local distribution and susceptibilities of pathogens based on each hospital’s antibiogram. All regimens should cover for S. aureus, P. aeruginosa, and other gram-negative bacilli based on the risk of mortality associated with the need for ventilator support. MSSA should be covered for VAP unless the patient has methicillin-resistant risk factors (see below).

MRSA should be covered for VAP if:

• Patient has had IV antibiotic use within past 90 days

• Hospital unit has greater than 10%-20% of S. aureus isolates are MRSA or MRSA prevalence unknown

Only one antipseudomonal agent should be used unless there are one of the following characteristics present, as described below.

Use two antipseudomonal agents in VAP if:

• Prior IV antibiotic use within 90 days

• Septic shock at time of VAP

• Acute respiratory distress syndrome preceding VAP

• 5 or more days of hospitalization prior to the occurrence of VAP

• Acute renal replacement therapy prior to VAP onset

• Greater than 10% of gram-negative isolates are resistant to an agent being considered for monotherapy

• Local antibiotic susceptibility rates unknown

In both HAP and VAP, antibiotics should be de-escalated to those with a narrower spectrum after initial empiric therapy, ideally within 72 hours and based on sputum or blood culture results. The guidelines support obtaining noninvasive sputum cultures in patients with VAP (endotracheal aspirates) and HAP (spontaneous expectoration, induced sputum, or nasotracheal suctioning in a patient who is unable to cooperate to produce a sputum sample). Patients who are improving clinically may be switched to appropriate oral therapy based on the susceptibility of an identified organism. Another key change is that of the standard duration of therapy. Previously, patients were treated for up to 2-3 weeks with antibiotics. The new IDSA/ATS guidelines recommend that patients should be treated with 7 days of antibiotics rather than a longer course.

The bottom line

Empiric therapy for HAP and VAP should be tailored to each hospital’s local pathogen distribution and antimicrobial susceptibilities, as detailed in an antibiogram. In HAP and VAP, empiric antibiotics should cover for S. aureus, but it only needs to target MRSA if risk factors are present, prevalence is greater than 20% or unknown, and – if HAP – a high risk of mortality. P. aeruginosa and other gram-negative bacilli should also be covered in empiric regimens. Dual antipseudomonal antibiotics is only recommended to be used in HAP if there are specific pseudomonal risk factors or a high risk of mortality. They should be used in VAP if there are multidrug-resistant risk factors present or there is a high/unknown prevalence of resistant organisms. All antibiotic regimens should be deescalated rather than maintained, and both HAP and VAP patients ought to be treated for 7 days.

References

1. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):557-82.

2. Beardsley JR, Williamson JC, Johnson JW, Ohl CA, Karchmer TB, Bowton DL. Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest. 2006 Sep;130(3):787-93.

Dr. Botti is a second-year resident in the family medicine residency program department of family and community medicine at Jefferson Medical College, Philadelphia. Dr. Mills is assistant residency program director and assistant professor in the department of family and community medicine and department of physiology at Jefferson Medical College, Philadelphia. Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia.

Hospital-acquired pneumonia (HAP) is pneumonia that presents at least 48 hours after admission to the hospital. In contrast, ventilator-associated pneumonia (VAP), is pneumonia that clinically presents 48 hours after endotracheal intubation. Together, these are some of the most common hospital-acquired infections in the United States and pose a considerable burden on hospitals nationwide.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recently updated their management guidelines for HAP and VAP with a goal of striking a balance between providing appropriate early antibiotic coverage and avoiding unnecessary treatment that can lead to adverse effects such as Clostridium difficile infections and development of antibiotic resistance.¹ This update eliminated the concept of Healthcare Associated Pneumonia (HCAP), often used for patients in skilled care facilities, because newer evidence has shown that patients who had met these criteria did not have a higher incidence of multidrug resistant pathogens; rather, they have microbial etiologies and sensitivities that are similar to adults with community acquired pneumonia (CAP).

Hospital-acquired pneumonia

MRSA should be covered with use of either vancomycin or linezolid in these cases.

Use two antipseudomonal antibiotics in HAP if the patient has these risk factors:

Pseudomonas risk factors:

• IV antibiotic treatment within 90 days

• Structural lung disease increasing the risk of gram-negative infection (bronchiectasis, cystic fibrosis)

• High-quality gram stain from respiratory specimen showing predominant and numerous gram-negative bacilli

High risk of mortality:

• Septic shock

• Need for ventilator support

Ventilator-associated pneumonia

General management of VAP is similar to HAP in that empiric treatment should be tailored to the local distribution and susceptibilities of pathogens based on each hospital’s antibiogram. All regimens should cover for S. aureus, P. aeruginosa, and other gram-negative bacilli based on the risk of mortality associated with the need for ventilator support. MSSA should be covered for VAP unless the patient has methicillin-resistant risk factors (see below).

MRSA should be covered for VAP if:

• Patient has had IV antibiotic use within past 90 days

• Hospital unit has greater than 10%-20% of S. aureus isolates are MRSA or MRSA prevalence unknown

Only one antipseudomonal agent should be used unless there are one of the following characteristics present, as described below.

Use two antipseudomonal agents in VAP if:

• Prior IV antibiotic use within 90 days

• Septic shock at time of VAP

• Acute respiratory distress syndrome preceding VAP

• 5 or more days of hospitalization prior to the occurrence of VAP

• Acute renal replacement therapy prior to VAP onset

• Greater than 10% of gram-negative isolates are resistant to an agent being considered for monotherapy

• Local antibiotic susceptibility rates unknown

In both HAP and VAP, antibiotics should be de-escalated to those with a narrower spectrum after initial empiric therapy, ideally within 72 hours and based on sputum or blood culture results. The guidelines support obtaining noninvasive sputum cultures in patients with VAP (endotracheal aspirates) and HAP (spontaneous expectoration, induced sputum, or nasotracheal suctioning in a patient who is unable to cooperate to produce a sputum sample). Patients who are improving clinically may be switched to appropriate oral therapy based on the susceptibility of an identified organism. Another key change is that of the standard duration of therapy. Previously, patients were treated for up to 2-3 weeks with antibiotics. The new IDSA/ATS guidelines recommend that patients should be treated with 7 days of antibiotics rather than a longer course.

The bottom line

Empiric therapy for HAP and VAP should be tailored to each hospital’s local pathogen distribution and antimicrobial susceptibilities, as detailed in an antibiogram. In HAP and VAP, empiric antibiotics should cover for S. aureus, but it only needs to target MRSA if risk factors are present, prevalence is greater than 20% or unknown, and – if HAP – a high risk of mortality. P. aeruginosa and other gram-negative bacilli should also be covered in empiric regimens. Dual antipseudomonal antibiotics is only recommended to be used in HAP if there are specific pseudomonal risk factors or a high risk of mortality. They should be used in VAP if there are multidrug-resistant risk factors present or there is a high/unknown prevalence of resistant organisms. All antibiotic regimens should be deescalated rather than maintained, and both HAP and VAP patients ought to be treated for 7 days.

References

1. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):557-82.

2. Beardsley JR, Williamson JC, Johnson JW, Ohl CA, Karchmer TB, Bowton DL. Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest. 2006 Sep;130(3):787-93.

Dr. Botti is a second-year resident in the family medicine residency program department of family and community medicine at Jefferson Medical College, Philadelphia. Dr. Mills is assistant residency program director and assistant professor in the department of family and community medicine and department of physiology at Jefferson Medical College, Philadelphia. Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia.

The VA Portland Healthcare System (VAPHCS) is a 277-bed facility that serves more than 85,000 inpatient and 880,000 outpatient visits each year from veterans in Oregon and southwestern Washington. The VAPHCS consists of a main tertiary care VAMC with an acute medical and surgical facility that includes 30 beds serving qualifying veterans. Supported surgical specialties include urology, general surgery, vascular surgery, otolaryngology, orthopedic surgery, ophthalmology, cardiothoracic surgery, transplant surgery, and neurological surgery. Neurosurgical patients account for about 12% to 13% of annual surgical patients. The VAPHCS also is partnered with Oregon Health & Science University in the training of health care professionals, such as physicians and nurses.

The expectation at the VAPHCS is that medical-surgical nurses care for 4 to 5 concurrent patients, often from different surgical services. Caring for patients with different medical and surgical needs, variable ambulatory, swallowing, and elimination functions, and different physician teams can become confusing; even within a single surgical service, postoperative care due to procedure complexity, specificity of care orders, and the real possibility of medical catastrophe can seem overwhelming. Therefore, subspecialty nursing training poses a challenge that requires technical in-service and didactic education and allocation of resources.

Despite systems level subspecialty nursing training, medical emergencies identified at the bedside can be mismanaged.¹ Errors in care can be due to an incomplete knowledge of the patient’s procedure and misunderstanding of positioning and activity limitations.

To encourage medical-surgical nurses to become more engaged and confident in subspecialty patient care, the authors developed a bedside neurosurgical nursing guide to allow for independent procedure related education. The comprehensive guide summarized the clinical course for postoperative neurosurgical patients undergoing cranial and spinal surgeries. This guide included appropriate surgery-related images, procedure overviews, management decisions, potential postoperative complications, and wound care directions. The guide was distributed to medical-surgical nurses caring for neurosurgical patients. The authors hypothesized that the guide would enable nurses to better predict adverse outcomes and respond appropriately and would improve confidence in patient care.

Methods

For educational purposes, a bedside neurosurgical nursing guide (text and graphics) was created for the 16 surgical subspecialty nurses at the VAPHCS. The guide detailed the most common cranial and spinal neurosurgical procedures performed at VAPHCS and was written based on a typical postoperative course for each procedure by the chief neurosurgery resident at VAPHCS with collaboration from the attending neurosurgeons (Figure).

A quality improvement (QI) project was undertaken to assess nursing confidence with neurosurgical patients’ care pre- and postfamiliarity with the bedside neurosurgical nursing guide. A literature search revealed no validated survey assessing nursing confidence, so one was created using the Likert scale. Specifically, an anonymous 6-question survey was completed by all 16 surgical nurses prior to familiarization with the guide. Responses were recorded as scores of 1 to 5 for questions 1, 3, and 4, with a response of 1 indicative of no comfort or confidence and a response of 5 indicative of the highest level of comfort or confidence. Responses were recorded as either true or false for questions 2 and 6, and never, occasionally, frequently, or always for question 5.

The guide was made available to nurses for 6 months without encouragement to use it. After 6 months, a 3-week period of familiarization with and education about the availability of the guide was instituted at morning nursing reports; the total availability of the guide to nursing staff was 6 months 3 weeks. After this period the same 6-question survey was distributed, and data were collected.

Survey responses were categorized into 2 groups. Responses to questions 1, 3, and 4 were categorized as group 1, and responses to questions 4 and 5 were categorized as group 2. Responses (never and occasionally) to question 5, were categorized as group 1 and responses (frequently and always) as group 2 (Table). Responses to questions 2 and 6 were grouped 1 for true and 2 for false. Nurses participating in this study ranged in age from 22 to 57 years, education level ranged from registered nurse to a bachelor of science in nursing, and years of experience ranged from < 1 year to 27 years.

Statistics were calculated using chi-square analysis with Yates correction online calculator. For the chi-square analysis, the prefamiliarization data for groups 1 and 2 were used as the expected values, and the postfamiliarization data were used for the observed values. In this manner, differences were discerned between the before and after questionnaire responses. The VAPHCS institutional review board determined that the study was not human research and exempt from review.

Findings

Anonymous survey responses were collected from all 16 surgical subspecialty nurses both prior and after familiarization with the nursing guide.The response rate was 100% with only a few incomplete responses excluded from the analysis. Three questions in the prefamiliarization questionnaire had no appropriate response, and 1 question in the postfamiliarization survey had no appropriate response.

Improvement was statistically significant in responses for questions 1, 3, 5, and 6 (P = .026, .008, .004, and .033, respectively). No significant differences were found for questions 2 and 4 (P = .974 and .116, respectively). It is possible that there was no significant difference in question 2 because prefamiliarization responses were already favorable. Even if nurses did not feel comfortable taking care of neurosurgical patients (as assessed in question 1), they noted confidence improvement by working on the ward and through informal assimilation of knowledge and skill, which would have accumulated naturally over 1 year.

Prior to familiarization with the guide, 7 nurses did not feel confident in assessing the need to contact a physician (question 4). After familiarization with the nursing guide, favorable responses increased from 9 to 14 nurses. Results trended toward but did not reach statistical significance, likely due to the small sample size.

Ultimately, in the 16 surgical subspecialty nurses surveyed, familiarization with the nursing guide was shown to improve comfort in taking care of neurosurgical patients and increase confidence in patient care skills. At the end of the QI project (6 months, 3 weeks), all nurses knew where to locate the bedside neurosurgical nursing guide and were familiar with it and its use. The guide remains accessible to the medical-surgical nurses and continues to be used.

Discussion

Nursing confidence has an undervalued effect on patient care.² Confidence, or a belief in one’s own ability, varies directly with competence. Systematic quantification of nursing competence has been extensively studied using self-report questionnaires and clinical simulations.^2,3 Competency can be quantified and normalized using formal assessment; however, confidence is somewhat intangible. Nursing confidence is a situation-dependent subjective feeling of security and is derived from an internalized assessment of skills that are commensurate with patient needs. Nursing confidence is further influenced by an intuited value within the care team, adequate knowledge of the patient’s condition, and procedures and protocols.⁴

A similar but less specific definition deconstructs nursing confidence as “significance of a professional network of coworkers” and the “importance of confirmation of professional role and competence.”⁵ The professional network of coworkers is invaluable as it underlies the essence of patient-centered care. The adaptive leadership framework is integral to the modern delivery of patient care, and via this framework frontline clinical staff, including nurses, are empowered.^6,7

The second portion of Haavardsholm and Nåden’s definition, “importance of confirmation of professional role and competence” describes the association of the most easily augmented correlate of confidence: competency.⁵ Nursing competency is supplemented continuously with in-service training and recertification processes; however, despite this, demands placed on nurses can be technologically advanced and extremely varied. Nursing competency is known to directly correlate with increasing education, as nurses holding a master’s degree have been shown to outperform those with a bachelor of nursing degree.³

Increased formal education as well as increased work experience (> 5 years) are correlated with increased critical thinking ability.^4,5 The critical thinking ability of health care providers can be fortified by clinical simulation, which leads to statistically significant improvement in clinical competency.^2,3

A literature review of Medline and the National Library of Medicine PubMed online databases for search terms (nurs*, confidence, bedside, guide) was performed but did not result in original research assessing nurse confidence related to bedside guides. In this population, nurses were anonymously compared against their own historical data obviating any effect of education or experience on survey measures.

Nursing Self-Confidence

Evidence suggests that nursing confidence is a complex manifestation of the security felt within the care team and the comfort of one’s own professional abilities.⁴ Patients’ trust in the team caring for them is based on the confidence exuded by the team.⁸ In this way, nursing confidence can affect the patient-care team profoundly. Value is maximized when a nurse’s self-confidence engenders patient confidence and trust. Due to the varied patient load and complexity of subspecialty nursing care, it is hypothesized that bedside manuals/guidelines can be used to educate the subspecialty nurses on specific patient-related issues.

Nursing practice competence and confidence is vital to providing care for patients with complex postsurgical health care needs. Patient safety and outcome are paramount. This can be intimidating for newly qualified surgical subspecialty nurses who have not yet had experience with or adequate exposure to patients with complex postsurgical needs. Surgical nursing continuing education places an emphasis on adaptation to ever-changing specialized surgical procedures and postoperative patient care. Nevertheless, it is difficult for surgical subspecialty nurses to learn and retain all the possible complexities of individual cases and to confidently, appropriately, and safely care for patients especially when adverse events arise.

Recognizing that leadership is personal and not dependent on hierarchy, surgical subspecialty nurses may be better suited to specific bedside training and counseling.^6,9 A key factor influencing nursing confidence is communication and collaboration with physicians.⁹ The role of the physician at VA medical facilities is no longer to be a commanding figure with complete medical autonomy; rather, a unified team of specialized practitioners collaboratively facilitate and deliver patient care.

There is no specific research detailing the use of bedside nursing guides in caring for postoperative patients. However, at VAPHCS, nurses created supplemental material regarding postoperative acute care of vascular surgery patients, which was found to be subjectively helpful in elevating nursing confidence. To the authors’ knowledge, no such supplemental information/guide exists for other specialty surgical services.

The surgical nursing guide created here detailed visuals of many common neurosurgical procedures performed at VAPHCS and included a prioritized checklist, which the 16 surgical subspecialty nurses could reference postoperatively. The authors hypothesized that this would enhance the nurses’ ability to efficiently manage specific situations while bridging communication gaps between surgical teams and nurses. The survey results agree with previous reports that suggested that the application of an adaptive leadership framework would empower nurses to deliver excellent patient-centered care, care that can be augmented with subspecialty nursing guides.^7,10

Based on these results the authors propose that subspecialty surgical services consider use of a practical nursing guide for all surgical subspecialty nurses to reference, improve familiarity with procedures, and provide guidance to manage adverse events. Since implementing this reader-friendly paradigm within neurosurgical care, a nurse driven expansion has now included other subspecialty services at the VAPHCS with success.

Limitations

Survey responses have inherent bias and sampling error rates. The sample size for this survey was small. Data were grouped for data analysis. Competency and patient outcomes were not measured.

Future Directions

Despite specific surgical specialty postoperative patient care training, an overall lack of confidence can persist. A physician-created neurosurgical nursing guide that detailed the most common neurosurgical procedures, expected postoperative care, and potential emergencies was shown to improve nursing confidence. Collaborative (physician and nursing leaders) QI projects, such as described here; development of specific surgical specialty initiatives designed to improve confidence and quality; and nurse-physician communication and teamwork could lead to improved patient satisfaction and outcome.

The costs associated with developing and using bedside nursing guides are relatively low, and efficiency can be considered high. Competency improvement could be measured by creating a specialty-specific case scenario question bank. Effects on patient satisfaction and outcome could be measured by a patient satisfaction survey. Improvements in beside catastrophe management could be prospectively tracked; for example, rates of mismanagement of mobility status, emergent transfers to the intensive care unit, or poor wound care could be compared pre- and postfamiliarization with a subspecialty guide.

Conclusion

Familiarization with the VAPHCS neurosurgical nursing guide had a positive impact on the confidence of medical-surgical nurses caring for neurosurgical patients. Medical-surgical nurses were more comfortable taking care of neurosurgical patients; they felt the guide helped improve skills and noted improved knowledge regarding involvement of physician oversight. Although objective parameters were not assessed, improvement in nursing confidence in general leads to improved overall nurse-physician communication and patient management. A further study might target objective parameters associated with guide usage, such as changes in the number of emergencies or calls to physicians regarding management.

Acknowledgments
The authors thank Andy Rekito, MS, for illustrative assistance.

The VA Portland Healthcare System (VAPHCS) is a 277-bed facility that serves more than 85,000 inpatient and 880,000 outpatient visits each year from veterans in Oregon and southwestern Washington. The VAPHCS consists of a main tertiary care VAMC with an acute medical and surgical facility that includes 30 beds serving qualifying veterans. Supported surgical specialties include urology, general surgery, vascular surgery, otolaryngology, orthopedic surgery, ophthalmology, cardiothoracic surgery, transplant surgery, and neurological surgery. Neurosurgical patients account for about 12% to 13% of annual surgical patients. The VAPHCS also is partnered with Oregon Health & Science University in the training of health care professionals, such as physicians and nurses.

The expectation at the VAPHCS is that medical-surgical nurses care for 4 to 5 concurrent patients, often from different surgical services. Caring for patients with different medical and surgical needs, variable ambulatory, swallowing, and elimination functions, and different physician teams can become confusing; even within a single surgical service, postoperative care due to procedure complexity, specificity of care orders, and the real possibility of medical catastrophe can seem overwhelming. Therefore, subspecialty nursing training poses a challenge that requires technical in-service and didactic education and allocation of resources.

Despite systems level subspecialty nursing training, medical emergencies identified at the bedside can be mismanaged.¹ Errors in care can be due to an incomplete knowledge of the patient’s procedure and misunderstanding of positioning and activity limitations.

To encourage medical-surgical nurses to become more engaged and confident in subspecialty patient care, the authors developed a bedside neurosurgical nursing guide to allow for independent procedure related education. The comprehensive guide summarized the clinical course for postoperative neurosurgical patients undergoing cranial and spinal surgeries. This guide included appropriate surgery-related images, procedure overviews, management decisions, potential postoperative complications, and wound care directions. The guide was distributed to medical-surgical nurses caring for neurosurgical patients. The authors hypothesized that the guide would enable nurses to better predict adverse outcomes and respond appropriately and would improve confidence in patient care.

Methods

For educational purposes, a bedside neurosurgical nursing guide (text and graphics) was created for the 16 surgical subspecialty nurses at the VAPHCS. The guide detailed the most common cranial and spinal neurosurgical procedures performed at VAPHCS and was written based on a typical postoperative course for each procedure by the chief neurosurgery resident at VAPHCS with collaboration from the attending neurosurgeons (Figure).

A quality improvement (QI) project was undertaken to assess nursing confidence with neurosurgical patients’ care pre- and postfamiliarity with the bedside neurosurgical nursing guide. A literature search revealed no validated survey assessing nursing confidence, so one was created using the Likert scale. Specifically, an anonymous 6-question survey was completed by all 16 surgical nurses prior to familiarization with the guide. Responses were recorded as scores of 1 to 5 for questions 1, 3, and 4, with a response of 1 indicative of no comfort or confidence and a response of 5 indicative of the highest level of comfort or confidence. Responses were recorded as either true or false for questions 2 and 6, and never, occasionally, frequently, or always for question 5.

The guide was made available to nurses for 6 months without encouragement to use it. After 6 months, a 3-week period of familiarization with and education about the availability of the guide was instituted at morning nursing reports; the total availability of the guide to nursing staff was 6 months 3 weeks. After this period the same 6-question survey was distributed, and data were collected.

Survey responses were categorized into 2 groups. Responses to questions 1, 3, and 4 were categorized as group 1, and responses to questions 4 and 5 were categorized as group 2. Responses (never and occasionally) to question 5, were categorized as group 1 and responses (frequently and always) as group 2 (Table). Responses to questions 2 and 6 were grouped 1 for true and 2 for false. Nurses participating in this study ranged in age from 22 to 57 years, education level ranged from registered nurse to a bachelor of science in nursing, and years of experience ranged from < 1 year to 27 years.

Statistics were calculated using chi-square analysis with Yates correction online calculator. For the chi-square analysis, the prefamiliarization data for groups 1 and 2 were used as the expected values, and the postfamiliarization data were used for the observed values. In this manner, differences were discerned between the before and after questionnaire responses. The VAPHCS institutional review board determined that the study was not human research and exempt from review.

Findings

Anonymous survey responses were collected from all 16 surgical subspecialty nurses both prior and after familiarization with the nursing guide.The response rate was 100% with only a few incomplete responses excluded from the analysis. Three questions in the prefamiliarization questionnaire had no appropriate response, and 1 question in the postfamiliarization survey had no appropriate response.

Improvement was statistically significant in responses for questions 1, 3, 5, and 6 (P = .026, .008, .004, and .033, respectively). No significant differences were found for questions 2 and 4 (P = .974 and .116, respectively). It is possible that there was no significant difference in question 2 because prefamiliarization responses were already favorable. Even if nurses did not feel comfortable taking care of neurosurgical patients (as assessed in question 1), they noted confidence improvement by working on the ward and through informal assimilation of knowledge and skill, which would have accumulated naturally over 1 year.

Prior to familiarization with the guide, 7 nurses did not feel confident in assessing the need to contact a physician (question 4). After familiarization with the nursing guide, favorable responses increased from 9 to 14 nurses. Results trended toward but did not reach statistical significance, likely due to the small sample size.

Ultimately, in the 16 surgical subspecialty nurses surveyed, familiarization with the nursing guide was shown to improve comfort in taking care of neurosurgical patients and increase confidence in patient care skills. At the end of the QI project (6 months, 3 weeks), all nurses knew where to locate the bedside neurosurgical nursing guide and were familiar with it and its use. The guide remains accessible to the medical-surgical nurses and continues to be used.

Discussion

Nursing confidence has an undervalued effect on patient care.² Confidence, or a belief in one’s own ability, varies directly with competence. Systematic quantification of nursing competence has been extensively studied using self-report questionnaires and clinical simulations.^2,3 Competency can be quantified and normalized using formal assessment; however, confidence is somewhat intangible. Nursing confidence is a situation-dependent subjective feeling of security and is derived from an internalized assessment of skills that are commensurate with patient needs. Nursing confidence is further influenced by an intuited value within the care team, adequate knowledge of the patient’s condition, and procedures and protocols.⁴

A similar but less specific definition deconstructs nursing confidence as “significance of a professional network of coworkers” and the “importance of confirmation of professional role and competence.”⁵ The professional network of coworkers is invaluable as it underlies the essence of patient-centered care. The adaptive leadership framework is integral to the modern delivery of patient care, and via this framework frontline clinical staff, including nurses, are empowered.^6,7

The second portion of Haavardsholm and Nåden’s definition, “importance of confirmation of professional role and competence” describes the association of the most easily augmented correlate of confidence: competency.⁵ Nursing competency is supplemented continuously with in-service training and recertification processes; however, despite this, demands placed on nurses can be technologically advanced and extremely varied. Nursing competency is known to directly correlate with increasing education, as nurses holding a master’s degree have been shown to outperform those with a bachelor of nursing degree.³

Increased formal education as well as increased work experience (> 5 years) are correlated with increased critical thinking ability.^4,5 The critical thinking ability of health care providers can be fortified by clinical simulation, which leads to statistically significant improvement in clinical competency.^2,3

A literature review of Medline and the National Library of Medicine PubMed online databases for search terms (nurs*, confidence, bedside, guide) was performed but did not result in original research assessing nurse confidence related to bedside guides. In this population, nurses were anonymously compared against their own historical data obviating any effect of education or experience on survey measures.

Nursing Self-Confidence

Evidence suggests that nursing confidence is a complex manifestation of the security felt within the care team and the comfort of one’s own professional abilities.⁴ Patients’ trust in the team caring for them is based on the confidence exuded by the team.⁸ In this way, nursing confidence can affect the patient-care team profoundly. Value is maximized when a nurse’s self-confidence engenders patient confidence and trust. Due to the varied patient load and complexity of subspecialty nursing care, it is hypothesized that bedside manuals/guidelines can be used to educate the subspecialty nurses on specific patient-related issues.

Nursing practice competence and confidence is vital to providing care for patients with complex postsurgical health care needs. Patient safety and outcome are paramount. This can be intimidating for newly qualified surgical subspecialty nurses who have not yet had experience with or adequate exposure to patients with complex postsurgical needs. Surgical nursing continuing education places an emphasis on adaptation to ever-changing specialized surgical procedures and postoperative patient care. Nevertheless, it is difficult for surgical subspecialty nurses to learn and retain all the possible complexities of individual cases and to confidently, appropriately, and safely care for patients especially when adverse events arise.

Recognizing that leadership is personal and not dependent on hierarchy, surgical subspecialty nurses may be better suited to specific bedside training and counseling.^6,9 A key factor influencing nursing confidence is communication and collaboration with physicians.⁹ The role of the physician at VA medical facilities is no longer to be a commanding figure with complete medical autonomy; rather, a unified team of specialized practitioners collaboratively facilitate and deliver patient care.

There is no specific research detailing the use of bedside nursing guides in caring for postoperative patients. However, at VAPHCS, nurses created supplemental material regarding postoperative acute care of vascular surgery patients, which was found to be subjectively helpful in elevating nursing confidence. To the authors’ knowledge, no such supplemental information/guide exists for other specialty surgical services.

The surgical nursing guide created here detailed visuals of many common neurosurgical procedures performed at VAPHCS and included a prioritized checklist, which the 16 surgical subspecialty nurses could reference postoperatively. The authors hypothesized that this would enhance the nurses’ ability to efficiently manage specific situations while bridging communication gaps between surgical teams and nurses. The survey results agree with previous reports that suggested that the application of an adaptive leadership framework would empower nurses to deliver excellent patient-centered care, care that can be augmented with subspecialty nursing guides.^7,10

Based on these results the authors propose that subspecialty surgical services consider use of a practical nursing guide for all surgical subspecialty nurses to reference, improve familiarity with procedures, and provide guidance to manage adverse events. Since implementing this reader-friendly paradigm within neurosurgical care, a nurse driven expansion has now included other subspecialty services at the VAPHCS with success.

Limitations

Survey responses have inherent bias and sampling error rates. The sample size for this survey was small. Data were grouped for data analysis. Competency and patient outcomes were not measured.

Future Directions

Despite specific surgical specialty postoperative patient care training, an overall lack of confidence can persist. A physician-created neurosurgical nursing guide that detailed the most common neurosurgical procedures, expected postoperative care, and potential emergencies was shown to improve nursing confidence. Collaborative (physician and nursing leaders) QI projects, such as described here; development of specific surgical specialty initiatives designed to improve confidence and quality; and nurse-physician communication and teamwork could lead to improved patient satisfaction and outcome.

The costs associated with developing and using bedside nursing guides are relatively low, and efficiency can be considered high. Competency improvement could be measured by creating a specialty-specific case scenario question bank. Effects on patient satisfaction and outcome could be measured by a patient satisfaction survey. Improvements in beside catastrophe management could be prospectively tracked; for example, rates of mismanagement of mobility status, emergent transfers to the intensive care unit, or poor wound care could be compared pre- and postfamiliarization with a subspecialty guide.

Conclusion

Familiarization with the VAPHCS neurosurgical nursing guide had a positive impact on the confidence of medical-surgical nurses caring for neurosurgical patients. Medical-surgical nurses were more comfortable taking care of neurosurgical patients; they felt the guide helped improve skills and noted improved knowledge regarding involvement of physician oversight. Although objective parameters were not assessed, improvement in nursing confidence in general leads to improved overall nurse-physician communication and patient management. A further study might target objective parameters associated with guide usage, such as changes in the number of emergencies or calls to physicians regarding management.

Acknowledgments
The authors thank Andy Rekito, MS, for illustrative assistance.

The VA Portland Healthcare System (VAPHCS) is a 277-bed facility that serves more than 85,000 inpatient and 880,000 outpatient visits each year from veterans in Oregon and southwestern Washington. The VAPHCS consists of a main tertiary care VAMC with an acute medical and surgical facility that includes 30 beds serving qualifying veterans. Supported surgical specialties include urology, general surgery, vascular surgery, otolaryngology, orthopedic surgery, ophthalmology, cardiothoracic surgery, transplant surgery, and neurological surgery. Neurosurgical patients account for about 12% to 13% of annual surgical patients. The VAPHCS also is partnered with Oregon Health & Science University in the training of health care professionals, such as physicians and nurses.

The expectation at the VAPHCS is that medical-surgical nurses care for 4 to 5 concurrent patients, often from different surgical services. Caring for patients with different medical and surgical needs, variable ambulatory, swallowing, and elimination functions, and different physician teams can become confusing; even within a single surgical service, postoperative care due to procedure complexity, specificity of care orders, and the real possibility of medical catastrophe can seem overwhelming. Therefore, subspecialty nursing training poses a challenge that requires technical in-service and didactic education and allocation of resources.

Despite systems level subspecialty nursing training, medical emergencies identified at the bedside can be mismanaged.¹ Errors in care can be due to an incomplete knowledge of the patient’s procedure and misunderstanding of positioning and activity limitations.

To encourage medical-surgical nurses to become more engaged and confident in subspecialty patient care, the authors developed a bedside neurosurgical nursing guide to allow for independent procedure related education. The comprehensive guide summarized the clinical course for postoperative neurosurgical patients undergoing cranial and spinal surgeries. This guide included appropriate surgery-related images, procedure overviews, management decisions, potential postoperative complications, and wound care directions. The guide was distributed to medical-surgical nurses caring for neurosurgical patients. The authors hypothesized that the guide would enable nurses to better predict adverse outcomes and respond appropriately and would improve confidence in patient care.

Methods

For educational purposes, a bedside neurosurgical nursing guide (text and graphics) was created for the 16 surgical subspecialty nurses at the VAPHCS. The guide detailed the most common cranial and spinal neurosurgical procedures performed at VAPHCS and was written based on a typical postoperative course for each procedure by the chief neurosurgery resident at VAPHCS with collaboration from the attending neurosurgeons (Figure).

A quality improvement (QI) project was undertaken to assess nursing confidence with neurosurgical patients’ care pre- and postfamiliarity with the bedside neurosurgical nursing guide. A literature search revealed no validated survey assessing nursing confidence, so one was created using the Likert scale. Specifically, an anonymous 6-question survey was completed by all 16 surgical nurses prior to familiarization with the guide. Responses were recorded as scores of 1 to 5 for questions 1, 3, and 4, with a response of 1 indicative of no comfort or confidence and a response of 5 indicative of the highest level of comfort or confidence. Responses were recorded as either true or false for questions 2 and 6, and never, occasionally, frequently, or always for question 5.

The guide was made available to nurses for 6 months without encouragement to use it. After 6 months, a 3-week period of familiarization with and education about the availability of the guide was instituted at morning nursing reports; the total availability of the guide to nursing staff was 6 months 3 weeks. After this period the same 6-question survey was distributed, and data were collected.

Survey responses were categorized into 2 groups. Responses to questions 1, 3, and 4 were categorized as group 1, and responses to questions 4 and 5 were categorized as group 2. Responses (never and occasionally) to question 5, were categorized as group 1 and responses (frequently and always) as group 2 (Table). Responses to questions 2 and 6 were grouped 1 for true and 2 for false. Nurses participating in this study ranged in age from 22 to 57 years, education level ranged from registered nurse to a bachelor of science in nursing, and years of experience ranged from < 1 year to 27 years.

Statistics were calculated using chi-square analysis with Yates correction online calculator. For the chi-square analysis, the prefamiliarization data for groups 1 and 2 were used as the expected values, and the postfamiliarization data were used for the observed values. In this manner, differences were discerned between the before and after questionnaire responses. The VAPHCS institutional review board determined that the study was not human research and exempt from review.

Findings

Anonymous survey responses were collected from all 16 surgical subspecialty nurses both prior and after familiarization with the nursing guide.The response rate was 100% with only a few incomplete responses excluded from the analysis. Three questions in the prefamiliarization questionnaire had no appropriate response, and 1 question in the postfamiliarization survey had no appropriate response.

Improvement was statistically significant in responses for questions 1, 3, 5, and 6 (P = .026, .008, .004, and .033, respectively). No significant differences were found for questions 2 and 4 (P = .974 and .116, respectively). It is possible that there was no significant difference in question 2 because prefamiliarization responses were already favorable. Even if nurses did not feel comfortable taking care of neurosurgical patients (as assessed in question 1), they noted confidence improvement by working on the ward and through informal assimilation of knowledge and skill, which would have accumulated naturally over 1 year.

Prior to familiarization with the guide, 7 nurses did not feel confident in assessing the need to contact a physician (question 4). After familiarization with the nursing guide, favorable responses increased from 9 to 14 nurses. Results trended toward but did not reach statistical significance, likely due to the small sample size.

Ultimately, in the 16 surgical subspecialty nurses surveyed, familiarization with the nursing guide was shown to improve comfort in taking care of neurosurgical patients and increase confidence in patient care skills. At the end of the QI project (6 months, 3 weeks), all nurses knew where to locate the bedside neurosurgical nursing guide and were familiar with it and its use. The guide remains accessible to the medical-surgical nurses and continues to be used.

Discussion

Nursing confidence has an undervalued effect on patient care.² Confidence, or a belief in one’s own ability, varies directly with competence. Systematic quantification of nursing competence has been extensively studied using self-report questionnaires and clinical simulations.^2,3 Competency can be quantified and normalized using formal assessment; however, confidence is somewhat intangible. Nursing confidence is a situation-dependent subjective feeling of security and is derived from an internalized assessment of skills that are commensurate with patient needs. Nursing confidence is further influenced by an intuited value within the care team, adequate knowledge of the patient’s condition, and procedures and protocols.⁴

A similar but less specific definition deconstructs nursing confidence as “significance of a professional network of coworkers” and the “importance of confirmation of professional role and competence.”⁵ The professional network of coworkers is invaluable as it underlies the essence of patient-centered care. The adaptive leadership framework is integral to the modern delivery of patient care, and via this framework frontline clinical staff, including nurses, are empowered.^6,7

The second portion of Haavardsholm and Nåden’s definition, “importance of confirmation of professional role and competence” describes the association of the most easily augmented correlate of confidence: competency.⁵ Nursing competency is supplemented continuously with in-service training and recertification processes; however, despite this, demands placed on nurses can be technologically advanced and extremely varied. Nursing competency is known to directly correlate with increasing education, as nurses holding a master’s degree have been shown to outperform those with a bachelor of nursing degree.³

Increased formal education as well as increased work experience (> 5 years) are correlated with increased critical thinking ability.^4,5 The critical thinking ability of health care providers can be fortified by clinical simulation, which leads to statistically significant improvement in clinical competency.^2,3

A literature review of Medline and the National Library of Medicine PubMed online databases for search terms (nurs*, confidence, bedside, guide) was performed but did not result in original research assessing nurse confidence related to bedside guides. In this population, nurses were anonymously compared against their own historical data obviating any effect of education or experience on survey measures.

Nursing Self-Confidence

Evidence suggests that nursing confidence is a complex manifestation of the security felt within the care team and the comfort of one’s own professional abilities.⁴ Patients’ trust in the team caring for them is based on the confidence exuded by the team.⁸ In this way, nursing confidence can affect the patient-care team profoundly. Value is maximized when a nurse’s self-confidence engenders patient confidence and trust. Due to the varied patient load and complexity of subspecialty nursing care, it is hypothesized that bedside manuals/guidelines can be used to educate the subspecialty nurses on specific patient-related issues.

Nursing practice competence and confidence is vital to providing care for patients with complex postsurgical health care needs. Patient safety and outcome are paramount. This can be intimidating for newly qualified surgical subspecialty nurses who have not yet had experience with or adequate exposure to patients with complex postsurgical needs. Surgical nursing continuing education places an emphasis on adaptation to ever-changing specialized surgical procedures and postoperative patient care. Nevertheless, it is difficult for surgical subspecialty nurses to learn and retain all the possible complexities of individual cases and to confidently, appropriately, and safely care for patients especially when adverse events arise.

Recognizing that leadership is personal and not dependent on hierarchy, surgical subspecialty nurses may be better suited to specific bedside training and counseling.^6,9 A key factor influencing nursing confidence is communication and collaboration with physicians.⁹ The role of the physician at VA medical facilities is no longer to be a commanding figure with complete medical autonomy; rather, a unified team of specialized practitioners collaboratively facilitate and deliver patient care.

There is no specific research detailing the use of bedside nursing guides in caring for postoperative patients. However, at VAPHCS, nurses created supplemental material regarding postoperative acute care of vascular surgery patients, which was found to be subjectively helpful in elevating nursing confidence. To the authors’ knowledge, no such supplemental information/guide exists for other specialty surgical services.

The surgical nursing guide created here detailed visuals of many common neurosurgical procedures performed at VAPHCS and included a prioritized checklist, which the 16 surgical subspecialty nurses could reference postoperatively. The authors hypothesized that this would enhance the nurses’ ability to efficiently manage specific situations while bridging communication gaps between surgical teams and nurses. The survey results agree with previous reports that suggested that the application of an adaptive leadership framework would empower nurses to deliver excellent patient-centered care, care that can be augmented with subspecialty nursing guides.^7,10

Based on these results the authors propose that subspecialty surgical services consider use of a practical nursing guide for all surgical subspecialty nurses to reference, improve familiarity with procedures, and provide guidance to manage adverse events. Since implementing this reader-friendly paradigm within neurosurgical care, a nurse driven expansion has now included other subspecialty services at the VAPHCS with success.

Limitations

Survey responses have inherent bias and sampling error rates. The sample size for this survey was small. Data were grouped for data analysis. Competency and patient outcomes were not measured.

Future Directions

Despite specific surgical specialty postoperative patient care training, an overall lack of confidence can persist. A physician-created neurosurgical nursing guide that detailed the most common neurosurgical procedures, expected postoperative care, and potential emergencies was shown to improve nursing confidence. Collaborative (physician and nursing leaders) QI projects, such as described here; development of specific surgical specialty initiatives designed to improve confidence and quality; and nurse-physician communication and teamwork could lead to improved patient satisfaction and outcome.

The costs associated with developing and using bedside nursing guides are relatively low, and efficiency can be considered high. Competency improvement could be measured by creating a specialty-specific case scenario question bank. Effects on patient satisfaction and outcome could be measured by a patient satisfaction survey. Improvements in beside catastrophe management could be prospectively tracked; for example, rates of mismanagement of mobility status, emergent transfers to the intensive care unit, or poor wound care could be compared pre- and postfamiliarization with a subspecialty guide.

Conclusion

Familiarization with the VAPHCS neurosurgical nursing guide had a positive impact on the confidence of medical-surgical nurses caring for neurosurgical patients. Medical-surgical nurses were more comfortable taking care of neurosurgical patients; they felt the guide helped improve skills and noted improved knowledge regarding involvement of physician oversight. Although objective parameters were not assessed, improvement in nursing confidence in general leads to improved overall nurse-physician communication and patient management. A further study might target objective parameters associated with guide usage, such as changes in the number of emergencies or calls to physicians regarding management.

Acknowledgments
The authors thank Andy Rekito, MS, for illustrative assistance.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at the

2016 ASH Annual Meeting

 

SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.

DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.

ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).

A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.

Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).

Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.

Earlier data from the phase 2 study have been reported in Hematology Times.

Phase 2 interim analysis

The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.

“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.

Patients then received a conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.

Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg.

“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”

Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.

The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.

The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.

At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.

Patient characteristics

Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.

The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.

Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.

Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.

Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.

Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.

Results

Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.

At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.

For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.

Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.

The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.

Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.

After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.

Adverse events

Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.

Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.

CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.

In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.

Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.

There were no cases of cerebral edema.

Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.

Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.

Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.

The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.

AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.

Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.

The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.

The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

Researchers say they have identified a genetic risk profile that can be used to predict which patients with sickle cell anemia (SCA) are likely to develop chronic kidney disease (CKD).

The team found evidence to suggest that a profile incorporating APOL1 G1/G2, α-thalassemia, and BCL11A can help physicians categorize SCA patients as having a high or low risk of CKD.

The researchers reported these findings in Haematologica.

Identifying SCA patients at the greatest risk of CKD can help physicians develop proactive, individualized strategies to reduce the high rate of early mortality due to CKD, said study author Santosh Saraf, MD, of the University of Illinois at Chicago.

“We looked at the genetic factors already known to be associated with kidney disease or the degree of red blood cell hemolysis and examined the relationship they had with the condition in sickle cell patients,” Dr Saraf said.

“Our hypothesis was that a genetic risk profile that integrated APOL1, α-thalassemia, and BCL11A would improve our ability to predict a patient’s risk for developing chronic kidney disease.”

To test this theory, Dr Saraf and his colleagues recruited 262 adult patients with SCA treated at a single center between 2010 and 2016. The team collected patient data, drew blood, analyzed genetic markers, and prospectively followed the patients to see if they developed CKD.

Stratification

The researchers used their genetic profile to stratify patients according to risk for CKD.

Patients were considered high-risk if they had APOL1 G1/G2 and wild-type BCL11A but did not have α-thalassemia.

Patients were considered low-risk if they were negative for APOL1 G1/G2 but had α-thalassemia (either α-/αα or α-/α-) and the BCL11A rs1427407 T allele (either G/T or T/T).

The researchers defined all other combinations as intermediate-risk.

The team found the genetic profile identified SCA patients at high and low risk for albuminuria or an estimated glomerular filtration rate less than 60 mL/min/1.73m².

The researchers also said application of the genetic profile revealed progressively higher rates of CKD progression.

Mechanisms

Dr Saraf and his colleagues noted that homozygosity or compound heterozygosity for APOL1 G1/G2 is the strongest genetic association for CKD in African Americans, and APOL1 G1/G2 is associated with proteinuria and albuminuria in SCA patients.

The researchers pointed out that APOL1 G1/G2 variants associate with CKD in African

Americans by unknown mechanisms, but the team found an association with

hemolysis in SCA, as reflected by hemoglobinuria.

As for α-thalassemia, it’s associated with reduced hemolysis and protection from albuminuria. The researchers said α-thalassemia reduces hemolysis in SCA by decreasing the

intra-erythrocyte concentration of sickle hemoglobin (HbS) and reducing

HbS polymerization.

Finally, Dr Saraf and his colleagues noted that BCL11A rs1427407 leads to higher fetal hemoglobin (HbF) levels, reduced hemolysis, and amelioration of SCA-related complications. The team said the BCL11A rs1427407 T variant leads to decreased function of BCL11A at the HbF promoter and therefore increases HbF, leading to decreased HbS polymerization.

“The results of this study are encouraging,” Dr Saraf said. “By understanding more about the genetic risk factors of kidney disease in sickle cell patients, we are one step closer to improving the length and quality of life for the millions of people worldwide living with sickle cell disease.”

“Using combinations of genes to better predict complications in sickle cell anemia is a new approach,” added study author Victor Gordeuk, MD, of the University of Illinois at Chicago.

“The results of this study indicate that it is effective and probably can be improved on in the future to be an important part of our evaluation of patients.”

The researchers said the small sample size and observational nature of this study are limitations, and they hope to validate the results with larger studies.