All posts by Adrianna Long

The Utility of MRI in the Emergency Department

Author: Adrianna Long, MD (Emergency Medicine Staff at Winn Army Community Hospital, Fort Belvoir, GA) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

It is important that providers make the correct choice for imaging when dealing with emergent conditions. MRI is a costly choice, but sometimes the most appropriate to evaluate for specific pathology. It is imperative to weigh the risk and benefits of MRI as compared to other imaging modalities. Also, in many facilities, MRI is only available during business hours, which makes obtaining emergent MRIs very difficult. So, when is ordering an MRI in the Emergency Department indicated?

MRI of the Brain

MRI has a significantly greater detection rate for acute ischemic infarction than CT, particularly in an early setting.  CT has been reported to have a sensitivity ranging from 73-88% for acute stroke within the first 12 hours. In comparison, MRI has a sensitivity of 93-100% and may be able to detect acute ischemic injury within a few minutes of onset.1,2 However, not all patients that have acute strokes are candidates for interventions including tPA or endovascular therapy, so it is important to choose the appropriate imaging modality as an MRI may not be indicated emergently.

There is no standard imaging protocol for the evaluation of acute stroke or TIA beyond head CT noncontrast. The goal of neuroimaging is to provide rapid information and increase providers’ decision-making with regards to reperfusion therapy without causing harm from delays.3

A study recently published reviewed the imaging of 8,247 patients who were evaluated with TIA or minor stroke in 2011, revealing that approximately 50% of patients underwent MRI imaging within 2 days of presentation. The use of MRI to evaluate TIA or stroke is limited in many facilities with lack of availability, and MRIs are often ordered by inpatient services rather than emergently.4

The American College of Neuroradiology, the American College of Radiology, and Society of NeuroInterventional Surgery have made a joint statement with regards to the imaging of acute stroke and TIA. When determining whether endovascular therapy should be considered, they have found that noncontrast CT with digital subtraction angiography, noncontrast CT with CTA, and MRI with MRA are equivalent options for clinicians.5 Of those imaging modalities, noncontrast CT with CTA is the preferred strategy currently when selecting intraarterial thrombectomy candidates, as CT is widely available and faster.6

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While a cavernous venous thrombosis (CVT) is a rare diagnosis, the use of MRV offers an alternative diagnostic modality. The MRV is more sensitive at diagnosis of a CVT than an unenhanced CT.7 Therefore, when considering CVT as a diagnosis, MRV may be considered for imaging, but CT venography is rapid, readily available, and an accurate technique to detect CVT.7

MRI of the Spine

The early diagnosis of an epidural abscess is essential to minimize patient morbidity and mortality. A study of 63 patients with spinal epidural abscess indicated that a delay in diagnosis greater than 24 hours occurred in 75% of cases, and persistent motor weakness resulted in 45% with diagnostic delays.8 The ACR ranks MRI of the spine with and without contrast as the most appropriate study to evaluate for infectious processes of the spine. When there is clinical suspicion for an epidural abscess, the emergency physician should insist on early MRI to prevent poor neurologic outcomes.9

The sudden onset of neurologic deficit due to neoplasm is another emergency that requires immediate imaging, neurosurgical consult, and treatment with high dose steroids.10

Epidural hematoma is a rare cause of back pain that may be associated with myelopathy and usually the result of recent spinal procedures or trauma. The symptoms may present similarly to an acute disc herniation. Patients who may be of particular risk are those on anticoagulant therapy.10

Cauda equina syndrome (CES) is suspected when there is severe lower back pain and radicular symptoms, especially at L5/S1, with saddle anesthesia and bowel/bladder/sexual dysfunction. The diagnosis of CES requires an emergent MRI followed by rapid surgical decompression.11

Basically, if serious underlying pathology is plausible or there is evidence of neurologic involvement in patients with back pain, MRI is the study of choice.9

MRI to evaluate for appendicitis

 Pediatric patients:

Efforts are being made to decrease ionizing radiation exposure in pediatric patients, and MRI has been shown to be useful for the diagnosis of acute appendicitis.12 MRI protocols have been created with combined use of ultrasound to diagnose appendicitis in many hospitals for adult and pediatric patients. In one institution over 30 months, MRI has been shown to have a sensitivity of 96.8%, specificity of 97.4%, negative predictive value of 98.9%, and positive predictive value of 92.4%.13

A retrospective study at another institution with utilization of MRI for 49 pediatric patients with suspected appendicitis after having indeterminate ultrasound found a sensitivity of 94% and a specificity of 100% for diagnosis of acute appendicitis. There were a total of 16 patients diagnosed with appendicitis. The use of MRI aided clinicians in obtaining final diagnoses as well, including other diagnoses such as pyelonephritis, constipation, pelvic inflammatory disease, ruptured ovarian cyst, hemorrhagic cyst, and epiploic appendagitis.14

A study of 662 pediatric patients imaged with CT versus MRI found  no significant difference in time to antibiotic administration, time to appendectomy, perforation rate, or hospital length of stay for patients imaged with either modality.15

Pregnant patients:

In 2011, the American College of Radiology (ACR) designated ultrasound as the initial imaging study choice to evaluate for acute appendicitis in pregnant patients.16 However, there have been multiple studies published indicating that ultrasound may not be the most appropriate imaging study to evaluate for appendicitis in pregnant patients since nonvisualization of the appendix has been reported to range as high as 68-97%.17-19 The efficiency of ultrasound may be limited due to bowel gas, body habitus, and anatomic displacement of the appendix, as well as patient tolerance in the setting of an acute abdomen.18

A meta-analysis of 6 articles analyzing the diagnostic strength of MRI in 359 pregnant women with suspected appendicitis found a specificity of 98% and 99% negative predictive value when a normal appendix is visualized.20

The ACR endorses the use of MRI when ultrasound cannot provide diagnostic information in pregnant patients. MRI has been shown to be useful for multiple diagnoses in pregnant patients with acute abdominal/pelvic pain.21 A retrospective study including 171 patients undergoing MRI with a pregnant appendicitis protocol had an appendix visualization rate of 69%. Furthermore, the overall diagnostic rate was 43.3% finding ovarian masses, ovarian torsion, uterine fibroid tumors, ectopic pregnancies, hernias, renal abscess, as well as appendicitis.22

MRI of the Hip

The use of MRI in the Emergency Department to evaluate for suspected hip fracture can be useful when the clinician has a high suspicion and there is a negative Xray or CT. Despite the use of CT to evaluate for hip fractures, there are still 2-4% with missed hip fractures.23,24 While there is a general consensus that a delay to surgery >48 hours is associated with a higher mortality, and a retrospective study of 6,638 patients with hip fractures indicated that surgery before 12 hours improved survival.25 The results of this study suggest that rapid diagnosis of a hip fracture is essential so patients can receive the appropriate treatment as soon as possible to avoid complications.

There is 100% sensitivity and 99% specificity in detecting hip fractures with abbreviated MRI. This hip protocol MRI may also be used to detect avascular necrosis (AVN) with a sensitivity of 97% and 100% specificity.26

Hazards in MRI scanning

Patients should be adequately screened prior to obtaining MRI, and alternative imaging should be considered in patients with:

  1. Renal disease (especially a GFR lower than 30mL/min)
  2. Allergy to gadolinium
  3. History of injury involving projectiles
  4. History of surgery with retained metallic items, e.g. surgical clips, pacemaker, stents
  5. Claustrophobia27

Nephrogenic systemic fibrosis (NSF) is a potentially fatal condition that has been associated with the use of gadolinium.28 A study of 8997 patients who received gadolinium showed a total of 15 patients (0.17%) who subsequently developed NSF, with a GFR of less than 30mL/min in all of the affected patients.29

Of note, there is inherent risk in sending patients who may become unstable during transport and time to obtain the MRI. Most MRIs require time away from the ED, utilizing emergency staff and equipment outside of the ED, for a prolonged period, or there may be a need to transport to a facility where MRIs are available.

Bottom line:

An MRI should only be ordered in the ED when the patient’s treatment and/or management will be affected.

The misuse of MRIs in the ED generates unnecessary costs to patients and increased time in the department.  It is essential to weigh the risk(s) of ordering an MRI for your patient in the ED.

The indications for emergency MRI Brain include clinical concern for acute ischemic stroke, particularly wherein the management may differ with possible intervention versus less aggressive treatment plans.

If there is clinical concern for new spinal cord compression from disease or injury, an emergency MRI evaluation is necessary. 

The indications for emergency spinal MRI include suspicion for:

  • Spinal cord compression (herniated disc, burst fracture, tumors, etc)
  • Spinal infection (i.e. abscess)
  • Spinal trauma (epidural hemorrhage, etc)
  • Demyelination with acute neurologic changes

Additionally, emergency MRIs may be considered if there is concern for:

  • Appendicitis in the pregnant or pediatric patient
  • Hip fracture not detected on plain film or CT

 

References/Further Reading:

  1. Krieger DA, Dehkharghani S. Magnetic Resonance Imaging in Ischemic Stroke and Cerebral Venous Thrombosis. Top Magn Reson Imaging. 2015;24(6):331-352.
  2. Lev MH. CT versus MR for acute stroke imaging: is the “obvious” choice necessarily the correct one? AJNR Am J Neuroradiol. 2003;24(10):1930-1931.
  3. Lin MP, Liebeskind DS. Imaging of Ischemic Stroke. Continuum (Minneap Minn). 2016;22(5, Neuroimaging):1399-1423.
  4. Chaturvedi S, Ofner S, Baye F, et al. Have clinicians adopted the use of brain MRI for patients with TIA and minor stroke? Neurology. 2017;88(3):237-244.
  5. Wintermark M, Sanelli PC, Albers GW, et al. Imaging recommendations for acute stroke and transient ischemic attack patients: a joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery. J Am Coll Radiol. 2013;10(11):828-832.
  6. Goyal M, Hill MD, Saver JL, Fisher M. Challenges and Opportunities of Endovascular Stroke Therapy. Ann Neurol. 2016;79(1):11-17.
  7. Leach JL, Fortuna RB, Jones BV, Gaskill-Shipley MF. Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. Radiographics. 2006;26 Suppl 1:S19-41; discussion S42-13.
  8. Davis DP, Wold RM, Patel RJ, et al. The clinical presentation and impact of diagnostic delays on emergency department patients with spinal epidural abscess. J Emerg Med. 2004;26(3):285-291.
  9. Seidenwurm DJ, Wippold FJ, 2nd, Cornelius RS, et al. ACR Appropriateness Criteria((R)) myelopathy. J Am Coll Radiol. 2012;9(5):315-324.
  10. Arce D, Sass P, Abul-Khoudoud H. Recognizing spinal cord emergencies. Am Fam Physician. 2001;64(4):631-638.
  11. Mukherjee S, Thakur B, Crocker M. Cauda equina syndrome: a clinical review for the frontline clinician. Br J Hosp Med (Lond). 2013;74(8):460-464.
  12. Moore MM, Brian JM, Methratta ST, et al. MRI for clinically suspected pediatric appendicitis: case interpretation. Pediatr Radiol. 2014;44(5):605-612.
  13. Kulaylat AN, Moore MM, Engbrecht BW, et al. An implemented MRI program to eliminate radiation from the evaluation of pediatric appendicitis. J Pediatr Surg. 2015;50(8):1359-1363.
  14. Rosines LA, Chow DS, Lampl BS, et al. Value of gadolinium-enhanced MRI in detection of acute appendicitis in children and adolescents. AJR Am J Roentgenol. 2014;203(5):W543-548.
  15. Aspelund G, Fingeret A, Gross E, et al. Ultrasonography/MRI versus CT for diagnosing appendicitis. Pediatrics. 2014;133(4):586-593.
  16. Rosen MP, Ding A, Blake MA, et al. ACR Appropriateness Criteria(R) right lower quadrant pain–suspected appendicitis. J Am Coll Radiol. 2011;8(11):749-755.
  17. Israel GM, Malguria N, McCarthy S, Copel J, Weinreb J. MRI vs. ultrasound for suspected appendicitis during pregnancy. J Magn Reson Imaging. 2008;28(2):428-433.
  18. Lehnert BE, Gross JA, Linnau KF, Moshiri M. Utility of ultrasound for evaluating the appendix during the second and third trimester of pregnancy. Emerg Radiol. 2012;19(4):293-299.
  19. Vu L, Ambrose D, Vos P, Tiwari P, Rosengarten M, Wiseman S. Evaluation of MRI for the diagnosis of appendicitis during pregnancy when ultrasound is inconclusive. J Surg Res. 2009;156(1):145-149.
  20. Long SS, Long C, Lai H, Macura KJ. Imaging strategies for right lower quadrant pain in pregnancy. AJR Am J Roentgenol. 2011;196(1):4-12.
  21. Furey EA, Bailey AA, Pedrosa I. Magnetic resonance imaging of acute abdominal and pelvic pain in pregnancy. Top Magn Reson Imaging. 2014;23(4):225-242.
  22. Theilen LH, Mellnick VM, Longman RE, et al. Utility of magnetic resonance imaging for suspected appendicitis in pregnant women. Am J Obstet Gynecol. 2015;212(3):345 e341-346.
  23. Hakkarinen DK, Banh KV, Hendey GW. Magnetic resonance imaging identifies occult hip fractures missed by 64-slice computed tomography. J Emerg Med. 2012;43(2):303-307.
  24. Iwata T, Nozawa S, Dohjima T, et al. The value of T1-weighted coronal MRI scans in diagnosing occult fracture of the hip. J Bone Joint Surg Br. 2012;94(7):969-973.
  25. Bretherton CP, Parker MJ. Early surgery for patients with a fracture of the hip decreases 30-day mortality. Bone Joint J. 2015;97-B(1):104-108.
  26. Khurana B, Okanobo H, Ossiani M, Ledbetter S, Al Dulaimy K, Sodickson A. Abbreviated MRI for patients presenting to the emergency department with hip pain. AJR Am J Roentgenol. 2012;198(6):W581-588.
  27. Institute for Magnetic Resonance Safety E, and Research (IMRSER). Magnetic Resonance (MR) Procedure Screening Form For Patients and Magnetic Resonance (MR) Environment Screening Form for Individuals. 2017.
  28. Grobner T. Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
  29. Prince MR, Zhang H, Morris M, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology. 2008;248(3):807-816.

 

The Dangers of Over-Resuscitation in Sepsis

Authors: Adrianna Long, MD (EM Senior Resident at SAUSHEC, USA) and Brit Long, MD (@long_brit – EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK – EM Attending Physician, UTSW / Parkland Memorial Hospital) and Manpreet Singh, MD (@MPrizzleER – Clinical Instructor & Ultrasound/Med-Ed Fellow / Harbor-UCLA Medical Center)

Sepsis can be life-threatening and is a commonly managed condition in the emergency department. This area is heavily researched, with studies evaluating multiple aspects of sepsis including evaluation, management, antibiotic use, intravenous and vasopressor resuscitation, and monitoring.  One specific area of research has focused on fluid resuscitation in sepsis, specifically the type and amount of intravenous fluid. With all of the new sepsis updates, what is the literature on the harms of over-resuscitation?

The evidence continues to indicate that over-aggressive fluid resuscitation in septic shock is associated with increased morbidity and mortality. While the Sepsis Campaign Guidelines indicate that a patient with sepsis and hypotension or an elevated lactate (≥4mmol/L) should be treated with a 30ml/kg dose of crystalloid fluids, there is a lack of evidence to support this recommended fluid dose.1

In previous discussions, we have addressed that IV fluid choices affect patient outcomes in septic shock, and we have shown the evidence that invasive monitoring coupled with aggressive treatments are actually harming our patients.  Please refer to these prior posts for more information:

  1. How much fluid is too much?
  2. Does fluid choice matter?

The question we now face is what is the result of over-resuscitation?

The results of the ProCESS, ARISE, PROMISE trials indicate that EGDT as defined by Rivers et al may be more invasive than what is actually necessary to provide adequate resuscitation for patients in septic shock.2-5 These trials did not address the question of potential harm with excessive fluid administration to our patients during resuscitation. The majority of the patients in these trials received approximately 1.5L to 3L of fluids in the first 6 hours of treatment, with resuscitation approaching 4L after 6 hours.

Evidence is now indicating that intravenous fluids may be harmful in patients with septic shock, as excess fluid may cause edema in the lungs, kidneys, and brain amongst other organ systems.6 All organ systems are affected with resuscitation and excess fluid, which is shown in Figure 1.

Sepsis

Figure 1 – Over-resuscitation effects on organ systems from Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80.

A more clearly defined endpoint of resuscitation in goal directed therapy should be defined in order to prevent fluid overload.7 To date, finding this endpoint has been problematic. Multiple studies have shown that a positive fluid balance is associated with increased mortality.8-12 One study found that a negative fluid balance in patients with septic shock was associated with increased survival.13 This study consisting of 36 patients admitted to the ICU found improved outcomes in patients with a negative fluid balance in the first 3 days of admission.

The FEAST trial explored the effects of fluid treatment in septic children and showed an increased 48-hour mortality in children who received more fluids, specifically bolus fluids. This was a randomized controlled trial conducted across several sites in Africa. The patients were ages 60 days to 12 years with severe infection, fever, and impaired perfusion. Patients were randomized to treatment arms of albumin bolus (20-40ml/kg), saline bolus (20-40ml/kg), or no fluid bolus.9 Patients receiving no bolus demonstrated a 3.3% survival benefit at 48 hours over the groups receiving bolus fluids.  Of note, this study contained a high percentage of patients with malaria, anemia (1/3 of patients had a hemoglobin < 5 g/dL) and respiratory distress (80% of patients).  Few patients were included with severe hypotension, and these patients were given bolus fluids.  The mechanism of excess mortality has been attributed to refractory septic shock or cardiogenic shock in patients treated with the higher doses of fluids.14,15

The SOAP study was an observational study of adults with sepsis that showed an association between a higher cumulative fluid balance in the first 72-hours of onset of sepsis and increased mortality.11 This study of 3,147 patients found predictors of poor prognosis included age, septic shock, cancer, and positive fluid balance.

One prospective observational study of patients with septic shock questioned whether the amount of initial IV fluids and cumulative IV fluids over the initial 72-hour period was associated with a higher mortality. This study included 364 patients and showed that initial fluid volume and total cumulative 72-hour fluid volume were not associated with increased mortality, which at first glance contrasts with the evidence published from the other studies listed above.16 At three days, patients with continued shock receiving more fluids demonstrated lower mortality. However, at 72 hours, patients on average had received 7.5L, vastly decreased from other studies approaching 20L.  These other studies demonstrated worse outcome with this fluid amount compared to patients receiving less.

This illustrates the need for randomized control trials to identify the appropriate amount of fluid that should be administered to patients with septic shock. These prior trials included patients of different ages, comorbidities, illness severity, and most importantly, differing definitions of the amount of fluid.

What does excess fluid do?

Several explanations exist for why excess fluid causes harm. These include release of natriuretic peptides in the setting of hypervolemia resulting in vasodilation, disruption of the glycocalyx, loss of physiologic compensation (sympathetically mediated) leading to cardiovascular collapse, fluid overload resulting in cardiotoxicity, increased interstitial edema, impaired gas exchange, and acid-base and electrolyte disturbances.17-19 As detailed in Figure 1, all organ systems may be affected by excess fluid.

Wait, the glycocalyx?

The glycocalyx is a thin layer containing several types of protein.  The components include proteoglycans, glycoproteins, albumin, and glycosaminoglycans which form a tight network of negatively charged ions. This layer is thought to maintain vascular permeability, mediate nitric oxide production, retain vascular protective enzymes, and modulate inflammatory markers such as cytokines.  Disruption of this layer may further edema, inflammation, hypercoagulability, platelet aggregation, and sepsis syndromes including capillary leak.  Studies are underway evaluating risk factors contributing to glycocalyx damage, other mechanisms of damage, and treatments aimed towards the glycocalyx.20-22

So what should the emergency provider do?

First, recognize that resuscitation goals include obtaining adequate perfusion pressure and microcirculatory flow, while limiting extra tissue edema.  These measures can be completed using adequate fluid loading, as the patient still requires fluids for preload. Providing three to four liters of crystalloid will likely not harm the patient, but will improve perfusion pressure and microcirculatory flow. Second, infusing peripheral vasopressors, specifically norepinephrine, for patients with poor perfusion following this fluid load is recommended to provide peripheral squeeze, further increasing preload.

Measure the response through multiple measures, rather than relying on just one. Closely evaluate urine output, capillary refill, mental status, and IVC variation on bedside US in combination. Unfortunately microcirculatory endpoints are currently not feasible in the ED, but many are undergoing validation for use in the critical care setting.

Summary:

The dosing of intravenous fluids in septic patients should be taken as seriously as any potentially lethal medication. It is essential for physicians to give appropriate doses of intravenous fluids while avoiding fluid overload. Patients’ fluid status must be re-evaluated after administration of fluids. Further research must be conducted to identify the appropriate dosing of intravenous fluid bolus at onset of sepsis and any patient subsets that require different treatment.

References/Further Reading

  1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
  2. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
  3. Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
  4. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311.
  5. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
  6. Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest. 2008;133(1):252-263.
  7. Kozek-Langenecker SA. Intravenous fluids: should we go with the flow? Crit Care. 2015;19 Suppl 3:S2.
  8. Sadaka F, Juarez M, Naydenov S, O’Brien J. Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality. J Intensive Care Med. 2014;29(4):213-217.
  9. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495.
  10. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care. 2008;12(3):R74.
  11. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-353.
  12. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259-265.
  13. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest. 2000;117(6):1749-1754.
  14. Maitland K, George EC, Evans JA, et al. Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. BMC Med. 2013;11:68.
  15. Myburgh J, Finfer S. Causes of death after fluid bolus resuscitation: new insights from FEAST. BMC Med. 2013;11:67.
  16. Smith SH, Perner A. Higher vs. lower fluid volume for septic shock: clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Crit Care. 2012;16(3):R76.
  17. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Critical care. 18(6):696. 2014.
  18. Hilton AK, Bellomo R. A critique of fluid bolus resuscitation in severe sepsis. Crit Care. 2012;16:(1)302.
  19. Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80.
  20. Chappell D, Westphal M, Jacob M. The impact of the glycocalyx on microcirculatory oxygen distribution in critical illness. Curr Opin Anaesthesiol. 2009 Apr;22(2):155-62.
  21. Burke-Gaffney A, Evans TW. Lest we forget the endothelial glycocalyx in sepsis. Crit Care. 2012 Dec 12;16(2):121.
  22. Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010 Jul 15;87(2):300-10.

Septic shock: Who should be treated with early pressors?

Author: Adrianna Long, MD (Senior EM Resident at SAUSHEC, US Army) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (EM Chief Resident at SAUSHEC, USAF)

 

A 74 year-old female is brought in by ambulance from a rehabilitation facility with a chief complaint of confusion and vomiting for the past day. Her husband reports that she is normally alert and oriented but has been more confused over the past day. She is in rehabilitation after a fall three weeks ago when she sustained a fracture to her left hip.

Her initial vital signs include temperature of 100.5°F, pulse of 114, blood pressure 76/34 mmHg (mean arterial pressure 48 mmHg), respiratory rate of 22, and saturating 98% on room air. Exam reveals suprapubic tenderness and right sided costovertebral angle tenderness. Laboratory values reveal leukocytosis with 18,200 WBCs, BUN/sCr of 32/1.6 and all other values within normal limits. The patient has frank pyuria with urinalysis markedly positive for nitrites, WBCs, RBCs, and bacteria.

You recognize that your patient is in septic shock due to a urinary tract infection, so you order an IV fluid bolus and initiate antibiotic therapy. With recognition that this patient already has poor renal function and a decreased MAP, when should you consider starting a vasopressor?

 

The true goal seems to be targeting the MAP

The current recommendations from the Surviving Sepsis Campaign are to maintain a MAP ≥ 65 mmHg (Level 1C).1 However, the current evidence does not indicate subsets of patients that may need to be treated differently (i.e. patients with chronic hypertension, patients with history of renal disease, etc.). Here are the studies available regarding MAP and septic shock:

  • A retrospective study of 274 septic shock patients indicated that one or more episodes of MAP decreased less than 60 mmHg was associated with an increased risk of death by 2.96. Further, one or more episode of MAP decreased less than 75 mmHg increased the need for renal replacement therapy.2
  • A prospective study on 10 patients with septic shock aimed to titrate norepinephrine to target a MAP of 65, 75 and 85 mmHg. There was no significant difference found in the serum lactate, UOP, skin capillary blood flow, or red blood cell velocity as the MAP increased higher than 65mmHg.3
  • Another prospective study of 28 patients with septic shock treated half of the patients with norepinephrine to target a MAP of 65 mmHg and the other half with norepinephrine to target a MAP of 85 mmHg, showing no significant difference in urine output or creatinine clearance.4
  • In 2014, a large prospective study of 776 septic shock patients targeted MAPs of 65 to 70 mmHg or 80 to 85 mmHg and found no significant difference in 28- or 90-day mortality. This study did indicate that the patients with targeted MAPs of 80 to 85 mmHg were found to have increased risk of new onset atrial fibrillation, were on vasopressors longer, and required higher doses of norepinephrine.5
  • A retrospective study of 111 patients with septic shock found a strong correlation with mortality and duration of time spent below MAP 65 mmHg.6

 

Should we “fill the tank” first? Or when should we initiate vasopressor therapy?

The current guidelines require that patients be treated with 30cc/kg of IV fluid before being treated with vasoactive medications, but not all patients are responsive to IV fluids and studies indicate the vitality in starting norepinephrine early.

  • A retrospective study of 2,849 septic shock patients found that mortality was lowest when vasoactive agents were begun 1-6 hours after onset.7
  • A retrospective study of 213 patients found that every hour of delayed treatment with norepinephrine was associated with 5.3% increased mortality. They also found that when norepinephrine was started within 2 hours of diagnosis of septic shock, patients were more likely to have increased MAPs, decreased serial serum lactates, and shorter duration of norepinephrine.8
  • A retrospective study in 2004 of 142 patients showed that norepinephrine started early may have some benefit.9

The basic theory behind giving IV fluids prior to vasopressors is that septic patients are often intravascularly volume depleted due to third-space losses, and there is concern that arterial constriction alone could impair perfusion. However, not all patients in septic shock are volume-depleted causing decreased perfusion. There are several factors that may lead to hypoperfusion in a septic patient to include venodilation, arterial dilation, cardiomyopathy, cor pulmonale, renal failure, in addition to dehydration/intravascular depletion. When initiating IV fluids, we are only treating one of these issues. Further, excess volume status is correlated with renal failure and increased mortality in shock patients.10 It is much more reasonable to address the patient’s physiological state especially assessing volume status prior to blindly treating with IV fluids and delaying treatment with vasopressors.

 

What is the problem in waiting to start vasopressors?

Renal and pulmonary injuries may be the result of delayed initiation of vasopressors, affecting morbidity and mortality. The kidneys are prone to experiencing hypoperfusion as a result of shock status.11 Renal injury is associated with septic shock and hypotension, which may be reduced with the use of norepinephrine and decrease the risk of renal failure.5,10 Also, patients who are resuscitated for septic shock often have resulting pulmonary edema, which may be the result of volume overload or the result of cytokine release with renal injury.12 Patients who suffer renal injury often have long-term sequelae as a result, including increased risk of chronic renal failure and end stage renal disease.13 The RIFLE classification for renal injury shows a clear increase in mortality with worsened renal failure.14

 

Can vasoactive drugs be given peripherally?

One barrier to starting vasoactive agents early is the concern for a need to have a central line for infusion of these medications. This is another reason that many providers may still prefer the fluid-first approach.

However, it has been shown that norepinephrine may be given peripherally for a limited period of time while stabilizing the patient. There is risk for extravasation, which can be minimized with appropriate protocols, use of a well-functioning proximal intravenous catheter, and a goal to obtain central venous access as quickly as possible. Intraosseous infusion of norepinephrine is also temporarily permissible with verification that the line has been placed appropriately.15

One benefit to starting vasoactive drugs peripherally is that they can be infused simultaneously with intravenous fluids to target an adequate MAP. If a patient is fluid responsive, the norepinephrine may be titrated down and potentially discontinued before central access is obtained.

 

More evidence is needed to make appropriate recommendations regarding the initiation of early vasopressor therapy and who would benefit.

In a patient who presents with MAPs less than 65 mmHg, it is unknown how quickly those patients should reach that target MAP to avoid renal injury. The data indicates that hypotension should be avoided to prevent hypoperfusion of the kidneys, but are there specific patients that are at higher risk for renal injury? Is there a rate at which we should be increasing MAP or a specific amount of time that the blood pressure must be corrected? The data and recommendations only indicate that we should urgently address a septic shock patient with a MAP less than 65 mmHg.

The studies that have been published regarding delay to vasopressor initiation and outcome are all retrospective and correlate time of onset with outcomes, but are all likely to have confounding variables. Subramanian et al found a trend toward increased mortality with initiation of early vasopressors, which was not significant.16 Beck et al found a correlation between early vasopressors and improved mortality.17 Waechter et al found that it may be detrimental to start vasoactive agents within the first hour after shock onset, but vasopressors started within 1-6 hours had the lowest mortality rates.7 Bai et al found an association between early norepinephrine and survival.8 Interestingly, Beck and Waechter used the same database of patients with the same research group and had differing results. Only one of these studies used norepinephrine only, while the others used a variety of vasoactive medications. This makes some question the clinical significance of these studies with regards to Emergency Department treatment because we are primarily concerned about the early use of norepinephrine.

Currently, the CENSER study is being performed, which is the first prospective randomized controlled trial to evaluate the use of early norepinephrine in septic shock with a control group of 5% dextrose water intravenous infusion. This study is not expected to finish until August 2017.18

 

Conclusions

  • Vital signs are vital! Drops in blood pressure lead to increased mortality, and blood pressure may not respond simply to fluids.
  • Vasopressors should be started early in septic shock patients, but there is controversy as to how early and what subsets of patients would benefit most due to a lack of evidence currently available.
  • Delaying norepinephrine in a septic shock patient with a low MAP while first attempting to fluid resuscitate may increase morbidity and mortality, but further studies must be conducted to confirm this.
  • A drop in MAP causes renal hypoperfusion and renal injury contributing to further complications and possibly worsening shock.
  • It is essential to assess your patient’s fluid status and weigh the risk of renal injury when considering initiation of vasopressor therapy.

 

 References / Further Reading

  1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
  2. Dunser MW, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35(7):1225-1233.
  3. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28(8):2729-2732.
  4. Bourgoin A, Leone M, Delmas A, Garnier F, Albanese J, Martin C. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33(4):780-786.
  5. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.
  6. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005;31(8):1066-1071.
  7. Waechter J, Kumar A, Lapinsky SE, et al. Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med. 2014;42(10):2158-2168.
  8. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18(5):532.
  9. Morimatsu H, Singh K, Uchino S, Bellomo R, Hart G. Early and exclusive use of norepinephrine in septic shock. Resuscitation. 2004;62(2):249-254.
  10. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney injury. Crit Care Med. 2008;36(4 Suppl):S179-186.
  11. Lehman LW, Saeed M, Moody G, Mark R. Hypotension as a Risk Factor for Acute Kidney Injury in ICU Patients. Comput Cardiol (2010). 2010;37:1095-1098.
  12. Basu RK, Wheeler D. Effects of ischemic acute kidney injury on lung water balance: nephrogenic pulmonary edema? Pulm Med. 2011;2011:414253.
  13. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516-524.
  14. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int. 2008;73(5):538-546.
  15. Weingart S. Podcast 107 – Peripheral Vasopressor Infusions and Extravasation. Emcrit. 2013.http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/
  16. Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O. Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study. Intensive Care Med. 2008;34(1):157-162.
  17. Beck V, Chateau D, Bryson GL, et al. Timing of vasopressor initiation and mortality in septic shock: a cohort study. Crit Care. 2014;18(3):R97.
  18. Permpikul C. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). https://clinicaltrials.gov/ct2/show/study/NCT01945983#contacts.