JOURNAL CLUB - FEBRUARY 2023

Journal Club Podcast February 2023

Dr Danny Marhaba Dr David McCreary Professor Peter Cameron

Welcome to the second Journal Club Podcast of 2023. We are joined by Professor Peter Cameron, Academic Director for the Alfred Emergency and Trauma Centre and Dr David McCreary, Emergency Consultant at Alfred Emergency and Trauma Centre.

BACKGROUND - A Primer on the history of Sepsis Literature

Wholistic discussions around sepsis can begin from 1991, when the ACCP (American College of Chest Physicians) and the SCCM (Society of Critical Care Medicine) convened a “Consensus Conference,” which as other conferences to follow implied, might be referred to as – Sepsis 1 {1}. This consensus defined sepsis as a response to infection manifested by ≥2 SIRS criteria. In 2001, this group expanded to include the ESICM (European Society of Intensive Care Medicine), the ATS (American Thoracic Society), and the SIS (Surgical Infection Society); their new definition – colloquially referred to as Sepsis 2 – largely maintained the definitions and divisions of sepsis, severe sepsis and septic shock {2).

In parallel the now infamous Rivers Trial, where a bundle of interventions termed EGDT (Early Goal Directed Therapy), showed that this bundle when applied to the 130 out of 263 patients with severe sepsis or septic shock who were randomised to its arm, dramatically reduced in hospital mortality from 44.4% to 29.2% {3}. This single centre trial with a relatively high control-group mortality led to the now well-known Surviving Sepsis campaign recommended the interventions of EGDT and continued doing so for the decade that followed {4, 5} – specifically, this was an era that can be differentiated by relatively liberal blood transfusions, continuous central venous co-oximetry, and dobutamine. The differences in actual interventions received such as transfusions, pulmonary artery catheterisation and intubation are shown in the original study’s Table 4 {3}, shown here as figure 1.

Though they took took over 10 years to plan and carry out, the three collaborative and harmonised international trials of ARISE (1600 patients in 51 oceanic hospitals, 2014), PROCESS (1351 patients in 31 American hospitals, 2014) and PROMISE (1260 patients in 56 UK hospitals, 2015) did not replicate the findings of the original Rivers trial – and the use of EGDT slowly waned {6 – 8}. In fact, today our practice can be characterised by avoidance where possible, of transfusions, central venous lines and invasive ventilation – the emphasis then became on early recognition, early intravenous fluids, and timely antibiotics.

In 2016 the Third International Consensus Definitions for Sepsis and Septic Shock – colloquially known as Sepsis 3 – made some improvements {9}; they did away with severe sepsis – keeping only the categories of simple infection, sepsis, or shock, – they placed an emphasis on SOFA scores and de-emphasized SIRS criteria in diagnosis, and they provided a good definition for sepsis – “life threatening end-organ dysfunction that results from a dysregulated response to infection. However, what followed was the 2016 guidelines of the Surviving Sepsis Campaign and it’s now infamous 2018 update {10, 11}, which brought on an uproar by many clinicians who these guidelines applied to. Specifically, two strong recommendations were perceived as being mismatched with their supporting evidence:

i) to rapidly administer 30mL/kg of crystalloid for any patient with hypotension or lactate ≥4mmol/L who was thought to be in septic shock.

ii) a 1hour door-to-antibiotics times for any patient with sepsis.

The first strong recommendation was challenged for the relative-lack of supporting evidence {12} as well as its potential to cause harm: titrating therapy to patient-centered parameters and clinical response is a more nuanced approach they may have better outcomes than rather large fluid boluses of pre-determined volumes {13}.

The second strong recommendation was challenged for its feasibility as well as the relative-lack of supporting evidence {14}: though earlier antibiotics are associated with survival in septic shock, the link in sepsis without shock is more elusive, and differentiating sepsis from the bulk of simple infections that people acquire is a process that commonly takes longer than 1 hour, especially in access blocked and overcrowded emergency departments.

Thus, we arrive at the current 2021 issue of the Surviving Sepsis Guidelines {15}, where antibiotics for possible sepsis carries a more reasonable recommendation of administration within 3 hours (timing for probable sepsis remains at <1hr), the advice for 30mL/kg of fluid was downgraded to weak strength and linked with dynamic measures to guide the fluid resuscitation, and norepinephrine (noradrenaline) was upheld as the first line vasopressor targeting a MAP of ≥66mmHg.

PAPER ONE

INTRODUCTION OF AN EMERGENCY MEDICINE PHARMACIST-LED SEPSIS ALERT RESPONSE SYSTEM IN THE EMERGENCY DEPARTMENT: A COHORT STUDY

READ IT HERE

CLINICAL QUESTION

The stated aim of this study was to evaluate the impact of a sepsis performance improvement program in the ED with early involvement of an EM pharmacist. The stated key findings of the study relate to whether the above implementation reduced key performance indicators including time to antibiotics.

JOURNAL

Emergency Medicine Australasia, 2023

LEAD AUTHOR

Christina Petronela Roman, EM Pharmacist

DESIGN

Single centre self-controlled prospective cohort study

POPULATION

180 patients presenting to a metropolitan major referral hospital’s ED during pharmacist working hours, who were admitted to ICU with a diagnosis of sepsis.

EXPOSURE

Sepsis alert response system which includes an EM-pharmacist, from February 2016 to February 2018.

COMPARISON

Self-controlled parameters for patients admitted to ICU from ED with a diagnosis of sepsis from January 2015 to February 2016.

OUTCOME

Primary:

• Proportion of patients who received antibiotics within 60 minutes.

Secondary Outcomes

• Proportion of patients completing the sepsis bundle within 60 minutes of arrival (fluid bolus, 2 blood cultures and serum lactate)

FINDINGS

Primary Outcome

• Proportion of patients receiving empiric antimicrobials improved from 26.3% to 81.7% (OR 12.6, 95% CI 6.2 – 25.4%, P<0.001).

Secondary Outcomes

• Proportion receiving IV Fluids improved from 47.5% to 72.1% (P=0.002)

• Proportion receiving blood cultures improved from 52.5% to 85.6% (P<0.001)

• Proportion receiving a serum lactate improved from 50.0% to 66.9% (P<0.001)

Secondary outcomes:

• No significant difference in pain at any measured time-point.

• No significant difference secondary outcomes in function questionnaires.

• Statistically significant difference in parent satisfaction on day 1 and analgesia use on day 1.

• While not statistically significant, trend for bandage group to be more likely to have used analgesia (except D1), and have missed school.

AUTHORS' CONCLUSIONS

The authors report that the implementation of a sepsis alert response that included early involvement of the EM pharmacist was associated with improvement in time to antimicrobials in the ED.

BOTTOM LINE

• Due to the breadth of confounders in any time-controlled study, it is difficult to use this as evidence for a cause-effect relationship.

• However, it does seem that whether it was due to a sepsis alert response or whether it was due to a department continuously improving its KPIs (probably both), time to antimicrobials, fluids and serum lactate seem to have improved between 2015 and 2018.

• Limiting the subjects to only those admitted to ICU was wise (and probably the only feasible was to arrive at a comparator). This is because time to antibiotics is a more appropriate measure in patients with septic shock, and typically those are the patients with sepsis who require intensive care. This also then means that the conclusions of this study do not extend to patients who did not require ICU.

• In my anecdotal experience, the presence of EM pharmacist in this sepsis alert response is very helpful – they track previous sensitivities, help identify dose adjustments when required, can safely chart the medicines decided upon with the medical officer, and seem to act as an advocate in reducing time-to-intervention in patients with sepsis.

• However, this study cannot differentiate the EM pharmacist from the sepsis alert response itself – therefore even if the study design enabled us to draw a clear link between the sepsis alert response and times to intervention, drawing out the effect of the EM-pharmacist from the sepsis alert would then still need to be shown.

• Operational decisions cannot be limited to only that which has high quality evidence, and therefore until a feasible high-quality trial that isolates and demonstrates the effects of an EM pharmacist within a sepsis alert bundle is conducted, I suspect that we will continue to see our pharmacist colleagues supporting us in offloading some of the pharmacological cognitive burdens that often accompany these alerts.

PAPER TWO

RESTRICTION OF INTRAVENOUS FLUIDS IN ICU PATIENTS WITH SEPTIC SHOCK

READ IT HERE

CLINICAL QUESTION:

What are the effects of a restriction of IV fluids on mortality and other outcomes in adult patients with septic shock in the ICU?

JOURNAL

The New England Journal of Medicine, June 2022

LEAD AUTHOR

Tine Sylvest Meyhoff, MD

DESIGN

Open Label Prospective Multicentre RCT

POPULATION

1554 patients ≥18 years of age who were admitted to ICU with suspected septic shock, as defined by suspected infection with lactate ≥2mmol/L, ongoing inopressors, and having received ≥1L IV Fluids within the prior 24 hrs.

EXPOSURE

Restrictive IV Fluid therapy for the following indications:

• Severe hypoperfusion => 250 – 500mL bolus

  1. lactate ≥4mmol/L,

  2. MAP <50mmHg despite inopressors,

  3. skin mottling score of ≥2

  4. urine output <0.1mL/kg/hr

• Fluid Losses => Replace the same volume

• Dehydration / Electrolyte derangements => Correct the derangement

• Total daily fluid => Top up to target total daily fluid intake of 1L

COMPARISON

Standard / Unlimited IV Fluid therapy for the following indication

1. Improve haemodynamic compromise

2. Replace expected or observed losses

3. Correct dehydration / electrolyte derangement

4. Maintenance fluids as per local ICU protocol

ACTUAL EXPOSURE VERSUS COMPARATOR

Intravenous Balance             and                  Cumulative Fluid Balance

D1: 1               vs 1.7 L            and                  +0.7L   vs +1.3L

D5: 2.3            vs 3.8L             and                  +1.6L   vs +2.4L

OUTCOME

Primary:

1. Death within 90 days post randomisation

Secondary Outcomes

1. Number of patients with ≥1 serious adverse event (CVA, MI, Mesenteric ischemia, or Limb ischemia.

2. Number of patients with ≥1 serious advance reaction to IV crystalloid (Seizures, Anaphylaxis, osmotic demyelination, severe hypernatremia, severe hyperchloremic acidosis, or severe metabolic alkalosis).

3. The number of days, at 90 days, where the patient wasn’t requiring life support or was alive and out of hospital.

WHAT WERE THE FINDINGS?

• No difference in death at 90 days (42.3 vs 42.1 %, ARR 1.0, 90% CI 0.89 – 1.13).

• No statistically significant difference in any of the secondary outcomes

AUTHORS' CONCLUSIONS

There was no significant difference in 90-day mortality or serious adverse events among patients who received restricted fluid therapy and those who received standard therapy.

CLINICAL BOTTOM LINE

• Technically this is an ICU trial, it therefore applies to ICU patients – not to ED patients, unless those patients are spending upwards of 12 hours in the ED.

• Don’t treat the algorithm, treat the patient. The lessons learnt over the past 30 years emphasize the avoidance of blanket interventions for all patients, instead emphasizing patient-specific clinical parameters – even the restricted arm of this trial factors lactate, skin mottling, blood pressure and urine output into the decision-making process.

• In deciding whether to give more fluids in Emergency Department patients with septic shock, we target MAP ≥65mmHg, CR <2, Conscious State, Urine Output and a point of care echo.

• The ED is certainly capable of providing good critical care (resuscitation), but it is not an ICU. When ICU patients spend ≥12 hours in the ED, change gears and use whatever good methodology your ICU teaches, I was taught to use FAST HUGS (Feeding, Analgesia, Sedation, Thromboprophylaxis, Head Up, Ulcer Prophylaxis and Glycaemic Management).

PAPER THREE

PERIPHERAL VASOACTIVE ADMINISTRATION IN CRITICALLY ILL CHILDREN WITH SHOCK: – A SINGLE CENTRE RETROSPECTIVE COHORT STUDY

READ IT HERE

CLINICAL QUESTION

What were the characteristics of critically unwell children on peripherally administered vasoactive medicines? What were the characteristics of the associated extravasation injuries?

JOURNAL

Journal of Pediatric Critical Care Medicine, August 2022

LEAD AUTHOR

Robert A. Levy, MD

DESIGN

Single-centre retrospective cohort study

POPULATION

231 patients with peripheral vasoactive access (PVA) and 525 patients with central vasoactive access (CVA), aged 31 days to 18 years who required adrenaline, noradrenaline or dopamine in a quaternary PICU.

EXPOSURE

Inotropes and vasopressors administered through a PVA.

COMPARISON

Inotropes and vasopressors administered through a CVA

OUTCOME

No primary outcome was differentiated from the basket of outcomes studied.

• Anthropomorphic characteristics within the two groups

• Percentages of Primary Diagnoses and of Invasive Interventions

• Proportions and doses of the various inotropes and vasopressors received

• Proportion of the PVA patients who ultimately required a CVA

• Proportion of the PVA patients who experienced extravasation injuries

WHAT WERE THE FINDINGS?

Patients who initially received vasoactive medicines through a PVA were:

• older (10.3 vs 9.4 years, p = 0.003) and heavier (30.9 vs 25.3 kg, p = 0.001).

• more likely to have sepsis (40.3 vs 19.8 %, p < 0.001)

• more likely to have had the vasoactive medicines initiated at night (64.5 vs 50.5 %, p < 0.001), less likely to have been intubated (50.7 vs 82.7 %, p < 0.001), less likely to have received CPR (3.0 vs 8.0 %, p < 0.001)

• Spent fewer days in PICU (2.8 vs 5.8 days, p < 0.001)

• Had a lower mortality (19.0 vs 10.4 %, p < 0.001)

• 75% of the PVAs used were 20 or 22 gauge.

• 4 out of 231 had an extravasation event, all in the hand. 3 of those received antidotes (phentolamine or terbutaline), none suffered from rebound hypotension.

Of Patients who initially received vasoactive medicines through a PVA, the 53.7% who went on to require a CVA were:

• Lighter in weight (26.8 vs 37.2 kg, p = 0.04)

• More likely to be intubated (63.7 vs 35.5 %, n < 0.001)

• Spent longer in PICU (3.8 vs 1.9 days, p < 0.001)

Had a higher mortality (15.3 vs 4.8 %, p = 0.009)

AUTHORS' CONCLUSION

Initial use of vasoactive medicines through a PVA may be an appropriate option while evaluating the need for CVA.

CLINICAL BOTTOM LINE

• This is informative data. It is particularly informative to see the low rate of extravasation in critically unwell children with 20- or 22-gauge cannulas.

• The characteristics of patients on vasoactive medicines through PVAs was different, they were older, more likely to have sepsis, and were typically less unwell than those who received CVAs – this is largely intuitive.

• When needing to start vasoactive medicines in children, one option is to initiate them peripherally – ideally through a high-quality cannula in a proximal vessel – whilst making a decision on the need for a CVA.

REFERENCES

1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644. PMID: 1303622.

2. Levy, Mitchell M. MD, FCCP; Fink, Mitchell P. MD, FCCP; Marshall, John C. MD; et al. For the International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Critical Care Medicine 31(4):p 1250-1256, April 2003. | DOI: 10.1097/01.CCM.0000050454.01978.3B

3. Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307. PMID: 11794169.

4. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. doi: 10.1097/01.ccm.0000117317.18092.e4. Erratum in: Crit Care Med. 2004 Jun;32(6):1448. Dosage error in article text. Erratum in: Crit Care Med. 2004 Oct;32(10):2169-70. PMID: 15090974.

5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. PMID: 23353941.

6. ARISE Investigators. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371(16):1496-506

7. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

8. Mouncey PR, Osborn TM, Power GS, et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015 Nov;19(97):i-xxv, 1-150. doi: 10.3310/hta19970. PMID: 26597979; PMCID: PMC4781482.

9. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. PMID: 26903338; PMCID: PMC4968574.

10. Rhodes, Andrew MB BS, MD, Evans, Laura E. MD, MSc, FCCM, Alhazzani, Waleed MD, MSc, FRCPC, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Critical Care Medicine 45(3):p 486-552, March 2017. | DOI: 10.1097/CCM.0000000000002255

11. Levy, Mitchell M. MD, MCCM, Evans, Laura E. MD, MSc, FCCM, Rhodes, Andrew MBBS, FRCA, FRCP, FFICM, MD. The Surviving Sepsis Campaign Bundle: 2018 Update. Critical Care Medicine 46(6):p 997-1000, June 2018. | DOI: 10.1097/CCM.0000000000003119

12. Marik PE, Byrne L, van Haren F. Fluid resuscitation in sepsis: the great 30 mL per kg hoax. J Thorac Dis. 2020 Feb;12(Suppl 1):S37-S47. doi: 10.21037/jtd.2019.12.84. PMID: 32148924; PMCID: PMC7024756.

13. Marik PE, Malbrain M. The SEP-1 quality mandate may be harmful: How to drown a patient with 30 mL per kg fluid! Anaesthesiol Intensive Ther 2017;49:323-8. 10.5603/AIT.a2017.0056

14. Sterling SA, Miller WR, Pryor J, et al. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Med. 2015 Sep;43(9):1907-15. doi: 10.1097/CCM.0000000000001142. PMID: 26121073; PMCID: PMC4597314.

15. Evans, Laura, Rhodes, Andrew, Alhazzani, Waleed, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine 49(11):p e1063-e1143, November 2021. | DOI: 10.1097/CCM.0000000000005337Danny is an Emergency Medicine Registrar at the Emergency and Trauma Centre and the current Senior Registrar for research. He trained in regional NSW before moving back to Melbourne to complete his training at the Alfred.

DR DANNY MARHABA

Emergency Registrar

Danny is an Emergency Medicine Registrar at the Emergency and Trauma Centre and the current Senior Registrar for research. He trained in regional NSW before moving back to Melbourne to complete his training at the Alfred.