Critical Care, Critical Care Alert, Cardiology, Airway

Critical Care Alert: PREPARE II - A Randomized Clinical Trial


Russell DW, Casey JD, Gibbs KW, et. Al. PREPARE II Investigators and the Pragmatic Critical Care Research Group. Effect of Fluid Bolus Administration on Cardiovascular Collapse Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial. JAMA. 2022;328(3):270-279.

To determine the effect of fluid bolus administration on the incidence of severe hypotension, cardiac arrest, and death in critically ill patients undergoing endotracheal intubation

Hypotension occurs in up to 40% of tracheal intubations in the ICU and can potentially lead to cardiac arrest.1 It results in part from medication-induced vasodilation as well as from decreased venous return to the heart due to increased intrathoracic pressure from positive pressure ventilation. To counteract this, a fluid bolus of crystalloid solution is given in roughly 50% of emergency intubations in current clinical practice with the thought that it may transiently increase intravascular volume.2

PrePARE was a randomized clinical trial published in 2019 that determined that a fluid bolus did not affect a composite outcome of cardiovascular collapse (severe hypotension, cardiac arrest, or death) in critically ill adults undergoing tracheal intubation.3 That being said, a subgroup analysis of this data set showed there was a benefit for patients who received positive pressure ventilation with a bag-mask device or a noninvasive ventilator during the intubation procedure. This result hinted that a fluid bolus might reduce the negative effects of reduced venous return from positive pressure ventilation, which the majority of ICU patients receive during intubation.1 This analysis served as the impetus for this study which sought to explore this subgroup in further detail.

This was a multicenter, parallel-group, unblinded, pragmatic randomized clinical trial. It was conducted in 11 ICUs across the U.S. with enrollment periods from 2/1/2019 - 5/24/2021 with a pause from 2/28/2020 - 8/24/2020 for the Covid-19 pandemic.

Patients were randomized using a 1:1 ratio to receive or not receive a 500 mL intravenous fluid bolus of isotonic crystalloid solution of the clinician's choice. The goal was to infuse as much of the solution prior to induction of anesthesia without delaying the intubation, otherwise the rest of the solution was administered during the procedure. In either group, all other aspects of the intubation procedure were deferred to the operator, such as the choice of induction agents, whether patients received vasopressors to prevent or treat hypotension, or the use of a fluid bolus to treat hypotension after induction of anesthesia.

The patient population included 617 men and 448 women with a median age of 62 years. A total of 538 patients were assigned to the fluid bolus group with 527 patients in the no fluid bolus group. About 60% of patients had acute respiratory failure as their indication for tracheal intubation.

Age > 18 years old undergoing endotracheal intubation with the planned use of both medications to induce anesthesia and positive pressure ventilation with either a bag-mask device or non-invasive ventilation between induction of anesthesia and laryngoscopy. The latter was meant to selectively enroll patients most likely to benefit from fluids.


  • Pregnant women
  • Incarcerated patients
  • Patients whose immediate need for tracheal intubation precluded randomization
  • If the operator (clinician performing the intubation) determined that administration of a fluid bolus was either required or contraindicated

Cardiovascular collapse, which was defined as the occurrence of 1 or more of the following:

  • New or increased vasopressor receipt (bolus or infusion) between induction of anesthesia and 2 min after intubation
  • A systolic blood pressure < 65 mm Hg between induction and 2 min after intubation
  • Cardiac arrest or death between induction of anesthesia and 1 hr after tracheal intubation

The incidence of death prior to day 28. There were a number of exploratory outcomes, which can be found in Supplement 2 of the paper.

Primary outcome
Cardiovascular collapse occurred in 113 patients (21%) in the fluid bolus group and in 96 patients (18.2%) in the no fluid bolus group with a nonsignificant absolute difference of 2.8%, [95% CI, −2.2% to 7.7%], p = 0.25. Administration of a fluid bolus did not statistically decrease the incidence of cardiovascular collapse in any prespecified sub-group.

Secondary outcomes
A total of 218 patients (40.5%) in the fluid bolus group died prior to day 28 compared with 223 patients (42.3%) in the no fluid bolus group with an absolute difference of -1.8%, [95% CI, −7.9% to 4.3%], p = 0.55. There were no statistically different outcomes in any of the exploratory outcome analyses.


  • This study was conducted in an ICU setting where patients had already benefited from fluid resuscitation prior to enrollment in the trial. The results may not be generalizable to ED patients who may be intravascularly depleted on presentation and during their intubation.
  • These results may not generalize to the tracheal intubation of patients experiencing cardiac or respiratory arrest as about 15% of patients were screened into the study but then were excluded because the urgency of the intubation did not permit performance of trial procedures.
  • The trial only evaluated the administration of a 500 mL fluid bolus. Whether the results might have been different with a greater volume of fluid or a more personalized administration is unknown. It also did not evaluate the use of a fluid bolus to treat hypotension that developed during tracheal intubation.
  • The study used a composite outcome of cardiovascular collapse, the most commonly triggered component being the administration of new or increased vasopressor therapy. This element of cardiovascular collapse may not be an important patient-centered outcome.

Administering an IV fluid bolus during tracheal intubation of critically ill adults did not significantly decrease the incidence of cardiovascular collapse in these cohorts of ICU patients. These results may simplify decision-making during intubation of patients without another clear indication for a fluid bolus.


  1. Russotto V, Myatra SN, Laffey JG, Tassistro E, Antolini L, Bauer P, Lascarrou JB, Szuldrzynski K, Camporota L, Pelosi P, Sorbello M, Higgs A, Greif R, Putensen C, Agvald-Öhman C, Chalkias A, Bokums K, Brewster D, Rossi E, Fumagalli R, Pesenti A, Foti G, Bellani G; INTUBE Study Investigators. Intubation Practices and Adverse Peri-intubation Events in Critically Ill Patients From 29 Countries. JAMA. 2021 Mar 23;325(12):1164-1172. doi: 10.1001/jama.2021.1727. Erratum in: JAMA. 2021 May 24;:null. PMID: 33755076; PMCID: PMC7988368.
  2. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM; Difficult Airway Society; Intensive Care Society; Faculty of Intensive Care Medicine; Royal College of Anaesthetists. Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth. 2018 Feb;120(2):323-352. doi: 10.1016/j.bja.2017.10.021. Epub 2017 Nov 26. PMID: 29406182.
  3. Janz DR, Casey JD, Semler MW, Russell DW, Dargin J, Vonderhaar DJ, Dischert KM, West JR, Stempek S, Wozniak J, Caputo N, Heideman BE, Zouk AN, Gulati S, Stigler WS, Bentov I, Joffe AM, Rice TW; PrePARE Investigators; Pragmatic Critical Care Research Group. Effect of a fluid bolus on cardiovascular collapse among critically ill adults undergoing tracheal intubation (PrePARE): a randomised controlled trial. Lancet Respir Med. 2019 Dec;7(12):1039-1047. doi: 10.1016/S2213-2600(19)30246-2. Epub 2019 Oct 1. PMID: 31585796; PMCID: PMC8852295.

Related Articles

ECG Challenge: April-May 2022

A 67-year-old male with a PMH of HTN, HLD, DM, and COPD presents to the emergency department due sudden chest discomfort. What is your interpretation of his ECG?

Critical Care Alert: Milrinone vs. Dobutamine in the Treatment of Cardiogenic Shock

Managing critically ill patients with cardiogenic shock often includes a decision between two inotropes: dobutamine and milrinone. Is there evidence to inform that choice?