SGEM#90: Hunting High and Low (Best MAP for Sepsis Patients)

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Date: October 1st, 2014

Guest Skeptics: Dr. Erin Brennan and Dr. Stuart Douglas. Residents in Emergency Medicine at Queen’s University.

This is another SGEM Journal Club. It was recorded live in Kingston, Ontario at Queen’s University. Thank you to Dr. Heather Murray and all the staff and residents. I had a great time and you have a great program.

There have been two previous SGEM JCs. The first one was at McGill University in Montreal. This is where Dr. William Osler started journal club “for the purchase and distribution of periodicals to which he could ill afford to subscribe”. I am pretty sure Dr. Osler would have been a big fan of FOAMed. SGEM#50 asked whether vasopressin, epinephrine and corticosteroid (VSE) protocol for in-hospital cardiac arrest resuscitation improve survival with favorable neurological outcomes compared to epinephrine alone.

The second episode took place at the home of evidence based medicine, McMaster University. This is where my mentor Dr. Andrew Worster taught me that the answer to any EBM question is “it all depends”. SGEM#55 asked whether an departmental guideline on controlled substance prescriptions reduce opioid abuse?

Case: 74-year-old man is brought by EMS for altered level of consciousness. He lives alone, family hadn’t heard from him in several days so went to check, found him to be coughing and mildly confused. EMS vitals: HR 115, RR 24, BP 103/70, O2 89% on room air, 99% on non-re-breather mask, T 38.4C and blood glucose is normal. The patient is not intubation, wishes no CPR, but full medical management.

Past medical history includes: COPD, type 2 diabetes, hypercholesterolemia, hypertension and peripheral vascular disease. He is triaged to acute care bed, IV access obtained and bolus 0f 1 liter normal saline provided. ECG shows sinus tachycardia and portable CXR demonstrates right lower lobe infiltrate. Laboratory tests are drawn and sent.

You start Early Goal Directed Therapy (EGDT) by rapidly recognized this man is septic, provided IV fluids and appropriate IV antibiotics for pneumonia. Now you are starting to think about more fluids +/- vasopressors to increase his Mean Arterial Pressure (MAP).

Question: Does a MAP of 80-85mmHg decrease 28 day mortality as compared to a MAP of 65-70mmHg?

Dr. Stuart Douglas and Dr. Erin Brennan

Background: Sepsis remains a major contributor to ED morbidity, carrying a short-term mortality of approximately 20% (ProCESS). With approximately 750,000 annual cases in the US, recognition and early treatment of severe sepsis and septic shock has become a pillar of Emergency Medicine.

Sepsis can be defined as a “clinical syndrome complicating severe infection characterized by inflammation remote from the site of infection. Disregulation of the inflammatory response can lead to multiple organ dysfunction.”

There is a continuum of sepsis ranging from SIRS (Systemic Inflammatory Response Syndrome) to septic shock.

SIRS – temperature <36 or >38’C, HR >90 RR >20 (or PaCO2 <32mmHg), WBC <4 or >12, or >10% immature forms
Sepsis – 2/4 SIRS criteria + infection.
Severe Sepsis – Sepsis + hypotension end organ failure
Septic Shock – Sepsis and hypotension refractory to fluid treatment

Mean Arterial Pressure (MAP) is the average arterial pressure during a cardiac cycle, represents the perfusion pressure seen by the organs/tissues. MAP = (CO x SVR) + CVP, or estimated by MAP = 2/3 Diastolic BP + 1/3 Systolic BP (inaccurate if tachycardic).

Sepsis management involves early recognition with early intervention. Rapid administration of broad spectrum antibiotics (then titrating to pathogen), and a sequential approach to fluid administration to CVP targets, vasopressor administration to MAP targets, and PRBC transfusion to hematocrit and ScvO2 targets has resulted in marked improvements in survival. Recent studies (ProCESS) have indicated that invasive blood pressure monitoring may not be required, as previously thought.

Early Goal Directed Therapy

There is a hypothesis that a higher MAP may be better than a lower MAP. Dunser et al (2009) found in a retrospective cohort study that MAP below 75mmHg were associated with increased need for renal replacement therapy. Badin et al (2011) found in a prospective cohort study that in patients presenting with septic shock and renal impairment at baseline, MAP targets of 72-82mmHg resulted in less AKI at 72h.

Reference: Asfar et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. NEJM 2014

Population: 29 centers in France, 776 patients >18y with septic shock refractory to fluids who required vasopressors at >0.1mcg/kg evaluated within 6h of initiation of vasopressors
- Defined Septic Shock – two or more diagnostic criteria of the systemic inflammatory response syndrome, proven or suspected infection and sudden dysfunction of at least one organ
- Defined Refractory – lack of response to the administration of 30ml of normal saline (NS)/kg or of colloids or was determined according to the clinician’s assessment of inadequate hemodynamic results on the basis of values obtained during the right-heart catheterization, pulse-pressure measurement, stroke-volume or ECHO
- Exclusion Criteria: No consent, not in the French health care system, pregnant, in another study with mortality as the primary end point, investigators decided not to resuscitate.
Intervention: Target MAP of 80-85mmHg for max of 5 days
Control: Target MAP 60-70mmHg for max of 5 days
Outcome:
- Primary Outcome: Death from any cause at 28 days.
- Secondary Outcome: 90 days mortality, days alive and free from organ dysfunction by day 28, length of stay in ICU and hospital. Serious adverse events classified as ischemic or other.

Authors’ Conclusions: “No significant difference between the two groups in the overall incidence of serious adverse events.”

Quality Check List for Randomized Control Trials:

The study population included or focused on those in the ED. Unsure
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Yes
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. Yes

Results: There were 776 patients enrolled in this study. They determined their sample size of 800 patients assuming a death rate of 45%. This was to provide a power of 80% to show a 10% difference in the primary outcome (death at 28days) with a two sided alpha level of 0.05.

Key Result: No statistically significant difference in mortality at 28 days

Primary Outcome: No significant difference in the primary outcome between the groups for mortality at 28 days. The mortality rate for the High MAP was 36.6% vs. 34.0% for the Low MAP target. This gave a Hazard Ratio of 1.07 (95% CI 0.84-1.38; p=0.57)

Secondary Outcomes: There were also no differences detected in the secondary outcome of mortality at 90 days.
- High 43.8% vs. Low 42.3%
- HR 1.04 (95%CI 0.83-1.3; p=074).
Adverse Events: No difference were found in serious adverse events.
- High 19.1% vs. Low 17.8%

Overall, this was a high quality study looking at a clinically relevant topic. It was good to try and stratify patients based on hypertension. However, the authors noted the challenge in determining patients’ baseline blood pressures. This is important as it may indicate patients who have auto-regulated to a higher baseline MAP, and therefore require a higher MAP in treatment of sepsis to perfuse end-organs.

Lack of clinician blinding is a threat to validity, but unfortunately cannot be overcome in this type of study. The MAP values exceeded the targets in both groups, but were still significantly different. A large number of patients excluded were excluded from the study. Many they did not get to in less than six hours. Was there any trend in the excluded patients that could have resulted in study bias?

More than 80% of patients in both groups received steroids. This is different from clinical practice in Canada. In addition, approximately 7% of patients in both groups received Protein C.

Mortality rate was different in this study compared to the ProCESS trial and the original Rivers study. The higher mortalities across groups seen in this French study compared with ProCESS may be because of different infection profiles at inclusion.

The inclusion of ICU patients in this Asfar study (presumably patients who have already identified themselves as “sick”) could also contribute to the increased mortality. In addition, ProCESS sample was younger, with a larger female proportion. Unfortunately baseline comorbidity scores differed between studies and cannot be used to compare the samples directly.

In patients with hypertension, higher MAP resulted in less renal injury and need for renal replacement therapy. Results suggest that other than an increased risk of atrial fibrillation in the high MAP group there is no significant difference.

Considering the clinical picture is important in determining target MAP. Patients with uncontrolled hypertension at baseline will require higher MAPs to maintain end organ perfusion. These results suggest that perhaps there is not an ideal target MAP and support clinical practice of adjusting MAP to target end organ perfusion.

Our Conclusions Compared to Authors’ Conclusions: We agree that this study does not demonstrate a 28 day mortality advantage of a higher targeted MAP in patients with septic shock undergoing resuscitation.

SGEM Bottom Line: The ideal target MAP in septic shock is still unclear – patient factors play a role and care should likely be individualized.

Case Resolution: The patient receives 4 liters of normal saline in the emergency department. His resuscitation also includes non-invasive positive pressure ventilation, a central line and levophed to support blood pressure. He is then admitted to the ICU for ongoing critical care.

Clinical Application: Reasonable to consider MAP above 65mmHg depending on the case.

What Do I Tell My Patient? It looks like you have a serious infection. We are going to give you intravenous fluids, increase your blood pressure with medication if needed, provide broad-spectrum antibiotics, monitor your response to treatment and admit you to the hospital for further care.

Keener Kontest: Winner last week was Jaime Davis from Florida. He knew the core competencies for geriatric fall prevention that emergency medicine residents needed to know graduation based on the guidelines.

In patients who have fallen, evaluate for precipitating causes of falls such as medications, alcohol use/abuse, gait or balance instability, medical illness, and/or deterioration of medical condition.
Assess for gait instability in all ambulatory fallers; if present, ensure appropriate disposition and follow-up including attempt to reach primary care provider.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.