PPV to Guide Fluid Management in the PICU

In pediatric critical care, it is difficult to discern a patient's intravascular fluid
status (hypovolemia, hypervolemia, euvolemia). Often, pediatric sepsis patients exhibit
profound hypovolemia and early aggressive fluid resuscitation has been shown to decrease
mortality (1,2). Within the first 48 hours of presentation, pediatric patients with sepsis
can have profound changes in physiology with changes in cardiac function and systemic
vascular resistance which can make it difficult to discern whether continued fluid
resuscitation or the addition of vasopressor support is needed (1,2). Similar physiology can
also be seen in other patients with systemic inflammatory response such as postoperative
cardiac patients and general pediatric post-surgical patients. While appropriate fluid
resuscitation is needed, it has been shown that fluid overload does increase mortality
(3-5). Clinicians often use clinical exam, vital signs, urine output and central venous
pressure (CVP) as guides for need of fluid resuscitation, but static measures such as
central venous pressure, pulmonary wedge pressure, and clinical exam have not been shown to
be strong predictors of fluid responsiveness and cardiac output in patients (6-8). A more
accurate way to discern fluid status and heart function is through measurement of cardiac
output, but in order to calculate cardiac output, additional tests such as an echocardiogram
is needed or additional invasive monitoring using thermodilution such as a continuous
cardiac output monitor is needed (7,8).

In the last 30 years, dynamic changes in arterial pressure during the respiratory cycle have
been described, where there is a decrease in cardiac preload during time of inspiration of a
positive pressure breath followed by an increase in cardiac preload during the expiration of
a positive pressure breath 9,10. Using this change in arterial pressure, information about
cardiac preload or volume status can be inferred. The most common forms of dynamic pressure
monitoring that are used are systolic pressure variation and pulse pressure variation.

Several adult studies have shown that systolic pressure variation (SPV) and pulse pressure
variation (PPV) more accurately predict fluid response (defined in majority of studies as
increase stroke volume index or cardiac index/output >15% after receiving a fluid bolus) in
mechanically ventilated critically ill patients compared to static measures, such as CVP
(2,10-24). PPV has also been shown to be predictive of fluid responsiveness in many patients
with many different pathologies including intraoperative patients, postoperative cardiac
bypass patients, patients in septic shock and patients with acute lung injury requiring
lower tidal volumes (11,13-15,17-23,25). PPV has also been validated as a helpful and
accurate guide for fluid responsiveness in clinical scenarios requiring vasopressors
(12,26). Lopes et al demonstrated not only that PPV accurately predicts fluid response, but
by using PPV directed fluid resuscitation in the operating room, patients had better
postoperative outcomes as defined by decreased ventilator time (1 vs 5 days, P<0.05), and
decreased length of hospital stay (7 vs 17 days, P< 0.1) (22).

There are very few studies evaluating pulse pressure variation in the pediatric patient
population and results have been mixed. Similar to the adult studies, these studies
evaluated dynamic parameters, including SPV and/or PPV, by comparing changes in dynamic
parameters to changes seen in stroke volume index calculated by continuous cardiac index
monitoring or echocardiogram. Fluid boluses were given and if the SPV or PPV decreased as
the stroke volume index increased, then these dynamic parameters were proven to be
predictive of fluid responsiveness. Some studies showed that PPV or SPV were not reliable
predictors of fluid responsiveness (27-29). In contrast, a study in infants and neonates
undergoing congenital heart surgery (ventricular septal defect and atrial septal defect
repairs) illustrated that PPV was predictive of fluid response both before and after repair
of the cardiac lesion (30). This study was particularly interesting since PPV was able to
predict fluid response in two different physiologic states, with and without an intracardiac
shunt (30). Two other pediatric studies also demonstrated that dynamic parameters were
predictive of fluid response (31,32). There have been no pediatric studies thus far that
have investigated if dynamic variable (PPV or SPV) guided fluid resuscitation improves
patient outcomes.

Dynamic pressure monitoring, including PPV and SPV, is considered standard of care within
the adult anesthesia setting and is currently being used in the adult operating rooms at
University of North Carolina Hospitals. Most of the monitors within the hospital are
equipped to measure PPV, including the monitors in the PICU. Several PICU attendings and
fellows are familiar with PPV and have been using it as an aid in fluid management over the
last couple of months. The investigator's hope is that with the use of PPV that physicians
will be better able to gauge a patient's intravascular status and judiciously give fluid
leading to appropriate fluid management and better patient outcomes in the Pediatric
Intensive Care Unit (PICU).

Hypothesis: Using pulse pressure variation will reduce the amount of fluid in the first 48
hours of acute illness (first 48 hours after placement of arterial line and intubation on
conventional mechanical ventilation) by 30%. Appropriate fluid management will reduce the
amount of time on the ventilator, the number of days in the PICU, and time on vasopressors.

Methods:

Patient Population and Recruitment: All patients admitted to the pediatric intensive care
unit will be screened for recruitment for study by pediatric critical care attending or
fellow. Patients that require standard mechanical ventilation and arterial line will be
eligible for the study. Study will include 75 patients admitted to the PICU that require an
arterial line and conventional mechanical ventilation that will be prospectively followed.
There will be 75 matched, historic patients that will be used for controls. The
investigators do not expect any difficulty enrolling 75 patients to the study as there were
1069 patients admitted to the PICU in the last year (July 2013 to July 2014).

Study Procedure: Prior to any accrual of patients, all nurses in the PICU and all PICU
physicians (attendings and fellows) will have formal education and training on use of PPV
and the study protocol. In addition, all physicians will have consent training. All patients
admitted to the pediatric intensive care unit who are mechanically ventilated on
conventional ventilator settings with arterial line will be eligible for the study. Primary
investigator (during the day) or physician on call in the PICU (during the night) will
obtain consent if patient is eligible for the study. The bedside physician (co-investigator)
will give fluid as needed based on standard clinical data (heart rate, central venous
pressure if available, blood pressure, urine output, physical exam, lactate level) and pulse
pressure variation. Boluses of 5 cc/kg will be given so as to give fluid incrementally.
Pulse pressure variation value before fluid bolus and after fluid bolus will be recorded in
the electronic medical record. Pulse pressure variation will be followed for 48 hours. Pulse
pressure variation, central venous pressure, total fluid for PICU stay, total fluid during
48 hours while on the PPV protocol (cc/kg/day), days mechanically ventilated, hours on
vasopressors, any echocardiograms, age, weight at admission, daily weights, sex, diagnosis
will be recorded in the patient's medical record. All data will be collected from patient's
record by the primary investigator.

Data Analysis: Continuous baseline variables will have descriptions with means and standard
deviations, and categorical baseline variables will be described with frequency
distributions. A two-sided t-test and corresponding confidence interval will be used to
compare matched historic controls to prospectively recruited test group subjects for total
amount of fluid in 48 hours (cc/kg/day). Wilcoxon Rank Sum tests for time-to-event data will
be applied to time on ventilator (days), time in the PICU (days), and time on vasopressors
(hours), together with Kaplan-Meyer curves for descriptive purposes.

Inclusion Criteria:

1. Admission to the University of North Carolina pediatric critical care unit, includes
all patients admitted to the pediatric critical care service as well as all
post-operative patients.

2. No limitations for age or gender.

3. Patient requires standard mechanical ventilation.

4. Patient has an arterial line in place.

Exclusion Criteria:

1. Patient not mechanically ventilated.

2. Patient does not have arterial line placed.

3. Patient requires extracorporeal life support.

4. Patient requires placement on high frequency oscillatory ventilation.

5. Pulse pressure variation unable to be obtained on monitor.

6. Patient has open chest.

7. Patient has arrhythmias.