Primecuts – This Week In The Journals

August 10, 2016

PrimeCuts 8 min read

Olympic_Trials_2016 By Nathan Teich, MD

Peer Reviewed

This week, Rio de Janeiro hosts the XXXI Summer Olympics games which had its official opening ceremonies on August 5th, 2016. Many controversies surround the games including doping scandals and concerns about safety in the host city [1]. However, many positives are also highlighted by the games, including athletes such as Syrian refugee Yusra Mardini whose Olympic journey includes her and another refugee pulling an overloaded dinghy across the Mediterranean to Greece saving the lives of 20 other people [2]. Other Olympic athletes return to represent their countries and push the limits of what is physically possible. From the global unity of athletic competition to medicine, we look at articles from around the world that offer hope for devastating diseases and potential changes to clinical practice.

Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers

Exertional rhabdomyolysis resulting from the breakdown of muscle tissue has been implicated in deaths involving athletes and military members. Sickle cell trait is a common hemoglobin mutation affecting 1.6% of the US population and 7.3% of black individuals and has been associated with an increased risk of rhabdomyolysis in affected persons exposed to demanding physical exertion [3]. Previous population-based studies have shown higher rates of death among black military recruits but have not adequately examined if sickle cell trait was present in those who died. The NCAA and United States Air Force have instituted universal screening for sickle cell trait, but concerns have been raised about the possibility of stigmatization of affected patients, particularly in the absence of evidence that screening prevents adverse events [4,5].

This week in the New England Journal of Medicine, a study was published that attempted to quantify the associations between sickle cell trait and death and exertional rhabdomyolysis [6]. This was a retrospective cohort study that examined data from the Stanford Military Data Repository (SMDR), a database of all health encounters for active-duty soldiers in the US Army. The records of 47,944 black soldiers who served at any time in active duty from Jan 2011 to Dec 2014 who had undergone HbAS testing before or during this time were included.  Main outcomes were exertional rhabdomyolysis and death. Cases were identified using ICD-9 codes for rhabdomyolysis and myoglobinuria.  Other cases due to trauma or toxicity were excluded. Sex, age, physical fitness (using army fitness testing), tobacco use, and drugs that may lead to rhabdomyolysis (statins, antipsychotics, stimulants) were identified as individual variables.

7.4% of the study population had sickle cell trait. 391 episodes of exertional rhabdomyolysis were identified over 1.61 million person months. Presence of sickle cell trait was associated with a 54% higher risk of exertional rhabdomyolysis compared with the absence of the trait (HR 1.54; 95% CI, 1.12 to 2.12; p=0.008). 96 deaths were noted among the study participants with no significant difference between those with and without sickle cell trait (HR 0.99; 95% CI 0.46 to 2.13, p=0.97). Women were at lower risk than men (HR 0.51; 95% CI 0.38 to 0.67; P<0.001). Those with age greater than 36 were at higher risk (HR 1.57; 95% CI 1.06 to 2.32; P=0.02). Obesity (HR 1.39; 95% CI 1.04 to 1.86; p=0.03), tobacco usage in the past 6 months (HR 1.54; 95% CI, 1.23 to 1.94; P<0.001), antipsychotic usage (HR 3.02; 95% CI, 1.34 to 6.82; P = 0.008), and statin usage (HR 2.89; 95% CI, 1.51 to 5.55; P = 0.001) were all associated with increased risk of exertional rhabdomyolysis.

This study suggests that there is no association between sickle cell trait and death, but there is a small excess risk for exertional rhabdomyolysis. The policy implications of these results in terms of preventing exertional rhabdomyolysis are not clear, given the small absolute increase in excess risk and that use of statins or antipsychotics conferred greater risk.  The study was limited by using ICD-9 codes to identify cases of rhabdomyolysis, as well as possible selection bias, in that individuals may have had an episode of exertional rhabdomyolysis prior to the study leading to their medical discharge. Also, universal screening for sickle cell trait is not standard practice in the Army, so the study may underreport cases associated with the trait.

Association Between Off-site Central Monitoring Using Standardized Cardiac Telemetry and Clinical Outcomes Among Non–Critically Ill Patients

Frequent telemetry alarms in non-ICU level patients lead to alarm fatigue and are without clinical significance in the vast majority of cases. Dedicated nursing to monitor telemetry alarms is associated with improved recognition of true rhythm events but these are often missed amidst the din of a hospital ward [7]. Inappropriate use of telemetry in patients without indications for it increases costs markedly and adds to alarm fatigue at the expense of recognition of true arrhythmic events.  The implementation of dedicated off-site telemetry monitoring along with standardization of telemetry utilization protocols have been proposed as methods of improving the recognition of true alarms and decreasing alarm fatigue by eliminating the distractions of the hospital environment.

This week in the Journal of the American Medical Association, a study was published examining outcomes from cardiac telemetry monitored at an off-site central monitoring unit (CMU) in non-ICU level patients at a major academic center and 3 regional hospitals. One telemetry nurse monitored up to 48 patients and were able to remotely activate Emergency Response Teams (ERT). Standardization of cardiac telemetry was also undertaken based on guidelines from 2004 American Heart Association necessitating electronic order with indication and advisory to document need for renewal at 72 hours. Total telemetry census was monitored in addition to the primary outcome of ERT activation within one hour based on rhythm and rate alarms. Total number of cardiopulmonary arrests were also tracked.  Data from the 13 month period prior the intervention was compared to the 13 month period post-intervention to generate study outcomes.

Telemetry orders were placed for 99,048 patients with the most common indication (16%) being known or suspected atrial or ventricular arrhythmia. The “other” category also made up 16% of telemetry orders with the most common free-text being monitoring for hypotensive state. The standardization of telemetry was associated with a 15.5% reduction in the weekly telemetry census compared to the preceding 13 month period and persisted throughout the study. The number of cardiopulmonary arrests was 126 pre-intervention and 122 post-intervention. The majority of calls (80%) were noted to be for lead failure.

During the study period, 3243 ERT activations occurred on telemetry monitored patients in which 979 had a detectable rate or rhythm change 1 hour prior to ERT activation. The central monitoring unit notified nursing staff in 772 of these 979 cases appropriately. In the remaining 207 patients that went without notification, 176 were missed events, 16 were alarms with simultaneous activation of the ERT, and 15 were process failures. Many of the missed events were due to rapid activation of the ERT by clinical staff or for minor HR changes of 10-20 which may be of no clinical significance.

In 105 events, the CMU directly activated the ERT in parallel to nursing. 44 of these events were monomorphic ventricular tachycardia, 36 were prolonged pauses/asystole, 14 were polymorphic ventricular tachycardia or fibrillation and 11 were other. 27 of these episodes were CPR events.

This study indicates that off-site telemetry monitoring may be a useful adjunct to current clinical practice as there was no change in cardiopulmonary arrests and a reduction in the weekly telemetry census. However, alarm fatigue remains an issue as 80% of calls from the CMU to the nursing unit were for lead failure. Furthermore, this study which was performed at a large tertiary center may be difficult to generalize to smaller or rural hospitals. [8]

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis

In multiple sclerosis, an acquired inflammatory autoimmune disease targeting the central nervous system, use of immune modulating therapies to target inflammation has had some success, however there is ultimately relapse and progression. Autoimmune disease regression in patients undergoing haemopoetic stem cell transplant (HSCT) for malignancy have been noted in previous studies [9]. Given this potential benefit, a phase 2 single arm study at 3 Canadian hospitals enrolled patients with a poor prognosis (early relapse, high probability of progression, disability) to undergo busulfan, cyclophosphamide, and anti-thymocyte globulin for immune-ablation and destruction of immunological memory followed by autologous HSCT, with the desired goal of eliminating CNS autoimmunity while still ensuring adequate immune function. Baseline and frequent interval follow-up MRI with gadolinium were performed to follow lesions along with evaluation of the Expanded Disability Status Scale (EDSS). Primary outcomes were MS activity-free survival at 3 years with events including: clinical relapse, new MRI lesions or progression on the EDSS. Secondary outcomes were time to treatment failure and overall morbidity and mortality due to HSCT. 24 patients with active disease underwent HSCT from 2001 to 2009.

The primary outcome of multiple sclerosis activity free survival at 3 years was 69.6% (95% CI 46.6-84.2) mainly driven by sustained progression in Expanded Disability Status Scale. From diagnosis of MS to transplantation, there were 167 relapses in 24 patients (mean 1.2 relapses per patient year). Following transplantation, there were no episodes of clinical relapse in any of the 23 patients who survived HSCT (0.0 relapses per patient year). There were 93 and 95 Gadolinium enhancing lesions on the two pre-treatment MRIs. After HSCT, none of the 327 follow-up scans showed Gadolinium enhancing lesions. One patient died due to hepatic necrosis and Klebsiella sepsis secondary to Busulfan dosing, which was adjusted during the trial to prevent further medication-related side effects.  Following HSCT, 6 patients (26%) suffered shingles, and 6 patients (26%) suffered secondary autoimmune events.

These results suggest that HSCT can result in lasting disease remission in patients with unrelenting, refractory MS. Though these a results are promising, a prospective randomized trial is needed to evaluate this therapy as a mainstay of treatment.  Notable limitations in the study include the lack of control group and that this was a small study cohort. The authors note that patient selection is key, given that previous studies with relapse occurred in patients without clear evidence of ongoing inflammatory disease secondary to MS [10].

Minicuts

A multi-center open label randomized controlled study at 10 pulmonary clinics in northern Vietnam found that point of care C-reactive protein testing reduced the use of antibiotics in acute respiratory tract infections without affecting patient recovery [11]

In a large chronic heart failure cohort taking statins there was no significant difference in exercise tolerance, aerobic capacity, and quality of life. This contrasts previous studies indicating decrease in exercise tolerance during statin usage [12]

Inflammatory bowel disease patients are 33% more likely to experience recurrent Clostridium difficile infection (rCDI) compared to the general population in the RECIDVISM study. Exposure to antibiotics, 5-ASA, certain biologics (Infliximab) are predictors of rCDI, along with having non-ileal Crohn’s disease [13]

Nathan Teich, MD is a second year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Benjamin Milgrom, MD Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References 

  1. Tom McGowan, John Sinnott, Eoghan Macguire and Shasta Darlington. Rio Olympics: Is Brazil ready for the 2016 Games? CNN. July 30 2016. http://edition.cnn.com/2016/07/29/sport/olympics-2016-venues-rio-brazil-russia-ban-zika/
  2. Jon Schuppe, and Kelly Cobiella. How Yursa Mardini Survived a 25-Day Trek From Syria And Became an Olympia. NBC News. August 5 2016. http://www.nbcnews.com/storyline/team-refugees/how-yusra-mardini-survived-25-day-trek-syria-became-olympian-n601946 
  3. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N. Engl. J. Med. 317: 781-7 (1987). http://www.ncbi.nlm.nih.gov/pubmed/3627196
  4.  Diggs, L. W. The sickle cell trait in relation to the training and assignment of duties in the armed forces: IV. Considerations and recommendations. Aviat. Space Environ. Med. 55, 487-492 (1984). http://www.ncbi.nlm.nih.gov/pubmed/6466242
  5.  Harmon, K. G., Drezner, J. A., Klossner, D. & Asif, I. M. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br. J. Sports Med. 46, 325-330 (2012).
  6.  Nelson, D. A. et al. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N. Engl. J. Med. 375, 435-442 (2016).  http://www.nejm.org/doi/full/10.1056/NEJMoa1516257
  7. Stukshis, I., Funk, M., Johnson, C. R. & Parkosewich, J. A. Accuracy of detection of clinically important dysrhythmias with and without a dedicated monitor watcher. Am. J. Crit. Care 6, 312-317 (1997).
  8. Cantillon, D. J. et al. Association Between Off-site Central Monitoring Using Standardized Cardiac Telemetry and Clinical Outcomes Among Non-Critically Ill Patients. JAMA 316, 519-524 (2016). http://jama.jamanetwork.com/article.aspx?articleid=2540401
  9. Arruda, L. C. et al. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr. Res. Transl. Med. 64, 107-113 (2016). http://www.sciencedirect.com/science/article/pii/S2452318616300022
  10. Atkins, H. L. et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet (2016).
  11. Do, N. T. et al. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob. Health. (2016). http://www.thelancet.com/journals/langlo/article/PIIS2214-109X(16)30142-5/references
  12. Kelly, J. P. et al. Statins and Exercise Training Response in Heart Failure Patients: Insights From HF-ACTION. JACC Heart Fail. 4, 617-624 (2016).
  13. Razik, R., Rumman, A., Bahreini, Z., McGeer, A. & Nguyen, G. C. Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study. Am. J. Gastroenterol. 111, 1141-1146 (2016). http://www.ncbi.nlm.nih.gov/pubmed/27215924