Children who are critically ill often require large amounts of fluid during their acute illness. It has been shown in multiple studies that appropriate administration of fluid decreases morbidity and mortality, but giving too much fluid can also cause increased morbidity and mortality. It is often difficult to discern from physical exam, vital signs and labs if the amount of fluid that has been given is appropriate or if a pediatric patient requires more fluid. Pulse pressure variation (PPV) is the change in blood pressure when a patient is on a ventilator or breathing machine. PPV has been used in multiple adult studies to help predict fluid needs in a critically ill patient. In this study, we would like to investigate if PPV can help better predict if critically ill pediatric patients in the pediatric intensive care unit (PICU) need fluid. The investigators hope that by having the additional information that PPV can provide, physicians can more judiciously give fluid and thereby improve morbidity of critically ill patients 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.

All subjects admitted to the pediatric critical care unit

Adverse events were recorded until subjects discharge from the pediatric critical care unit.

There was no recording or evaluation of adverse events in the retrospective group since they were evaluated retrospectively. The adverse events recorded are more likely secondary to the critically ill nature of the cohort rather than PPV itself.