Sickle Cell, Pain and the Emergency Department

January 27, 2020January 25, 2020 ~ Bryn Dhir, USA ~ Leave a comment

It’s 2 AM, and the Pediatric Emergency Department (ED) at a community hospital in New York is overflowing with children and caregivers. A young Nigerian boy is being transported down the center of a hallway, past a long line of doors to patient rooms. The porter is calm and walks briskly, determined to bring this boy to get immediate care. The boy winces, his hands outstretched next to him, rigid, and frozen in space, and while he is seated in the wheelchair, his legs bent at the knees are thin frames, held in place with his feet planted on the wheelchair pedestals. He is afraid to move any of his extremities; tears are rolling down his face; he is fighting the urge to grimace and furrow his brow. He cries how much it hurts to move. He knows he needs help. Behind him, his mother follows close holding a one-year-old baby in her arms, and behind her, five other young children aged 3 through to thirteen stream in. There is quiet concern on all of their faces. The older siblings have seen this before. We learn that he has Sickle Cell Disease (SCD). He has been in excruciating pain for the past 4 hours and is now presenting with dactylitis. This case has not been the first in this ED, and like other EDs across the United States and in the world, the number of cases presenting with SCD will increase.

Sickle Cell Disease (SCD)

SCD is a condition that causes red blood cells to morph from a biconcave dumbbell-shaped disc, into a rigid semi-circular shape. This disease is inherited genetically by receiving two sickle genes, one from each parent and risk for complications are attributed to a variety of factors, including deoxygenation, dehydration. It is most common in African Americans as well as Latinos and people of Middle Eastern, Indian, Asian and Mediterranean backgrounds. In the United States, SCD is the most common genetic blood disorder and affects approximately 100,000 Americans(1) and although babies are screened at birth, management plans vary with the degree of disease progression and exacerbation severity, as well as with the availability of resources and education.

RBCs in Sickle Cell Disease — Image: Sickle cells and normal red blood cells from Sickle Cell Disease, Genome. Gov

Why Emergency Physicians need to be Familiar with SCD

SCD affects both pediatric and adult patients, and it has been reported that patients between the ages of 18 to 30 years old have increased emergency department utilization. A major reason for this is due to the transition by young adults from pediatric to adult care in the management of SCD, and this population is simultaneously also learning to navigate the health care system and community resources (pediatric to adult care, insurance, independent decision making, housing, education, workforce) as discussed further below(2). In addition, the use of community health workers is important as they can act as liaisons between the health care systems and patients to disseminate information and resources. However, despite the awareness of the disproportionate use of the ED among patients with SCD, the social factors that impact care remain unknown(3) and more research and investigation is needed to understand this patient population.

Often when a complication or crisis occurs in patients with SCD, patients seek immediate care in the Emergency Department. Included in the potential list of complications include infections, such as those with encapsulated bacteria; sepsis; stroke; splenic sequestration, and early treatment is essential in managing patients. Of these complaints, the emergent cases to be aware of in the ED include vaso-occlusive crisis and pain, sickle cell anemia (SCA)(4) central nervous system such as stroke, and acute chest syndrome (ACS), where ACS due to blocked capillaries in the lungs, may be caused by infections, asthma exacerbations and/or pulmonary embolisms, and is the leading cause of morbidity in patients with SCD. Further, the Emergency Severity Index (ESI) Version 4 triage system, commonly used in the majority of EDs in the United States, suggest that patients with SCD be triaged as ESI level 2, indicating a very high priority, and that rapid placement be facilitated(5).

Although the discussion of complications of SCD including the presentation and management is a complex topic, and will be covered in detail in future posts, information and algorithms for clinicians are available online for reference. One such resource is a treatment algorithm that acts as a how-to guide for SCD and is available online in the Annals of Emergency Medicine(6). This approach is based on the point-of-care hemoglobin level, and discusses issues such as myonecrosis, aplastic crisis, ACS.

Pain in SCD

When tissues and organs are not adequately perfused with oxygen, in part due to the sickled shape of RBCs, tissue damage and death can occur. Patient management of vaso-occulusive crisis and pain varies by practices and the medications available for use around the world, however it is important to note that pain in patients with SCD is often extreme and may require treatment with opioids. In a response to the American Society of Hematology (ASH) draft recommendations to Sickle Cell Disease-Related Pain in May 2019(7), emDOCs.net published a response to the drafted recommendations and offered insight to pain management and includes an algorithm(8). The insight provided is essential in decreasing the suffering experienced by patients during an SCD crisis, and notes the use of Dilaudid, Ketamine, Dexmedetomidine, and Lidocaine. Further, the understanding of limiting the use of NSAIDS due to impaired renal function caused by the disease is also outlined in the response.

Management of pain in pediatric patients with SCA and vaso-occulsive pain also varies according to hospital and individual provider practices, and scientific investigation and patient research is needed to provide proper care to this population. An example includes a study by PECARN addressing the use of a normal saline bolus in pediatric emergency departments found an association with poorer pain control(9). Identifying and implementing results from research studies is important in understanding and managing SCD in both adult and pediatric patients.

Emergency Physicians around the world should be aware of strategies for identifying SCD, and management, specifically in areas around the world where refugees from countries with SCD prevalence is common. Countries where refugees and migrants are commonly are known to disembark, such as those in southern Europe(10) and certain areas in the United States and Canada would benefit from in-depth analysis of the issue and could allow for appropriate and accessible health care to vulnerable populations, as well as educate providers who are unexposed to managing emergencies in SCD patients while setting in place integrated and individual health plans away from emergency room dependence(11). In developing countries with SCD populations, such as Nigeria, there is a high prevalence of pediatric emergency cases, and the proper management of the disease as well as policy and hospital organization for high volume and off-hour admissions, may reduce hospital stays(12). Further, the self-efficacy of adult patients with SCD, from education, pro-active efforts, understanding of disease management, also can allow for decreased ED visits and hospitalizations for pain(13).

Investigations, Resources, Education

A number of investigative studies, clinical trials and research is being conducted around the world for a better understanding of SCD, including patient care in adult and pediatric patients, genetic factors, supportive services, associated co-morbidities, and search for cures. Investigations around the world include collaborations and information sharing between academic researchers, patients, clinical providers, and health care providers and officials around the world.

The National Heart, Lung, and Blood Institute hosted a series of Webinars in September 2018, during Sickle Cell awareness month from experts in blood science and sickle science research and are available to watch for free online(14). Some of the key highlights from two of the webinars: Serving the Sickle Cell Disease Community Here and Abroad; Sickle Cell Transitional Care from Childhood to Adulthood, are discussed here.

Webinar Overview Serving the Sickle Cell Disease Community Here and Abroad
Presented by Dr. Keith Hoots, Director of Division of Blood Diseases and Resources, NHLBI

Prevalence of the disease is so much larger in Africa than most places in the world. There are as many babies born with SCD born in Nigeria there are babies born with SCD, by estimate, as there almost are total people with SCD in the United States.
There is a need to share research and practices in the developed world with the developing world.

Three New Research Initiatives in Africa:

The Sickle Pan-African Research Consortium (SPARCO)
Overview: The study sites for this research include East Africa (Tanzania), West Africa (Ghana, Nigeria) and central Africa (Cameroon, Democratic Republic of Congo) with the goal to later include 20 sites in 15 countries. SPARCO’s aim is to develop an SCD database, standards of care, and strengthen research investigation.
Realizing Effectiveness Across Continents With Hydroxyurea (REACH):
Overview: Safety and dosing of hydroxyurea therapy for SCA in pediatric patients in sub-Saharan Africa; sponsored by the Children’s Hospital Medical Center, Cincinnati
Sickle Cell Disease Genomics of Africa (SickleGenAfrica)
Overview: The purpose is to develop strategies to predict, prevent and treat organ damage in SCD and to investigate biomarkers associated with the development of organ damage, including molecules released during red blood cell damage in sub-Saharan African populations.

Webinar Overview: Sickle Cell Transitional Care from Childhood to Adulthood
Part 1 Presented by Dr. David Wong, MD, FAAP, Medical Officer, Office of Minority Health

SCD is no longer a childhood disease. Young adults are at a higher risk for hospitalization due to illness and pain.
Treatment and management examples in childhood include annual transcranial dopplers to assess for risk of stroke; vaccinations; hydroxyurea; L-glutamine; opioids for pain management; penicillin prophylaxis; RBC transfusions; water intake to avoid exacerbations due to dehydration; splenectomy. The cure available is bone marrow transplant.
Prior to July 2017, Hydroxyurea was the only FDA approved therapy for 20 It is used in adults and children. It has been shown to reduces hospital admissions, pain crisis, and ACS however barriers to hydroxyurea use exist. These include difficulty with communicating the use to patients and caregivers, issues with frequent monitoring, lack of adherence, lack of provider knowledge and comfort with its use.
Community Health Workers (CHWs) are key players in effective patient care. CHW can provide information affected by social and health determinants from local economic and environmental (housing, employment), local communities (families, safety, support), activities (learn, work, play, move, shop), lifestyles (alcohol, drugs, smoking, sexual health, physical activity, and individual needs (age, genetics). CHW are experts in condition-specific information and navigating complex health systems, including accessing care in a medical home (the approach to providing comprehensive care). This is particularly important when care is not always contained or organized by one organization, where care should be accessible, continuous, comprehensive, family-oriented, coordinated, compassionate and culturally competent. Pediatric medical home principles include family-centered partnerships, community-based systems, transition care, value. Interventions for education such as warning signs and treatment options and links to care are important.
The SCD Newborn screening program, and the Sickle Cell Disease Treatment Demonstration Program for patients who solely rely on the ED for SCD care, aid the care options for patients with SCD.

Follow this iEM story for part two which will include information on adult and pediatric management of SCD in the ED, as well as an overview of four NHLBI webinars: Holistic Health and Sickle Cell Disease A Focus on Mental and Behavioral Health; Genetic Therapies in Sickle Cell Disease; Bone Marrow Transplants, Other Therapies, and Sickle Cell; Improvement Initiatives and Ongoing Research.

References

1 Centers for Disease Control and Prevention: Sickle Cell Disease

2 Sickle Cell Transitional Care from Childhood to Adulthood: Youtube

3 Journal of Pediatric Hematology/Oncology. 42(1):e42–e45, JANUARY 2020, DOI: 10.1097/MPH.0000000000001669 PMID: 31743315

4 Porter M. Rapid fire: sickle cell disease. Emerg Med Clin North Am. 2018;36:567–576

5 Evidence Based Management of Sickle Cell Disease: Report

6 Sickle Cell Crisis and You: A How-to Guide, Raam R., Mallemat H., Jhun P., Herbert M. (2016) Annals of Emergency Medicine, 67 (6) , pp. 787-790

7 The American Society of Hematology Website:

8 ED Management of Sickle Cell Vaso-occlusive Crises: Myths, Facts, and A Novel Approach to Acute Pain Management, EMdocs.net website

9 Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso-occlusive pain, Am J Hematol. 2019 Jun;94(6):689-696

10 Lucia De Franceschi, Caterina Lux, Frédéric B. Piel, Barbara Gianesin, Federico Bonetti, Maddalena Casale, Giovanna Graziadei, Roberto Lisi, Valeria Pinto, Maria Caterina Putti, Paolo Rigano, Rossellina Rosso, Giovanna Russo, Vincenzo Spadola, Claudio Pulvirenti, Monica Rizzi, Filippo Mazzi, Giovanbattista Ruffo, Gian Luca Forni; Access to emergency departments for acute events and identification of sickle cell disease in refugees. Blood 2019; 133 (19): 2100–2103

11 Sickle Cell Disease Training And Mentoring Program Website

12 Robert M Cronin, Tim Lucas Dorner, Amol Utrankar, Whitney Allen, Mark Rodeghier, Adetola A Kassim, Gretchen Purcell Jackson, Michael R DeBaun, Increased Patient Activation Is Associated with Fewer Emergency Room Visits and Hospitalizations for Pain in Adults with Sickle Cell Disease, Pain Medicine, Volume 20, Issue 8, August 2019, Pages 1464–1471

13 Enyuma, Callistus Oa et al. “Patterns of paediatric emergency admissions and predictors of prolonged hospital stay at the children emergency room, University of Calabar Teaching Hospital, Calabar, Nigeria.” African health sciences vol. 19,2 (2019): 1910-1923. doi:10.4314/ahs.v19i2.14

14 National Heart, Lung, and Blood Institute Webinars

* Images from The Sickle Cell Disease Tool Kit.

Cite this article as: Bryn Dhir, USA, "Sickle Cell, Pain and the Emergency Department," in International Emergency Medicine Education Project, January 27, 2020, https://iem-student.org/2020/01/27/sickle-cell-pain-and-the-emergency-department/, date accessed: April 2, 2023

Advantages of Global Health and International Emergency Medicine Outreach Experiences

December 4, 2019December 4, 2019 ~ Bryn Dhir, USA ~ Leave a comment

Wherever you go, be all there

– Jim Elliot

International medicine is among the most valuable experiences not only for residents and students, but for physicians from all specialties. Emergency medicine (EM) physicians, in particular, have previously been highlighted with critical qualities and characteristics essential to successfully providing medical aid and care in some of the most remote regions, rugged wilderness, and disaster zones. In recent years, the practice of physicians travelling overseas with the goal of outreach, and professional and personal development, has been met with the flux of international patients travelling to the United States and Canada in search of medical treatment, as well as international physicians seeking to develop their own clinical skills and enhance medical practices to take back home. Physicians and patients both face challenges associated with these new experiences: the stresses of traveling, financial concerns, family obligations, cultural practices, and preparing for the unknown. As such, it is important to remember that patients also encounter anxiety, cultural and communication differences, have concerns for the continuity of care associated with filling in missing gaps in their own medical records and fluctuating medical aid providers and often lack medical knowledge and understanding of health issues. Interactions that patients have with visiting physicians can also allow patients to gain insight into new practices, cultures and traditions. These experiences can be life-changing for everyone involved.

While global outreach, international medicine or disaster preparedness isn’t for everyone, it is important to remember that global health does not equate to the definition of international medicine, and that there is a strong need for domestic medical outreach in rural America and Canada, in locations that present with similar challenges of underserved patient populations and with limited resources. Nonetheless, the benefits of medical work in new environments outside of comfort zones can provide tremendous benefits and contributes to the overall continuous development of a well-rounded physician. The advantages of participating in global health and international medicine are extensive, and this article highlights only some of the major benefits.

Strengthen leadership, communication and interpersonal skills

Before EM physicians begin their medical work with patients, the potential to strengthen leadership, communication and interpersonal skills through interactions with local residents is often experienced with language being a major factor in effective communication. This includes not only the spoken word, knowledge of key phrases in the native tongue, but the use of body language, eye contact, and hand gestures. Understanding different approaches to patient scheduling, staff and local perceptions about meal, travel and leisure times, administrative and medical support, and negotiation and conflict management skills, allows for a more productive and enjoyable experience. Further, not only are individual skills, but so is teamwork and an understanding of the functional dynamics. Participation in outreach contributes to the development of many skills including independent decision making, project management (from funding to administration, allocation of materials and supplies, to public relations and follow up), and creativity in the face of limited resources.

Cultural Competency

Exposure to patients contributes to cultural awareness, understanding of the impact of socioeconomic factors on health care, historical and geographical issues, and puts to use clinical and language skills while immersed in a new environment. Participating in local events is a valuable learning experience, and clinical work in the developing world or remote rural locations in North America can contribute to a physician’s ability to understand and advocate for patient health care needs.
These basics will allow for a better understanding of cultural differences, institutional and policy barriers, communication barriers, managing through unknown and incomplete medical records, financial constraints which can limit tests and treatments, and influence management as medical work begins. Numerous resources are available for emergency physicians entering new environments for the first time to help provide insights regarding gender issues, cultural practices, religion, politics, current social events to name a few. It is important to do thorough background research into patient populations and to be aware of the community you will be entering. For EM physicians in rural North America, opportunities to work with nongovernment organizations and refugees can provide exposure to international and global patient populations who need your clinical skills and medical training. The American College of Emergency Physicians(1), Emergency Medicine Residents Association(2), Society for Academic Emergency Medicine(3), offer thorough information and resources for rotations and fellowships for international emergency medicine, and the American Academy of Family Physicians lists resources for physicians interested in Global Health(4). A list of additional reading and resources is provided below.

Exposure to new practices and health care systems

Physician shortages and limited financing of healthcare are global concerns; however, there is an excellent benefit for physicians who learn to treat and understand a variety of patient populations despite these limitations.

This is an essential obligation of EM physicians. International medical rotations are a concept that has slowly been incorporated into medical schools. Nearly ten years ago, a survey published in Academic Medicine concluded that international rotations broadened medical knowledge and reinforced physician examination skills(5).

International rotations broadened medical knowledge and reinforced physician examination skills.

– Academic Medicine

Further, learning about other healthcare systems, medication preferences and availability, and equipment as well as protocols and practices, can allow for incorporating practices back home, as well as suggesting sustainable changes for improvement overseas.

The challenge of thinking outside the box and learning to be resourceful with equipment is yet another benefit to international medicine, where poverty-related diseases demand thoughtful consideration to resources and long-term management of patient cases. Distinguishing differences among clinical practice and procedural skills in a respectful, intuitive manner and with an understanding of varying standards of care and limited resources is also essential for international outreach. While dealing with these issues may be frustrating, maintaining confidence in one’s own training, calling on previous life experiences and harnessing multi-disciplinary teams with diverse cultural backgrounds, will prove to be beneficial in providing effective patient treatment. Besides, exposure to other health care systems can allow for research into the best strategies for administration and management, for not only physician practices, but for patients and health care systems at large.

Medical Knowledge, Self-Sufficiency, Resources and Equipment

Caring the patients reveal the diversity of diseases and disorders and provide insight on the local health care issues. The variety of cases differs between hospital and ambulatory settings. EM physicians have the opportunity to see and manage rare diseases and disorders uncommon back home, with a highlight on cases involving infectious diseases, toxicology, advanced diseases. Knowledge of disease presentations, prevalence, and exposure to the seemingly foreign diseases has been a recent consideration with the migration of people not only at the international scale, but at the local level across the States. Social, mental, and financial support is another layer that health care systems are working to provide for these vulnerable patient populations. Moreover, the added pressure of finding solutions for medical cases requiring advanced procedures can be disheartening, and EM physicians must become the nurse, specialist, social worker, therapist, surgeon, administrator, pharmacist and physical therapist all in one. Creative uses of equipment, thinking outside the box, and making use of what is available are other factors that will be frequently tested while in the field. Training in the wilderness and extreme medicine, as well as rural family medicine practices is advantageous for physicians in the global setting where multiple uses for one instrument is applied in various situations. Nonetheless, adhering to the training in medical school and residency is the basis for all medical work and ethical best practice, professionalism and management are the foundation to providing patient care regardless of location.

In response to the growing interest and need for physicians in underserved global populations, there has been an increase in funding opportunities.Prior to embarking into unknown territory and patient scenarios, it is recommended that a physician’s own resources are known, including potential health risks, and that support systems are in place in order to maintain a mental and physical balance to provide care where it is desperately needed. Culture shock, grief and sadness, personal debriefing and reflection, and adjusting to life back home is an additional element to tend to.

Outreach, Education, Research, Mentorship

The opportunity to provide preventative and screening information directly to patients through clinics and to physicians at training sessions allows for direct two-way communication, clarity and the sharing of knowledge bases. Additional outreach at clinics and mobile health units often add to the overall value and maximizes a physician’s ability to provide outreach and education. Furthermore, opportunities may exist for collaborations with clinicians and scientists as well as health policy advisors. Although the notion of global health has attracted the fad of medical tourism and entails a certain novelty of volunteering abroad, emergency physicians have a great opportunity to make a lasting difference on the lives of their patients as well as those of international colleagues who are either interested in practicing in North America(6) or who will stay with the communities and health systems they are in. Therefore, building and fostering a network of connections for the future is an important and positive outcome, with the potential to provide up to date journal articles, resources to evidence-based medicine and free online medical education, and can allow you to incorporate global health initiatives and outreach back home. At the end of the day, physicians who are driven to extend their medical knowledge and clinical skills into regions with a desperate need for health care and vulnerable patient populations are often those who have made the commitment to serve as an emergency physician.

The experience of a global project and working in a clinic on an international scale enables EM physicians and students from all levels of training to provide care in emergent situations from disaster and humanitarian relief to outreach clinics. For physicians and students who opted to pursue medical education in a global setting, as an international graduate or for North American physicians who thrive on global health and international outreach, the experiences are unlike those in North America, and there is an abundance of personal and professional learning and development to gain. Experiences outside of comfort zones, whether in rural America or overseas, create a global community to better medical practices and often advocacy for health care continues long after a global project has concluded.

The Model of the teaching hospital, which links research to teaching and service is what's missing in global health

– Paul Farmer

This article touched on the advantages and benefits of stepping outside comfort zones to provide medical care to vulnerable patient populations, and a follow up to this article will be how to overcome the challenges and barriers that physicians may encounter. Have you participated in a global health project or international outreach? Please feel free to share your own thoughts and reflect on your experiences in the comments section below.

Additional Reading and Resources

What is International Emergency Medicine? Academic Life in Emergency Medicine – link
International Emergency Medicine Section, American College of Emergency Physicians – link
The Practitioner’s Guide to Global Health, American College of Emergency Physicians – link
US Residents: Discover the World with Emergency Medicine, Emergency Medicine Residents Association – link
Fellowship Database, Society for Academics Emergency Medicine – link

Link To References

Images for Global Health and International Medicine courtesy of author, Bryn Dhir.

Cite this article as: Bryn Dhir, USA, "Advantages of Global Health and International Emergency Medicine Outreach Experiences," in International Emergency Medicine Education Project, December 4, 2019, https://iem-student.org/2019/12/04/advantages-of-global-health/, date accessed: April 2, 2023

The Research of Predicting Septic Shock

How computational medicine is changing critical care in 5 questions

August 12, 2019September 4, 2019 ~ Bryn Dhir, USA ~ Leave a comment

Participating in Research

As a new school year approaches, many medical students are opting to take a gap year dedicated to research. This trend is unique for students not in MD/PhD programs in the USA who have a deep interest in understanding and participating in research. A popular emerging field for the future of health care and medicine, known as computational medicine, is become an integral part of patient care. Regardless of location, students, as well as interns and health care professionals around the globe who are interested in emergency and critical care medicine, should consider this unique area of study as a part of their research gap year.

In this blog entry for the International Emergency Medicine Education Project (iEM), I discuss the role of computational medicine in detecting sepsis, one of the most important diagnoses to detect early, with Professor Rai Winslow, Director of the Institute for Computational Medicine at The Johns Hopkins University. As outlined on the Institute’s website, computational medicine “aims to improve health care by developing computational models of disease, personalizing these models using data from patients, and applying these models to improve the diagnosis and treatment of disease.” Patient models are being used to predict and discover novel sensitive and specific risk biomarkers, predict disease progression, design optimal treatments, and discover novel drug targets. Applications include cardiovascular and neurological diseases, cancer, and critical care and emergency medicine (1).

How is computational medicine changing critical care?

5 Questions

5 Answers

Why Sepsis

What was the starting point for your work on sepsis and septic shock in adults?

A starting point for my work on sepsis and septic shock was reading a paper that demonstrated how every hour of delayed treatment in patients with septic shock could lead to an eight percent increase in mortality, per hour. That statement really stood out because what it told me was the natural time course of evolution of the disease, and whatever was happening in septic shock, was happening very quickly. Because of this rapid disease progression, this suggested that accurate prediction of those patients with sepsis who would progress to septic shock must be based on data collected from the patient on a time scale of minutes rather than hours. The challenge was that this high-rate data is not routinely collected in hospitals.

Data and algorithms

What live data are the algorithms capturing from patients for studying and understanding sepsis and septic shock?

Today’s electronic health record (EHR) is typically used to store data such as vitals and lab results and clinical observations made at irregular intervals and at low rates. Given the rapid evolution of septic shock, we hypothesized that advanced prediction and early detection of septic shock must be based on data collected at the minute rather than hour time scales. This was the driving interest in developing a novel software platform called PhysioCloud. PhysioCloud captures physiological vital signs data at minute intervals from patient monitors. These data are then stored in a specialized database that is designed to capture large numbers of real-time data streams at high-rate. Data collection also includes waveforms, such as ECG, respiratory rates, and SpO2, sampled at 125 times per second. Nowhere else in the USA that I am aware of, is capturing these physiological data from patients, making them a part of the patient electronic health record. Our algorithm uses these high rate data, as well as low-rate data from the patient EHR, to predict those patients with sepsis who will develop septic shock.

The importance of the transition state to septic shock

Computational medicine and algorithms can be uncomfortable terms for medical students, interns and researchers who do not have experience with it. Simply put, how do research and studies such as this help doctors in emergency medicine and critical care units, in managing their patients?

Everyday critical care and emergency medicine physicians ask two questions of every patient they see: what is the state of my patient?; how will their state change over time? The latter is a prediction problem of the sort that data scientists often confront. In the context of sepsis, the physician would like to know if their patient will at some future time develop septic shock, or will their condition improve. If an algorithm can reliably predict those patients with sepsis who will develop septic shock at some future time point, then physicians will have a window of time in which they can intervene to prevent this transition from happening. Our goal was to develop such an algorithm. To do this, we utilized the obvious fact that if a patient has sepsis and their condition is getting worse and possibly evolving towards septic shock, it means their physiology must be changing over time as they get sicker. We, therefore, decided to develop a “risk score,” a number ranging between 0 and 1 that is the probability that a patient will develop septic shock. This risk score was computed in an optimal way from the minute by minute physiological vital signs data complemented by clinical data from the EHR. If this risk score exceeds a threshold value, then we decide that this patient with sepsis will develop septic shock at some future time point. This approach works very reliably, achieving high sensitivity and specificity. It’s the worlds simplest machine learning method. Predicting the transition from sepsis to septic shock can enable physicians the ability to follow their patients and see how various states are evolving over time, so that they can intervene to deliver earlier care. Right now, this approach is being applied in retrospective studies using patient data. In the future, we plan to compute this risk score in real-time, generating alerts for caregivers when the risk score exceeds threshold signaling that patients are likely to go into septic shock.

Pre-Shock

In a recent publication in Scientific Report (2), the new concept of a pre-shock state was outlined. How was this possible to do?

Our work hypothesized that it was possible to identify the presence of a physiological signature in sepsis patients before the clinical onset of septic shock was diagnosed. We were able to identify a signature to calculate a risk score for the pre-shock state. The changes in variables such as lactate and heart rate are so small; they are still statistically significant, but so small. When discussed with physicians, some say that they would not have noticed it. These variables are changing together in a small way, but the algorithm is able to catch the changes together and compute it into a risk score and make useful predictions. Some of our very new work not published yet shows that post-threshold, changes in patient risk score happen very quickly (30-60 minutes) and are very large. We have shown that the larger the post-threshold risk score, the more reliable is our prediction that the patient will go into shock. Positive predictive value can be as high as 80-90%.

Fluids and Vasopressors

Evidence-based studies and protocols such as the SOFA score (3), Surviving Sepsis Campaigns (4) are listed on the American College of Emergency Physician (ACEP) website (5) as well as the SALT-ED (6) and SMART (7) trials. These are referred to by emergency physicians in the emergency department, and EM residents are trained with these resources. How do these studies tie into computational medicine, machine learning and predictive analysis for developing septic shock?

Our algorithm looked at tens of thousands of patients, and computationally phenotyped them through every minute of data using the international consensus definition of septic shock, and based on early warning times, found clinical ground truth. We also discovered that the Sepsis 2 definition had a property that was temporarily unstable. This is to say that the state of a patient with sepsis as defined by Sepsis 2, was changing all the time, and it was not possible to predict ground truth. With found the Sepsis 3 definitions to be temporarily stable with few state transitions. The major factor was that the criteria in Sepsis 2 had included a diagnosis of SIRS before sepsis was considered as a diagnosis, and it was removed from 3. We believe that SIRS was causing frequent state changes, as an ambiguous diagnosis.

We are able to predict those patients with sepsis who will transition to shock many hours before they go into shock. We are also able to identify distinct temporal patterns of the risk score corresponding to patient populations with high (up to 60%) versus low (10-20%) mortality. For each of these groups, we looked at comorbidities, diagnoses such as kidney failure and cancer, but we do not know what the relationship is or what is different about these patient groups and the fact that they are in the 60% mortality pool. We know their physiology is saying they are in the mortality pool, but not why. What this means is how these patients are being treated could be the issue (physicians with different levels of training, and other factors involved in treatment decisions). In our work, patients were classified into high and low risk. We found that patients in the low risk received vasopressors and adequate fluid resuscitation and for patients in the high-risk pool, fewer had received vasopressors or fluids. The question is, why are these patients not getting these things. Our algorithm to predict the transition to septic shock can positively influence treatment decisions made by many physicians, to confirm the value of treatment and prevent the development of septic shock. We’ve also identified and know the time to look for proteomic and genomic biomarkers for the early predictive shock signature that could correlate with this high risk/these measures are not routinely done clinically, and this line of work could be very helpful in understanding the fundamental biology of the very rapid change in patient state when they cross the risk score threshold.

Thank you to Professor Winslow for taking the time to discuss the research involved in computational medicine and investigating the transition from sepsis to septic shock. In closing, regardless of medical specialty interests, medical students around the globe interested in taking a gap year to gain research skills will find the experience invaluable and will be introduced to new ways of thinking, writing, and understanding the scientific influences on patient management and health care. Research such as this in the USA can also be implemented at international hospitals and remote clinics, to further aid patient care and management. There are many areas of interest in which research is taking place in critical care units and emergency departments, and discovering the technology involved such as machine learning and computational medicine, is a step towards understanding the potential advances in the future of medicine and patient care.

Please feel free to share your own particular research area(s) of interest and pose any questions you may have in the comments section below.

References and Further Reading

The Institute for Computational Medicine (ICM) – https://icm.jhu.edu/
Liu R, Greenstein JL, Granite SJ, Fackler JC, Bembea MM, Sarma SV, Winslow RL. Data-driven discovery of a novel sepsis pre-shock state predicts impending septic shock in the ICU. Scientific reports. 2019 Apr 16;9(1):6145. – https://www.nature.com/articles/s41598-019-42637-5.pdf
Faust J. No SIRS; quick SOFA instead. Annals of Emergency Medicine. 2016 May 1;67(5). – https://www.annemergmed.com/article/S0196-0644(16)00216-X/pdf
Surviving Sepsis Campaign (SSC) – http://www.survivingsepsis.org/Pages/default.aspx
ACEP Statement on SSC Hour-1 Bundle – https://www.acep.org/by-medical-focus/sepsis/
Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, Slovis CM, Lindsell CJ, Ehrenfeld JM, Siew ED, Shaw AD. Balanced crystalloids versus saline in noncritically ill adults. New England Journal of Medicine. 2018 Mar 1;378(9):819-28. – https://www.nejm.org/doi/full/10.1056/NEJMoa1711586
Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD. Balanced crystalloids versus saline in critically ill adults. New England Journal of Medicine. 2018 Mar 1;378(9):829-39. – https://www.nejm.org/doi/full/10.1056/NEJMoa1711584