madman
Super Moderator
Purpose of review ICU survivors frequently suffers significant, prolonged physical disability. ‘ICU Survivorship’, or addressing quality-of-life impairments post-ICU care, is a defining challenge, and existing standards of care fail to successfully address these disabilities. We suggest addressing persistent catabolism by treatment with testosterone analogs combined with structured exercise is a promising novel intervention to improve ‘ICU Survivorship’.
Recent findings One explanation for lack of success in addressing post-ICU physical disability is most ICU patients exhibit severe testosterone deficiencies early in ICU that drives persistent catabolism despite rehabilitation efforts. Oxandrolone is an FDA-approved testosterone analog for treating muscle weakness in ICU patients. A growing number of trials with this agent combined with structured exercise show clinical benefit, including improved physical function and safety in burns and other catabolic states. However, no trials of oxandrolone/testosterone and exercise in nonburn ICU populations have been conducted.
Summary Critical illness leads to a catabolic state, including severe testosterone deficiency that persists throughout the hospital stay, and results in persistent muscle weakness and physical dysfunction. The combination of an anabolic agent with adequate nutrition and structured exercise is likely essential to optimize muscle mass/ strength and physical function in ICU survivors. Further research in ICU populations is needed.
INTRODUCTION
Critical illness remains a major US public health crisis. Critical illness currently affects 5.7 million Americans per year and every American can expect to average 1.7 ICU admissions in their lifetime [1]. Cost savings of up to $1 billion/quality life-year gained can be achieved with improved management of ICU-related illness and disability [2]. Innovations in ICU care resulted in yearly reductions in-hospital mortality from sepsis [3], and recent data indicates more than 90% of ICU patients survive ICU stays. However, survival comes at a cost. ICU survivors frequently experience significant disabilities, commonly physical including muscle weakness and functional impairments that can persist for years [4–6]. Muscle weakness in the ICU is associated with delayed liberation from ventilation, extended ICU and hospital stay, worse long-term survival, and physical functioning and quality of life [4–7]. These same data reveal many ICU survivors’ do not return home to functional lives following ICU care, but instead are discharged to rehabilitation settings where it is unclear if they ever return to a meaningful quality of life [6]. Collectively, these impaired physical functions are defined as ICU-acquired weakness (ICU-AW) or post-ICU Syndrome (PICS) [6,8&&]. Although we have improved therapies to increase the initial survival from critical illness, the challenge of optimizing recovery and survivorship after ICU care is yet to be meaningfully addressed.
WHY IS IT ESSENTIAL TO DEVELOP NOVEL, INNOVATIVE THERAPIES FOR ICU-ACQUIRED WEAKNESS?
PHYSICAL REHABILITATION/EXERCISE INTERVENTIONS ALONE FAIL TO CONSISTENTLY ADDRESS MUSCLE LOSS AND RECOVERY OF QUALITY OF LIFE IN ICU SURVIVORS
WHY DO ICU REHABILITATION EFFORTS FAIL TO ADDRESS MUSCLE AND PHYSICAL FUNCTION RECOVERY IN ICU SURVIVORS?
ROLE OF TESTOSTERONE DEFICIENCY IN ICU CATABOLISM AND POOR FUNCTIONAL RECOVERY
Suggestions for testosterone and Oxandrolone dosing
Suggestions for testosterone and Oxandrolone dosing See Table 1 for a summary of commonly used testosterone and testosterone analogs. Testosterone and testosterone analogs have two primary properties: androgenic and anabolic. The different mechanisms include modulation of androgen receptor expression and interference of glucocorticoid receptor expression, which results in anticatabolic and anabolic effects. Targeted anabolic testosterone analogs have modified the testosterone structure to maximize anabolic properties while attempting to eliminate/ minimize unwanted androgenic effects. Targeted anabolic testosterone agents, such as Oxandrolone or nandrolone exhibit significantly higher selectivity for muscle recovery and anabolic properties, with minimal androgenic effects (anabolic: androgenic activity ratio of 12: 1 and 13: 1, respectively) [54]. Consequently, the potential for adverse outcomes including aromatization and virilizing effects in women is significantly minimized.
Typical adult dosing used in studies of burned patients from our preliminary results and previous literature in burn injury and other illnesses shows 10 mg two times a day has been effective in improving muscle strength, muscle function, and clinical outcomes [55–57]. In most studies, this is given starting a few days after hospital admission (typically within 96 h of ICU admission) until hospital discharge. Nandrolone, an anabolic-specific testosterone agent has also been published in case reports of ICU patients to address ICU-acquired weakness [58& ]. Other testosterone delivery methods may also be effective, such as traditional intramuscular testosterone cypionate (which is a common outpatient testosterone replacement formulation) given at a dose of 200–400 mg every 2 weeks. Testosterone patches can also be utilized (typical dose supplied 4 mg patch), although this often is not as effective absorbed in critically ill patients with edema and altered skin perfusion and may not adequately correct the severe deficiencies seen in ICU patients. Following testosterone levels throughout care is essential to ensure adequate testosterone replacement is occurring with elevated levels being observed. Further, weekly liver function tests should be monitored, although elevations of LFTs from shorter-term ICU Oxandrolone and testosterone use are relatively rare [55–57].
STRUCTURED, MULTIDOMAIN REHABILITATION
ROLE OF NUTRITION IN ICU RECOVERY UTILIZING ANABOLIC AGENTS AND STRUCTURED EXERCISE
CONCLUSION
In conclusion, critical illness leads to a catabolic state, including severe testosterone deficiency that persists throughout the hospital stay. This results in persistent muscle weakness, physical dysfunction, and impaired functional QoL. We believe the combination of an anabolic agent with early exercise and adequate nutrition is the essential triad required to optimize muscle mass/strength and physical function in ICU survivors (see Fig. 1). We believe all three key pathways (anabolism, exercise, and nutrition) must be addressed in an ICU recovery intervention if we hope to ultimately improve ‘ICU Survivorship’, address impaired post-ICU quality of life in ICU survivors, and triumph over ‘the defining challenge of critical care’ for this century [22].
Recent findings One explanation for lack of success in addressing post-ICU physical disability is most ICU patients exhibit severe testosterone deficiencies early in ICU that drives persistent catabolism despite rehabilitation efforts. Oxandrolone is an FDA-approved testosterone analog for treating muscle weakness in ICU patients. A growing number of trials with this agent combined with structured exercise show clinical benefit, including improved physical function and safety in burns and other catabolic states. However, no trials of oxandrolone/testosterone and exercise in nonburn ICU populations have been conducted.
Summary Critical illness leads to a catabolic state, including severe testosterone deficiency that persists throughout the hospital stay, and results in persistent muscle weakness and physical dysfunction. The combination of an anabolic agent with adequate nutrition and structured exercise is likely essential to optimize muscle mass/ strength and physical function in ICU survivors. Further research in ICU populations is needed.
INTRODUCTION
Critical illness remains a major US public health crisis. Critical illness currently affects 5.7 million Americans per year and every American can expect to average 1.7 ICU admissions in their lifetime [1]. Cost savings of up to $1 billion/quality life-year gained can be achieved with improved management of ICU-related illness and disability [2]. Innovations in ICU care resulted in yearly reductions in-hospital mortality from sepsis [3], and recent data indicates more than 90% of ICU patients survive ICU stays. However, survival comes at a cost. ICU survivors frequently experience significant disabilities, commonly physical including muscle weakness and functional impairments that can persist for years [4–6]. Muscle weakness in the ICU is associated with delayed liberation from ventilation, extended ICU and hospital stay, worse long-term survival, and physical functioning and quality of life [4–7]. These same data reveal many ICU survivors’ do not return home to functional lives following ICU care, but instead are discharged to rehabilitation settings where it is unclear if they ever return to a meaningful quality of life [6]. Collectively, these impaired physical functions are defined as ICU-acquired weakness (ICU-AW) or post-ICU Syndrome (PICS) [6,8&&]. Although we have improved therapies to increase the initial survival from critical illness, the challenge of optimizing recovery and survivorship after ICU care is yet to be meaningfully addressed.
WHY IS IT ESSENTIAL TO DEVELOP NOVEL, INNOVATIVE THERAPIES FOR ICU-ACQUIRED WEAKNESS?
PHYSICAL REHABILITATION/EXERCISE INTERVENTIONS ALONE FAIL TO CONSISTENTLY ADDRESS MUSCLE LOSS AND RECOVERY OF QUALITY OF LIFE IN ICU SURVIVORS
WHY DO ICU REHABILITATION EFFORTS FAIL TO ADDRESS MUSCLE AND PHYSICAL FUNCTION RECOVERY IN ICU SURVIVORS?
ROLE OF TESTOSTERONE DEFICIENCY IN ICU CATABOLISM AND POOR FUNCTIONAL RECOVERY
Suggestions for testosterone and Oxandrolone dosing
Suggestions for testosterone and Oxandrolone dosing See Table 1 for a summary of commonly used testosterone and testosterone analogs. Testosterone and testosterone analogs have two primary properties: androgenic and anabolic. The different mechanisms include modulation of androgen receptor expression and interference of glucocorticoid receptor expression, which results in anticatabolic and anabolic effects. Targeted anabolic testosterone analogs have modified the testosterone structure to maximize anabolic properties while attempting to eliminate/ minimize unwanted androgenic effects. Targeted anabolic testosterone agents, such as Oxandrolone or nandrolone exhibit significantly higher selectivity for muscle recovery and anabolic properties, with minimal androgenic effects (anabolic: androgenic activity ratio of 12: 1 and 13: 1, respectively) [54]. Consequently, the potential for adverse outcomes including aromatization and virilizing effects in women is significantly minimized.
Typical adult dosing used in studies of burned patients from our preliminary results and previous literature in burn injury and other illnesses shows 10 mg two times a day has been effective in improving muscle strength, muscle function, and clinical outcomes [55–57]. In most studies, this is given starting a few days after hospital admission (typically within 96 h of ICU admission) until hospital discharge. Nandrolone, an anabolic-specific testosterone agent has also been published in case reports of ICU patients to address ICU-acquired weakness [58& ]. Other testosterone delivery methods may also be effective, such as traditional intramuscular testosterone cypionate (which is a common outpatient testosterone replacement formulation) given at a dose of 200–400 mg every 2 weeks. Testosterone patches can also be utilized (typical dose supplied 4 mg patch), although this often is not as effective absorbed in critically ill patients with edema and altered skin perfusion and may not adequately correct the severe deficiencies seen in ICU patients. Following testosterone levels throughout care is essential to ensure adequate testosterone replacement is occurring with elevated levels being observed. Further, weekly liver function tests should be monitored, although elevations of LFTs from shorter-term ICU Oxandrolone and testosterone use are relatively rare [55–57].
STRUCTURED, MULTIDOMAIN REHABILITATION
ROLE OF NUTRITION IN ICU RECOVERY UTILIZING ANABOLIC AGENTS AND STRUCTURED EXERCISE
CONCLUSION
In conclusion, critical illness leads to a catabolic state, including severe testosterone deficiency that persists throughout the hospital stay. This results in persistent muscle weakness, physical dysfunction, and impaired functional QoL. We believe the combination of an anabolic agent with early exercise and adequate nutrition is the essential triad required to optimize muscle mass/strength and physical function in ICU survivors (see Fig. 1). We believe all three key pathways (anabolism, exercise, and nutrition) must be addressed in an ICU recovery intervention if we hope to ultimately improve ‘ICU Survivorship’, address impaired post-ICU quality of life in ICU survivors, and triumph over ‘the defining challenge of critical care’ for this century [22].
