UMEM Educational Pearls - By Lucas Sjeklocha

Enter the WATERFALL trial into the present flood of fluid strategy trials, a multi-country (primarily Spain) open-label RCT of “Aggressive” versus “Moderate” fluid resuscitation with lactated ringers for early mild acute pancreatitis.

Population: 249 adults (1/3 of the planned enrollment) presenting to the ED within 24hrs hours of abdominal pain onset diagnosed with mild acute pancreatitis. Numerous exclusions for local pancreatic complications, acute or chronic organ dysfunction (including CHF and CKD), among many others. Average age of 57, 51% female, 61% due to gallstones, median Charleson index of 2, median BISAP of 1, and 52% clinically judged hypovolemic on enrollment.

Interventions: 1:1 randomization to two complex protocols, both with time points every 48 hours and same criteria for initiating oral diet.

  • “Aggressive”: Immediate 20ml/kg bolus of LR hours with repeat 20ml/kg boluses for hypoperfusion followed by 3ml/kg/hr infusion for 12hrs, then 1.5-3ml/kg/hr for at least 36hrs
  • “Moderate”: 10ml/kg bolus only if hypovolemic with repeat 10ml/kg boluses for hypoperfusion followed 1.5 ml/kg/hr infusion for 20hrs

Outcomes/Results: Primary outcome was development of moderate of severe pancreatitis with no difference found between the two strategies. Median fluid at 72 hours was 8.3L (IQR 7.1- 10.8) in the aggressive arm and 6.6L (IQR 4.1 - 8.0) in the moderate arm.  Several point estimates favor the moderate group, but none statistically significant and there was not a difference in symptom or SIRS improvement at 72 hours.  The trial was stopped after 1/3 enrollment when the monitoring board noted a significantly increased rate of fluid overload in the aggressive arm (20.5%) versus the moderate arm (6.6%). 

Discussion:

-Aggressive fluids for mild acute pancreatitis didn’t show benefit over a moderate strategy and showed some harms in contrast to previous smaller studies and some guideline recommendations in mild disease

-Only reached 1/3 of target enrollment significantly limiting analysis

-This was by design not a trial of severe or critical disease

-The open label nature may have affected some endpoints, including safetly endpoints

-Another trial to shift our thinking a bit about how to use and safely limit fluid resuscitation

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Hemodynamic instability and cardiac arrest are major complications following endotracheal intubation.  The mantra “resuscitate before you intubate” has prompted several studies of how to prevent this.

The PREPARE II trial is a multicenter ICU-based trial studying the effect of 500cc of crystalloid versus no crystalloid pre-emptively to prevent hypotension following endotracheal intubation. The study enrolled 1067 critically ill patients in United States ICUs. Some 60% of patient were intubated for respiratory failure and 20% were already on vasopressor.  The primary induction drugs we etomidate and rocuronium. Importantly, urgent intubation was an exclusion. There were no differences in multiple endpoints including hypotension, new need for vasopressors, cardiac arrest, or 28-day mortality. 

This was in some ways this in not unexpected and patients already in an ICU setting have typically received some form of fluid loading already. Being ICU based and primarily a more smoldering medical population this has limited application to more emergent and undifferentiated settings, but study underscores the need for a broad and nuanced view of what “resuscitate” means. Positive pressure may exacerbate hypovolemia, but the patient’s underlying disease, the effect of anesthetic drugs both by direct action via relief of pain, discomfort, or dyspnea may predominate if you think the patient is euvolemic.

Remember to dose anesthetics/sedatives/RSI drugs with an eye toward hemodynamics and consider starting vasopressors prior to intubation

Bottom Line:

-In a broad well-conducted ICU-based study a 500cc peri-intubation bolus doesn’t prevent hypotension

-Have a broad view of what resuscitation for intubation might entail

-Having fluid ready for intubation is helpful, hemodynamic dosing of drugs and having a plan for vasopressors might be even more helpful

-Applicability to ED environments is limited in this ICU-based trial

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Enthusiasm for early transfusion of blood products in patients with traumatic shock has increased with increasing availability of pre-hospital blood and plasma and results of studies such as the PAMPer trial of pre-hospital plasma have shown potential mortality benefits.  The deployment of prehospital blood for patients in hemorrhagic shock is promising but has significant cost and logistical considerations.

The RePHILL trial was a UK pre-hospital-based study of packed red blood cells and lyophilized plasma versus normal saline in trauma patients with presumed hemorrhagic shock.  Patients older than age 16 with an SBP<90 or an absent radial pulse were eligible to get up to 1L of the study intervention.  Multiple centers took part in the trial with 1:1 randomization stratified by study center.  The primary outcome was a combination of mortality or lactate clearance less than 20% per hour or both.

A total of 432 patients were assigned a study fluid. The population was 82% male, median of 38 years old, with 78% of injuries classified as blunt, and 82% of the presumed hemorrhage classified at non-compressible. This was a very ill population with an average SBP of 73, an average GCS of 7 and an ISS of 36. The average from emergency call to EMS arrival was 30 minutes, average to study intervention was 26 minutes and time from EMS activation to ED arrival was 90 minutes.

The results showed no difference in the primary composite endpoint (64% vs 65%), with no difference in mortality (43% vs 45%) or lactate clearance (50% vs 55%).  Interestingly, patients in the blood product arm had similar vital signs, lactate, and INR on ED arrival but received more blood products in the first 24 hours after ED arrival (pRBC 6.34 vs 4.41, p=0.004 and Plasma 5.04 vs 3.37, p=0.002). The was a trend toward improved early mortality at 3hr in the pre-hospital blood group (16% vs 22%, p=0.08).

Bottom Line(s):

Prehospital packed red blood cells and lyophilized plasma as compared to saline for traumatic shock did not improve mortality or lactate clearance in a well conducted multicenter RCT. 

The use of prehospital blood products is promising but population which benefits, and the optimal type of product and delivery mechanism remain unclear.

Increased blood utilization and lower early mortality in the blood product group may represent alteration in the spectrum of disease that requires different early management.

The reasons for this counterintuitive result are unclear and further trials of whole blood as well as fibrinogen concentrates are ongoing.

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Category: Critical Care

Title: DOREMI: Milrinone Versus Dobutamine in Treatment of Cardiogenic Shock

Keywords: Cardiogenic Shock, Milrinone, Dobutamine (PubMed Search)

Posted: 10/28/2021 by Lucas Sjeklocha, MD (Updated: 12/7/2022)
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Background: A cornerstone of therapy for cardiogenic shock is inotropic support with medications including dobutamine, epinephrine and milrinone.  Few studies have examined these head-to-head and between dobutamine and milrinone (including only one RCT of 36 patients)

The investigators conducted a RCT of milrinone versus dobutamine for cardiogenic shock in a single quaternary care center cardiac ICU.

Inclusion: Patients over 18 with cardiogenic shock (largely clinical determination)

Exclusion: Out-of-hospital cardiac arrest, pregnancy, prior initiation of dobutamine or milrinone, or physician discretion.

Methods: 1:1 randomization stratified by affected ventricle (LV vs RV). Primary outcome was a composite of in-hospital death, resuscitated cardiac arrest, cardiac transplant, mechanical circulator support, nonfatal MI, TIA, stroke, or renal replacement therapy. Powered to detect a 20% improvement in this measure in the milrinone group (192 pts).

Results:  192 patients enrolled (96 in each arm). Average age was 70, 36% female, 90% LV dysfunction, 67% ischemic disease, 33% non-ischemic, average LVEF 25%, 68% on vasopressors. ICU admission to randomization was 23+/-92.6h for dobutamine and 17.6+/-50.6h for milrinone arms. 80% were SCAI class C shock.

Primary outcome for milrinone 49% versus dobutamine 54%, HR 0.9(0.69-1.19), p=0.47, death was the primary driver of the composite (37% vs 43%).  Arrythmia requiring intervention was not different between groups (50% vs 46%). No difference in a host of other endpoints including AKI (92% vs 90%), RRT (22% vs 17%), HR, lactate, MAP, UOP, and creatinine.

Discussion: No significant differences observed in outcomes for patients with cardiogenic shock randomized to milrinone versus dobutamine.  The trial addressed an important clinical question for management of cardiogenic shock and relied largely on clinical diagnosis for inclusion and likely reflected a somewhat broad range of patients. The trial was too small given observed treatment effects and few patients with RV failure. Notably, similar rates of adverse events observed in each group.  

Many limitations for practice including a single specialized ICU setting, limited information on events leading to ICU admission including invasive or medical interventions during the index visit and no long term follow-up.  Time to randomization, exclusion of cardiac arrest, and lack of reporting pre-ICU setting (ED, floor, cath lab) also significantly limits utility in an emergency setting.

Bottom Line: 192 patient single-center cardiac ICU-based trial shows no difference in composite or secondary endpoints between milrinone and dobutamine for cardiogenic shock, adds to a body of very limited RCTs comparing inotropes in cardiogenic shock but provides no practice changing evidence.

 

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Background: Interest in moving to balanced fluid administration has grown after publication of the SPLIT trial and SALT-ED/SMART trials, which showed respectively evidence of benefit to balanced crystalloid over normal saline on mortality and major adverse kidney events at 30 days.

Population/Intervention: The BaSICs trial is an RCT in 75 ICUs in Brazil, testing P-Lyte versus NS (with each arm getting two different infusion rates that were analyzed as a separate trial) for volume administration per protocol.

--10,520 ICU patients requiring fluid expansion, expected ICU stay >1 day, and 1 additional risk factor for AKI (age>65, hypotension, sepsis, MV, NIV, oliguria, elevated creatinine, cirrhosis, or acute liver failure).

--Exclusions: severe dysnatremia, expected RRT within 6 hours, expected death.

--Average age was 61, with a SOFA score of 4, and 48% on were elective surgical admissions.

Outcome:

--No difference in 90 days mortality (P-Lyte 26.4% v NS 27.2, aHR p=0.47), AKI or RRT out to 7-days, or in duration of MV, ICU LOS or hospital LOS

--Median study fluid by day 3 was 2.9L in each group

--Higher neurological SOFA score observed in P-Lyte group

--Higher mortality seen with P-Lyte in TBI subgroup (P-Lyte 31.3% vs NS 21.1%, p=0.02)

Discussion:

--Adds contrasting negative data to previous large positive RCTs showing benefit of balanaced fluids

--Expect further reanalysis/metanalysis of BSS versus NS trials

--Signal for harm in TBI pts with P-Lyte correlates with SMART point estimates that were not significant

--Compared to SMART trial population BaSICs had: 2x higher mortality, more planned surgery, received about 1L more study fluid in the first 3ds

Takeaway:

--Balanced crystalloid versus normal saline debate will continue considering this large negative trial

--Signal for possible harm in TBI population with balanced crystalloids compared to normal saline

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