VCOM Carolinas Research Day 2023

Clinical Case-Based Reports

Compartment Syndrome of All Extremities in the Setting of COVID-19 Induced Myopathy and Systemic Capillary Leak Syndrome Robert Zeller, OMS-III, Casey Morehouse, OMS-III, Aaron Provisor, MD, Michael Naylor, MD, Tom Lindsey, DO. Prisma Health – Tuomey, Sumter, SC Edward Via College of Osteopathic Medicine – Carolinas Campus Abstract # CBR-25

Hypotheses & Limitations. The COVID-19 pandemic has been met worldwide with immense fear and controversy, and it remains not fully understood or met with skepticism [28] . This case is reported in the hopes that the scientific community and public may gain a better understanding of the potential impacts of this disease. A significant limitation is that much of this paper’s discussion demands hypothetical reasoning based on known facts and reasonable pathophysiology, as well as knowledge of similar cases that have been previously described [13],[18],[20],[22],[24],[25],[28],[29] . The case presented here is also limited by the situational demands, which restricted the initial workup. Though not mandatory for the diagnosis, we would like to have obtained evidence of monoclonal gammopathy of undetermined significance (MGUS), seen in 85-95% of SCLS cases by serum protein electrophoresis (SPEP)( Figure 4 ) [8] . Pathophysiology. Figure 1 was created to explain what is currently understood about SCLS [7] . Further, it is known that there is a Th1 skewed cytokine storm experienced in certain populations with COVID-19, which initiates the cascade required for SCLS to occur [30],[31] . Elsewhere, SCLS may occur in response to autoimmune phenomena and certain medications [8],[29] . Presently, it is unknown what may predispose a COVID-19 patient to experience SCLS; however, the years to come may unravel more through COVID-19 cases continuing even today . Management. The extravasation phase of SCLS is typically when recognition becomes possible, as the prodromal phase presents like several viral illnesses [7] . During this stage, there is no exact known way to treat SCLS. In addition, there is a very delicate balance to resuscitation ( Figure 3 ) [9] . In our case, dehydration was thought to be occurring, leading to aggressive fluid treatment, which made the hypotension less apparent here. Too much fluid use will preserve the perfusion to vital structures and compromise the areas of 3rd spacing, while under-resuscitation leads to death due to shock and end-organ failure. The primary goal currently revolves around early recognition of extravasation based on the 3 “H”s, and diuresis during the early recovery phase. While our fluids may have contributed to ACS, we are grateful for preserving end-organ function while the patient shifted into the extravasation phase and was not clinically observed. Future treatments of interest are looking into anti-inflammatory therapy upon recognition with serum markers [8],[10] . Prognosis. The prognosis in SCLS is extremely poor, which may be due to its ability to mimic other presentations and the fluctuating patient appearance affecting clinical judgment. SCLS prognosis is made worse by its ability to be recurrent in certain populations [8] . In those who have recurrent attacks, theophylline and/or IVIG has shown some success. During the initial episode, the primary objective remains to be damage control after recognition. It is worth noting that this is not the first case of SCLS with development of ACS in all extremities. However, we are thankful that it is the first occurrence in which the outcome resulted in complete recovery of the patient, who has now been discharged from wound care and follow-up with the Vascular Surgeon.

Presentation. A 57-year-old female is seen in the Emergency Department for evaluation of flu-like symptoms including myalgias, generalized weakness, fatigue, and mild dyspnea for the previous 2 days. She is fully vaccinated for COVID-19, but due for a booster, and tested positive for the virus five days prior. She comes in today because she has begun to experience pain in her extremities. Early examination was relatively benign appearing, but in the following days, she began having increasing pain and swelling in all extremities. On day 2, vascular ultrasound of the upper extremities was obtained, looking for thromboses, with mild vasospasms observed distally. These were presumed to be clinically insignificant when obtained. Differential Diagnosis. Differentials while results were pending included the following: 1.COVID-19 with other manifestations 2.Severe Dehydration 3.Primary Polycythemia 4.Idiopathic Rhabdomyolysis 5.Viral hepatitis with renal injury Figure 2. Symmetric distal extremity swelling and mottling . The symmetric swelling in all extremities made it difficult to understand the patient’s baseline appearance; however, mottling of the extremities is a possible sign for pooling of deoxygenated blood beneath the skin. Image obtained from Fardet et al., 2004 , but appeared nearly identical to our patient on day 3.

COVID-19. A well-known viral pathogen (SARS-CoV-2), COVID-19 emerged over three years ago and is known to cause a spectrum of respiratory presentations along with various symptoms affecting the nervous, gastrointestinal, and cardiovascular systems. The case described here will expand on this virus’s role as a nidus for further rare clinical impacts. Acute Compartment Syndrome (ACS) . ACS is typically associated with traumatic etiologies in which significant blunt injury causes excessive increases in muscular intracompartmental pressures. It is hallmarked clinically by increasingly painful passive range of motion (ROM), with paralysis as a late finding, and often requires a low clinical suspicion for early recognition [1] . It can also be attributed to atraumatic etiologies in which there is significant ischemia or myositis, leading to muscle breakdown and subsequent pressure increases while the body removes the dead tissue [2],[3] . Myopathies. Classification of muscle injury can be graded on a spectrum – asymptomatic creatinine kinase elevation, to myalgias, myopathies, and rhabdomyolysis. Typically, diagnosis of a myositis requires a muscle biopsy. Rhabdomyolysis as a diagnosis requires a clinical diagnosis, confirmed by obvious creatine kinase (CK) elevation. In this case, no biopsy was obtained, but the CK elevation and myalgias in the preceding days leads to a presumption that a myopathy had been occurring as is seen in COVID patients elsewhere [4],[5] . Systemic Capillary Leak Syndrome (SCLS) . SCLS, or Clarkson’s disease , is a relatively new diagnosis with only ~260 reported cases since its original description by Dr. Clarkson himself [6] . It is hallmarked by the “Three ‘H’s”: H ypotension , H ypoalbuminemia , and H emoconcentration . Mortality is high, and the presentation is known to appear much like septic shock, dehydration, primary polycythemia, and various other concerning presentations – leading most to believe it is largely misdiagnosed [7] . In addition, there are 3 phases, with the “Extravasation Phase” being the most dangerous if left unrecognized ( Figure 1 ). The pathophysiology in COVID-19 involves a cytokine storm, with increasing angiogenic and vasodilatory factors. There have been multiple similar cases described in the literature, with the most reasonable explanations for COVID being that of a similar pathophysiology [11] – [26] .

Table 1. Patient lab findings . Labs obtained during the patient’s hospitalization are shown to the right. The days provided are approximate and chosen to show the shift in appearance during each of the phases: from initial labs, to ICU admission, and recovery. It is worth noting that she had been experiencing the “Prodromal Phase” approximately 2 days prior to presentation.

Extravasation Phase . During pre- rounds on day 3, the patient’s pain had worsened to become uncontrolled with use of hydromorphone. She had also lost sensation in the superficial peroneal distribution bilaterally, and her distal extremities began to take on a mottled appearance ( Figure 2 ). A decision was made to escalate care to the intensive care unit (ICU) with a vascular surgery consult. Here, intracompartmental pressures of the legs were read using a Stryker device, confirming our suspicions. Symmetric and similar appearance and subjectively reported worse pain levels in the upper extremities led to the decision to treat as compartment syndrome as well. Treatment . ACS does not have any medical treatment [27] . The patient was taken to the operating room for immediate fasciotomy of all compartments in the arms, forearms, and legs. The thigh compartments were spared. In the following days and into the recovery phase, she required multiple transfusions and vasopressors. Her course was also complicated by bacterial pneumonia. A month later, she was stable for discharge from the ICU to a tertiary facility for monitoring and wound care management. She remained here for another 2 weeks, and she continued to be managed with wound care in the outpatient setting.

Figure 3. Fluid resuscitation during extravasation . Recognition of the condition typically occurs during the extravasation phase. During this time, the endothelium permits uncontrolled fluid losses. Fluids must be administered in a balanced manner to avoid complications of excessive, or unfruitful, resuscitation. Image adapted from Siddall et al., 2017 .

Figure 4. Approach to SCLS Diagnosis . Adapted from Xie et al. 2014 , the following algorithm has been proposed to assist in making the diagnosis. Note the 3 major steps involving the hallmark 3 “H”s of SCLS (Hypotension, Hemoconcentration, Hypoalbuminemia).

Figure 1. Pathophysiology of Systemic Capillary Leak

Syndrome . It has been observed that immune mediated cytokine storms form in response to the virus resulting in endothelial compromise. There is widespread “3 rd spacing” of plasma resulting in hemoconcentration. Fluids must be carefully administered to avoid complications of excessive or unfruitful resuscitation. Image adapted from Siddall et al., 2017 .

References & Acknowledgements

A special thank you to our patient, her family, VCOM, and the many providers at Prisma involved in this patient’s care – especially Drs. Michael Naylor, Aaron Provisor, and Corrielle Caldwell.

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