Reference: N Engl J med. 2018 Jul 19 (level 2 [mid-level] evidence)
Sickle cell disease has a complex pathophysiology that isn’t fully elucidated, especially with regard to vaso-occlusive pain crises, which are episodic and vary significantly in frequency and severity. For all patients with sickle cell disease, regardless of crisis severity, these crises uniformly disrupt their lives, often requiring inpatient hospitalization, and contribute to morbidity and mortality.
Oxidative stress appears to play a large role in vaso-occlusive crises in that sickled red cells have a lower oxidation-reduction cofactor ratio than normal RBC’s. Sickled RBC’s increase their uptake of L-glutamine several-fold when compared with non-sickled RBC’s. L-glutamine appears to be able to improve sickled RBC response to oxidative stress and potentially raise the threshold of oxidative injury required to trigger a full blown vaso-occlusive crisis (Free Radic Biol Med. 2013 Dec). Of significance, earlier studies of L-glutamine confirmed that a dose of 30 g/day, generated a consistent change in redox ratio (Free Radic biol Med. 2013 Dec).
To investigate the clinical benefits of reducing the NAD redox ratio within sickle cells through the use of L-glutamine as a treatment in Sickle Cell Disease, a recent multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was undertaken (N Engl J Med. 2018 Jul 19). 230 patients (aged 5-58 years, mean age 21 years) with sickle cell anemia or sickle beta thalassemia with history of ≥ 2 pain crises within the previous year (defined as pain treated with parenteral narcotic or ketorolac in the emergency department or during hospitalization) were randomized to L-glutamine powder (N=152) 0.3 g/kg of body weight orally twice daily vs. placebo powder (N=78) for 48 weeks (Free radic biol Med. 2013 Dec). 66.5% of patients were taking Hydroxyurea at a stable dose for ≥ 3 months prior to enrollment and continued throughout the trial. Patients were excluded if they had clinically important renal or liver disease or had received treatment with L-glutamine within 30 days prior to screening. Of the patients (L-glutamine 36.2%, Placebo 24.4%) that dropped out of the trial (withdrew consent, were lost to follow-up, or discontinued treatment for other reasons not related to trial treatment), all were included in the analyses using imputed results.
Following treatment at 48 weeks, compared to placebo, L-glutamine demonstrated a decreased median number of pain crises (3 vs 4, p = 0.005), increased median time to first pain crisis (84 vs 54 days, p = 0.005) with consistent results noted independent of Hydroxyurea usage. Further, the L-glutamine group compared to placebo had a decreased number of hospitalizations (2 vs 3, p = 0.005), decreased number of hospital days (6.5 vs 11 days, p = 0.02), and less patients with ≥ 1 episode of acute chest syndrome (8.6% vs 23.1%, p=0.003, number needed to treat [NNT] 7). Less patients in the treatment group experienced adverse events compared to placebo (98% vs 100%) as well as serious adverse events (78.2% vs. 87.1%).“Serious adverse events” were defined by the authors of the study as: “any adverse event, occurring while the patient was receiving the trial medication or placebo at any dose that resulted in death, a life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or clinically significant disability or incapacity, or a congenital anomaly or birth defect”. Despite an overall reduced incidence of adverse events in the L-glutamine group, patients in the treatment group were found to have a greater incidence of side effects including nausea (between group difference 21%), arm or leg pain (between group difference 8.2%), and back pain (between group difference 6.8%).
The limitations of this study include a significant drop out rate (64% L-glutamine group, 75% placebo group completed the study). The data was analyzed with intention to treat analysis and for the patients who dropped out, the number of pain crises was “imputed as either the mean number of crises (rounded to nearest integer) in patients in the same trial group who completed the trial or the actual number of crises the patient had at the time of discontinuation, whichever was greater”. Given the dropout rate of well above 20%, the use of imputed data likely had a significant effect on the final study conclusions and it may have skewed the data to favor L-glutamine patients who dropped out as they may have been less likely to have favorable outcomes and more adverse effects from the treatment.
However, despite these many limitations, the results of this study contributed to the Federal Drug Administration’s (FDA) approval of L-glutamine as a treatment option to reduce the rate of acute vaso-occlusive pain crises in patients with sickle cell disease aged ≥ 5 years.
Sickle Cell disease significantly shortens the lifespan of those affected, and pain crises result in significant healthcare expenditure and prolonged patient hospitalizations. Given prior basic scientific evidence exhibiting L-glutamine’s effect of increasing the redox ratio, the clinical evidence from this study supporting a possible decrease in the frequency of sickle cell crises, and the absence of significant, life-threatening side effects, L-glutamine may be a helpful treatment option for decreasing morbidity in patients with sickle cell disease.
For more information, see the Sickle Cell Disease in Adults and Adolescents topic in DynaMed.
Ashley Hawes, MD, is originally from Snellville, Georgia. She received her undergraduate degree in Biology and Spanish from the University of Georgia. Dr. Hawes went on to obtain her medical degree from Mercer University School of Medicine at the Savannah, Georgia Campus. She is fluent in Spanish and plans to stay in her home state of Georgia to practice medicine and help provide access to the underserved communities of Georgia. Her interests include Obstetrics and full scope Family Practice. Dr. Hawes is currently finishing her PGY-1 year at Memorial Medical Center in Savannah, Georgia. When she is not seeing patients, Dr. Hawes enjoys spending time with her husband and dog, Solo, watching movies, playing board games, and spending time with friends.
Faculty contribution by Dr. Marvin Sineath