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Systematic review and meta-analysis of 5 studies with a total of 929 patients comparing early vs. late initiation of norepinephrine in patients with septic shock

• all were single-center studies
• included RCTs, prospective and retrospective cohort studies

Primary outcome:

• short-term mortality of the early group was lower than that of the late group ([OR] = 0.45; 95% CI, 0.34 to 0.61)

Secondary outcome:

• no difference in ICU LOS
• time to achieved target MAP of the early group was shorter than that of the late group (mean difference = − 1.39; 95% CI, −1.81 to −0.96)
• in the three studies that assessed the volume of intravenous fluids within 6 h, the volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = − 0.50L; 95% CI, −0.68 to −0.3)

Caveat:

• no clear definition of “early” initiation (ranged from within 1 to 6 hrs)

Take home point:

Early norepinephrine usage may improve mortality in septic shock

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Design
-Two-center prospective observational study with 157 patients admitted to the ICU for pneumonia and being treated with HFNC
-ROX (Respiratory rate-OXygenation) index = ratio of SpO2/FIO2 to RR

Results:
-ROX index ≥4.88 at 12 hours after HFNC onset with a sensitivity of 70.1%, a specificity of 72.4%, PPV of 89.4%, NPV of 42%, LR+ of 2.54, and LR- of 0.41 in predicting treatment failure

Validation study: Roca, 2019
-results similar, but ROX index ≥4.88 at 12 hour with LR+ of only 1.82
-also found that a ROX index of <3.85 at 12 hours had a sensitivity of 23.5%, specificity of 98.4%, PPV of 88.9, NPV 69.9, LR+ of 14.47, and LR- 0.78

Pitfalls:
-decision to intubate was not made based on ROX index
-criteria for intubation was also part of the ROX index
-NIV was not part of their treatment algorithm
-created and validated prior to current COVID-19 pandemic

Takeaways:
- The ROX index can be a tool to help predict whether a patient with pneumonia on HFNC may need mechanical ventilation or higher level of care
- May be most helpful with patients with pneumonia on HFNC boarding in the ED
- At 12 hours of HFNC, ROX index of >4.88 suggests patient likely to succeed with HFNC vs. <3.85 which suggests likely need for mechanical ventilation

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Clinical Question: Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes?

Methodology:

Design: Randomized, unblinded clinical trial among adults with sepsis-associated hypotension comparing PLR-guided SV responsiveness as a guide for fluid management (intervention) versus “usual care” at 13 hospitals in the United States and the United Kingdom (randomization was in a 2:1 allocation of SV-guided to usual care).

Inclusion criteria:

-patients presenting to the ED with sepsis or septic shock and anticipated ICU admission.

-refractory hypotension (MAP ≤ 65mmHg after receiving ≥ 1L and < 3L of fluid)

Exclusion criteria:

-infusion of > 3L of IV fluid prior to randomization

-hemodynamic instability due to active hemorrhage

-pregnancy or being incarcerated

-indication for immediate surgery

-acute CVA, acute coronary syndrome, acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, drug overdose, injury from burn or trauma, status epilepticus

-inability or contraindication to passive leg raising

Intervention (in ICU):

-PLRs were performed prior to any treatment of hypoperfusion with either fluid bolus or vasopressors for the first 72 hours after ICU admission or until ICU discharge (whichever occurred first)

-If patient was FR (increase in SV ≥10%) a 500 ml crystalloid fluid bolus was given with repeat PLRs after every fluid bolus

-If the patient was non-FR, initiation or up-titration of vasopressors was prompted with repeat PLRs after significant escalation (an increase of 1 mcg/kg/min norepinephrine)

Results:

-83 patients in Intervention arm, 41 in Usual Care arm

-Both arms received a similar volume of resuscitation fluid prior to enrollment (2.4 ± 0.6 L Intervention vs. 2.2 ± 0.7L Usual Care)

-Positive fluid balance at 72 hours or ICU discharge, was significantly less in the Intervention arm (-1.37L favoring Intervention, 0.65 ± 2.85L Median: 0.53L Intervention vs. 2.02 ± 3.44L Median: 1.22L Usual Care, p=0.02).

-Fewer patients required RRT (5.1% vs 17.5%, p=0.04) or MV in Intervention arm compared to Usual Care (17.7% vs 34.1%, p=0.04)

-ICU length of stay was similar in the two arms  

-There was no difference in overall 30-day mortality (6.3% difference, Intervention: 15.7% vs. Usual Care: 22.0%, 95% CI -21.2%, 8.6%)

Implications:

Although this is a smaller, unblinded (also funded by maker of SV monitoring device) study, Douglas et al. demonstrate that limiting fluid administration using dynamic assessments of fluid responsiveness to guide resuscitation in patients in septic shock is likely safe. In fact, this may actually decrease the need for renal replacement therapy and mechanical ventilation amongst this patient population. At the very least, this study adds to the body of literature showing the harms of excessive fluid administration and positive fluid balance.

Bottom line:

If possible, use dynamic assessments of fluid responsiveness in patients with septic shock to guide interventions, particularly for further resuscitation beyond initial fluid resuscitation (~2 liters in this study).

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Clinical Question: Does a lower MAP target (60-65 mmHg) for ICU patients ≥ 65 years-old reduce 90-day mortality?

Methodology:

-Design: multicenter (across 65 UK ICUs), randomized clinical trial (not blinded), ultimately with 2598 patients

-Inclusion criteria: ICU patients ≥ 65 years-old receiving vasopressors for vasodilatory hypotension with adequate fluid resuscitation

-Exclusion criteria: vasopressors being solely used for bleeding or acute RV/LV failure or post-cardiopulmonary bypass vasoplegia, ongoing treatment for brain/spinal cord injury, death perceived as imminent

-Intervention:

• Permissive hypotension group – MAP target of 60-65 mmHg
• Usual care group – received vasopressors at discretion of treating clinician
• Choice of vasopressor (norepi, vaso, terlipressin, phenylephrine, epi, dopamine, and metaraminol) left to discretion of treating clinician

Results:

-Patients in the permissive hypotension group had a lower exposure to vasopressors compared with those in the usual care group

• median duration 33 hours compared with 38 hours (difference, –5.0; 95% CI, –7.8 to –2.2)
• mean duration, 46.0 hours compared with 55.9 hours (mean difference, –9.9 hours; 95% CI, –14.3 to –5.5)

-Mean MAP was on average 6 mmHg lower in permissive hypotension group

-At 90 days, there was no statistically significant difference in all-cause mortality

• 500 deaths (41.0%) among of 1221 patients in the permissive hypotension group compared with 544 (43.8%) among 1242 patients in the usual care group (absolute risk difference, −2.85%, 95% CI, −6.75 to 1.05; P = .15)

-No significant difference in mean duration of ICU and hospital stay, duration and days alive and free from advanced respiratory and renal support to day 28

-No significant different in number of serious adverse events (severe acute renal failure, supraventricular and ventricular cardiac arrhythmia, myocardial injury, mesenteric ischemia, and cardiac arrest)

Bottom line:

A lower MAP goal of 60-65 mm Hg appears to be safe for ICU patients ≥ 65 years-old being treated for vasodilatory hypotension

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(*It is important to note that many of the percentages in these early studies will change as more asymptomatic or minimally symptomatic patients are identified with increased testing)

Epidemiology

Among more than 44,000 confirmed cases of COVID-19 in China as of Feb 11, 2020:

- 30–69 years: ~78%

- severely or critically ill: ~19%

Case-fatality proportion: 

-60-69 years: 3.6%

-70-79 years: 8%

-≥80 years: 14.8%. 

-With no underlying medical conditions: overall case fatality of 0.9%

-With comorbidities: 

-cardiovascular disease (10.5%), diabetes (7%)

-chronic respiratory disease, hypertension, and cancer (6% each)

Presentation

For patients admitted to the hospital, many non-specific signs and symptoms: 

- fever (77–98%) and cough (46%–82%) were most common

- of note, gastrointestinal symptoms (~10%) such as diarrhea and nausea present prior to developing fever and lower respiratory tract signs and symptoms.

Diagnosis

No general lab tests have great sensitivity or specificity            

A normal CT scan does NOT rule out COVID-19 infection

-In an early study, 20/36 (56%) of patients imaged 0-2 days (‘early’) after symptom onset had a normal CT with complete absence of ground-glass opacities and consolidation

Treatment-

Mainstay of treatment will be management of hypoxemia including early intubation if necessary. However, specifically:

-Steroid therapy is controversial and the WHO is currently recommending against it unless it is being administered for another reason

-has not been associated with any benefit

-associated with possible harm in previous smaller studies with SARS and MERS

-associated with prolonged viremia

-intravenous remdesivir (a nucleotide analogue prodrug with promising in-vitro results against SARS-CoV and MERS-CoV) is available for compassionate use

            -lopinavir-ritonavir has been used without any associated benefit

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Adequate treatment of adrenal crisis (AC) is often delayed, even when a h/o adrenal insufficiency is known.

• most important predictor of AC is a h/o of AC

Besides refractory hypotension, also consider in pts with:

• critically ill pts with eosinophilia (cortisol typically suppresses eosinophil counts)
• cancer patients who are on check-point inhibitor immunotherapy (they can cause severe hypophysitis or adrenalitis)
• (inhaled glucocorticoids and topical creams also cause a degree of adrenal insufficiency)

Beware of triggers:

• trauma, recent surgery, even emotional stress/exercise
• recent initiation of medications that increase hydrocortisone metabolism (avasimibe, carbamazepine, rifampicin, phenytoin, and St. John’s wort extract)
• recent withdrawal of medications that decrease hydrocortisone metabolism (voriconazole, grapefruit juice, itraconazole, ketoconazole, clarithromycin, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and conivaptan)

Treatment:

• 100 mg IV hydrocortisone STAT as a loading dose, followed by 50 mg IV hydrocortisone q6h
• can also give 40 mg IV methylprednisolone if hydrocortisone is not immediately available
• can also give 4-6 mg IV decadron instead (will preserve integrity of ACTH stim test to diagnose adrenal insufficiency if it is performed later)

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Blood Transfusion Thresholds in Specific Populations

Sepsis - 7 g/dL

• non-inferior to 9 g/dL (which was previously recommended in early goal-directed therapy and early Surviving Sepsis guidelines)

Acute Coronary Syndrome - no current specific recommendations pending further studies

• recent MINT pilot study showed unexpected trend toward higher combined mortality and major cardiac events in restrictive transfusion arm (8 g/dL) vs. liberal arm (10 g/dL)

Stable Cardiovascular Disease - 8 g/dL

• no difference in 30-day mortality compared to 10 g/dL, excluding those who have undergone cardiac surgery

Gastrointestinal Bleeds

• UGIB - 7 g/dL (unless intravascularly volume depleted or h/o CAD)
  • better 6 week-survival, less re-bleeding compared to 9 g/dL
• LGIB - 7 g/dL, limited evidence, but based on UGIB data

Acute Neurologic Injury - Traumatic Brain Injury - 7 g/dL

•  no significant difference in neurologic recovery at 6 weeks or mortality vs. 10 g/dL, although there were more brain tissue hypoxia events in restrictive arm
•  anemia and transfusions both associated with worse outcomes in TBI

Postpartum Hemorrhage - 1:1:1 ratio strategy

• FFP/RBC ratio ≥  1 associated with improved patient outcomes

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The Kidney Transplant Patient in Your ED

• Acute bacterial graft pyelonephritis is the most frequent type of sepis (bacterial pneumonia is the second most common source)
• Obtain renal transplant imaging to evaluate for sources of infection (i.e. urinary tract obstruction, renal abscess, or urine leakage)
• BK polyomavirus may reactivate and lead to nephritis, ureteral stenosis, or hemorrhagic cystitis
• Pneumocystis pneumonia is the most common fungal infection in patients without prophylaxis and after prophylaxis discontinuation (adjunctive steroids for treatment is controversial)
• Vascular access may be challenging. Avoid subclavian lines or femoral venous acess on the side of the graft
• Cardiovascular disease is the leading cause of mortality (accounts for 40-50% of deaths after the first year following renal transplant)

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