Aim of the Work This study aimed to evaluate the degree of pulmonary hypertension as well as alterations in the pulmonary vascular resistance in critically ill children with ARDS using bed- side echocardiography. Materials and Methods This cross-sectional case control study was conducted at the PICU of Ain Shams University Hospital on 20 critically ill mechanically ventilated patients with ARDS. The study comprised 11age- and sex-matched healthy children as controls. Those with underlying heart disease or chronic pulmonary disease were excluded. An informed consent was obtained from the parents or caregivers before enrollment. The study protocol was approved by the ethics committee of the Pediatric department, Ain Shams University. ARDS was diagnosed according to the American European Consensus Committee definitions of ARDS, 1994 (acute onset of the condition, bilateral infiltrates on chest radiograph sparing the costophrenic angles, a partial pressure of arterial oxygen to fractional inspired oxygen concentration ratio (Pa02/ Fi02 < 200mmHg) regardless of PEEP and lack of clinical evidence of left ventricular failure 1. Detailed history was taken from the caregivers for risk factors and etiology of ARDS. Full clinical evaluation was done to specify signs suggestive of ARDS and pulmonary hypertension. The type of ventilation was reported. Conventional ventilation (SIMV-PC) using (Neobort E 360 machine) was applied on 13 patients (65%) while, high frequency oscillatory ventilation using (SLE 5000 machine) was applied on 7 patients (35%). The ventillatory settings were assessed (fraction of inspired oxygen FIO2,ventillatory rate, peak inspiratory pressure (PIP), positive end expiratory pressure (PEEP) and inspiratory time (IT). Chest radiograph and arterial blood gases using Blood Gases Analyser ABL 50 were done. PaO2 was used to calculate the hypoxemia score which is the ratio of arterial O2 pressure to fraction of inspired O2 (PaO2/FiO2) - an important parameter for detecting the ARDS score. The ARDS score was calculated using the lung injury score which grades four parameters on a scale from (0 to 4). These parameters are (PaO2/FiO2) ratio, total respiratory compliance, level of PEEP used, and number of quadrants involved on chest radiograph 5. The final value was obtained by dividing the aggregate sum by the number of components that were used. [Score 0] indicates that there is no lung injury, [score (0.1-2.5)] denotes mild to moderate lung injury while [Score (>2.5)] means that lung injury is severe denoting ARDS 6. Echocardiography was performed using the GE Vivid I (Vingmid ultrasound, Horten, Norway) and the pediatric 5S probe (GE, Horten, Norway) to rule out an underlying cardiac disease, to detect left ventricular dimensions and function and to detect the parameters used for the assessment of pulmonary artery pressure and pulmonary vascular resistance. The right ventricular systolic pressure (RVSP) was detected by quantifying the tricuspid regurgitation jet velocity. Using the Bernoulli equation to measure the systolic gradient between the right ventricle and the atrium, RVSP is then determined from the equation RVSP=4(TR velocity)2+p RA where TR velocity is the maximum velocity of the tricuspid regurgitation jet (in meters per second) and P RA is an estimate of the right atrial pressure 7. Pulmonary artery end diastolic pressure (PAEDP) was estimated using a similar approach applied to the pulmonary regurgitation flow. Pulmonary velocity acceleration time was detected by applying PW Doppler sample volume at the level of the pulmonary valve to measure the interval between the onset of flow and the peak flow. The right ventricular outflow tract time-velocity integral (TVI RVOT) (cm) was obtained by placing a 1- to 2- mm pulsed wave Doppler sample volume in the proximal right ventricular outflow tract just within the pulmonary valve when imaged from the parasternal short axis view. As described by Abbas et al., 2003 4, Pulmonary vascular resistance was calculated using the equation: PVR= TRV / TVI RVOT 10 + 0.16 Statistical Methodology SPSS version 20 (IBM Corp., Armonk, NY) was used for statistical analysis. Normally distributed numerical data were presented as mean (95% CI Vol. 2 - No.3 July - September 2015 67
for the mean) and SD. Skewed numerical data were presented as median, interquartile range, minimum and maximum. Qualitative data were presented as number and percentage. Mann-Whitnney test was used to compare between the patient and the control groups and between Survivors and non-survivors. Correlation between variables was done using correlation coefficient (r). P value of <0.05 indicates significant results. Results This study was conducted on 20 consecutive critically ill children (17males and 3 females) on mechanical ventilation who were diagnosed as ARDS. Sixty-five percent of patients were below the age of 1 year. The youngest was 2 month old and the oldest was 14 years old with a median of 6.3 months and IQR of (4.3-28.5 months). The mean of their ARDS score was 3.7± 0.5 and the median was 4 and IQR of (3.3-4). The most common etiology for ARDS was septic shock in 13 patients (65%), followed by bronchopneumonia in 5 patients (25%). One patient (5%) had pancreatitis and one (5%) developed transfusion-related acute lung injury. Ninety percent of patients had elevated RVSP and PVR when compared to the normal standard values. The values of echocardiographic parameters used for the assessment of pulmonary hypertension and PVR among patients are expressed in table (1). Table 1: Echocardiographic parameters assessing pulmonary hypertension and PVR among patients Mean SD Median IQR TRV (m/s) 2.83 0.46 2.93 2.57-3.11 RVSP (mmhg) 43.43 10.22 44.50 36.3-48.5 PAEDP (mmhg) 13.34 5.57 13.80 8.35-16.6 PAAT (ms) 62.70 19.59 59.00 52.0-70.5 RVOT TVI (cm) 11.39 3.52 10.95 8.8-14.1 PVR 2.90 1.18 2.59 2.05-3.42 TRS, tricuspid regurge velocity; RVSP, right ventricular systolic pressure; PAEDP, pulmonary artery end diastolic pressure; PAAT, pulmonary artery acceleration time; PVR, pulmonary vascular resistance. Comparison between patients and controls as regards to PVR and RVSP are shown in table (2). Table 2: Comparison between patients and controls as regards to PVR and RVSP Controls ARDS cases (n=11) (n=20) Median IQR Median IQR Mann- P value Whitney RVSP (mmhg) Estimated PVR 25 23.5-26.0 1.5 1.1-1.6 44.5 36.3-48.5 2.6 2.1-3.4 U 1.5 <0.001(SS) 2 <0.001(SS) Table 3: Correlation between ABG indices and echocardiographic parameters assessing pulmonary hypertension and PVR TRV (m/s) RVSP (mmhg) PAEDP (mmhg) PAAT (ms) RVOT TVI (cm) PVR ph r or ρ -0.063-0.034-0.086 0.126 0.313-0.371 P 0.791 0.887 0.720 0.598 0.179 0.108 PaCO2(mmHg) r or ρ 0.174 0.181-0.062 0.007-0.169 0.306 P 0.464 0.444 0.796 0.976 0.476 0.190 PaO2(mmHg) r or ρ -0.055-0.019 0.129 0.155 0.112-0.208 P 0.819 0.935 0.589 0.515 0.639 0.378 HCO3(mmol/l) r or ρ 0.327 0.311 0.084 0.105 0.134-0.071 P 0.159 0.182 0.725 0.661 0.573 0.767 BE(mmol/l) r or ρ 0.099 0.074 0.248 0.125 0.411-0.291 P 0.678 0.756 0.291 0.599 0.072 0.213 PaO2/FiO2 ratio r or ρ -0.474* -0.421-0.362 0.045 0.088-0.385 P 0.035* 0.065 0.117 0.851 0.711 0.094 *Correlation is significant at the 0.05 level (2-tailed). TRV, tricuspid regurge velocity; RVSP, right ventricular systolic pressure; PAEDP, pulmonary artery end diastolic pressure; PAAT, pulmonary artery acceleration time; TVI/RVOT, right ventricular outflow tract time velocity integral; PVR, pulmonary vascular resistance. Vol. 2 - No.3 July - September 2015 68
Table 4: Correlation between ventillatory settings and echocardiographic parameters assessing pulmonary hypertension and PVR TRV (m/s) RVSP (mmhg) PAEDP (mmhg) PAAT (ms) RVOT TVI (cm) PVR FiO2 r or p 0.469* 0.439 0.529* 0.094-0.054 0.334 P 0.037 0.053 0.017 0.694 0.822 0.150 Ventilator rate (cycle/min) r or p -0.259-0.296-0.189 0.068-0.046-0.063 P 0.270 0.204 0.426 0.774 0.846 0.791 PIP (cmh2o) r or p 0.262 0.275 0.264-0.084-0.368 0.513* P 0.265 0.240 0.262 0.724 0.111 0.021 PEEP (cmh2o) r or p 0.352 0.349 0.400-0.016-0.335 0.440 P 0.128 0.132 0.080 0.948 0.149 0.052 *Correlation is significant at the 0.05 level (2-tailed) TRV, Tricuspid regurgitation velocity; RVSP, right ventricular systolic pressure; PAEDP, pulmonary artery end diastolic pressure; PAAT, pulmonary artery acceleration time; TVI/RVOT, right ventricular outflow tract time velocity integral; PVR, pulmonary vascular resistance. The median and IQR of RVSP 45(44.23-48.55) mmhg and the estimated PVR 3.1(2.23-3.55) were higher among the high frequency ventilated group when compared to the conventionally ventilated group 40.4(34.93-46.83)mmHg and 2.4(2.05-3.36) respectively but this was statistically insignificant (P value= 0.285 and 0.451) respectively. There was a negative correlation between the hypoxemic index (PaO2 /FiO2) and the TRV among the studied population and this was statistically significant as shown in table (3). Correlation between (FiO2 and TRV), (FiO2 and PAEDP) and between (PIP) and PVR are expressed in table (4). Three patients out of 20(15%) survived the ARDS. The median and IQR of ARDS score was higher among non-survivors 4 (3.3-4) when compared to survivors 3(2.7-3.8) and the median and IQR of the hypoxemia score (PaO2/FiO2) was higher in survivors 135(80.6 156.2) when compared to non-survivors (85.5-71.1-101.3) but these were statistically insignificant (P values =0.179 and 0.358) respectively. The median and IQR of RVSP, PAEDP and PVR were higher among non survivors when compared to survivors, but these were statistically insignificant as expressed in table (5). Discussion In this study, the hypoxemic score (pao2/fio2 ratio) was lower among non Survivors when compared to survivors, but it was statistically insignificant mostly due to the small number of survivors. Steinberg and Hudson (2000) 8 found that the severity of ARDS at the time of first diagnosis as measured by the hypoxemic index (Pao2/Fio2) generally had not been associated with different outcomes, suggesting that there is no correlation between Pao2/Fio2 and mortality. However, Lodha et al. (2001) 9 noted that changes in the ratio of Pao2/Fio2 following initial treatment of ARDS may be a useful discriminator between survivors and non survivors. Also, Dahlem et Table 5: Comparison between survivors and non survivors as regards to echocardiographic parameters assessing pulmonary hypertension and PVR Survivors (n=3) Non survivors (n=17) Median IQR Median IQR Mann-Whitney U P value TRV (m/s) 2.6 2.2-2.85 2.9 2.57-3.13 14.5 0.244(NS) RVSP (mmhg) 37 33.25-42.55 44.8 36.5-49.15 14 0.223(NS) PAEDP (mmhg) 5.7 5.03-10.88 15.5 9.6-17.43 7 0.050(NS) PAAT (ms) 67 55.75-83.5 59.0 52.0-68.75 20 0.555(NS) RVOT TVI (cm) 11.8 9.1-16.6 10.7 8.8-14.1 22 0.711(NS) PVR 1.9 1.75-2.95 2.6 2.1-3.58 13.5 0.203(NS) TRV, Tricuspid regurgitation velocity; RVSP, right ventricular systolic pressure; PAEDP, pulmonary artery end diastolic pressure; PAAT, pulmonary artery acceleration time; TVI/RVOT, right ventricular outflow tract time velocity integral; PVR, pulmonary vascular resistance. Vol. 2 - No.3 July - September 2015 69
al. (2003) 10 suggested a possible association between the hypoxemic index (Pao2/Fio2) and the outcome. On the contrary, Atabai and Matthay (2002) 11 found that the initial Pao2/Fio2 ratio was unpredictive of mortality in their clinical trial. The ARDS score revealed a higher median value among non survivors as compared to survivors. Murray and colleagues (1988) 5 had developed the lung injury score (LIS) which quantified the severity of lung injury from the degree of arterial hypoxemia, level of PEEP, radiographic abnormalities and respiratory compliance when available, and proposed it as a prognostic factor of mortality in ARDS. Ninety percent of patients had higher PVR and RVSP. This was supported by Beiderlinden et al. (2006) 12 who found that 92.2% of their studied patients with ARDS had pulmonary hypertension. Also the higher median of both PVR and RVSP among our patients was in agreement with Vieillard-Baron et al., (2002) 13 who found that acute lung injury is a recognized cause of pulmonary hypertension and right ventricular dysfunction. Over 30 years ago, Zapol and Snider, (1977) 14 reported increased PVR and pulmonary arterial hypertension in each of the 30 patients with severe ARDS in their series. They also noted that survivors had progressive decreases in PVR as the disease evolved, whereas non survivors tended to maintain or increase PVR. Histologic studies from the 1970s and 80s revealed diffuse pulmonary endothelial injury in early ARDS associated with macro- and microthrombi consisting of fibrin and red and white cell clots that were thought to be either embolic or formed in situ or both 15. These changes evolved after the first few days, with development of fibrocellular intimal proliferative changes that obliterated small pulmonary vessels 16. Radiologic studies using balloon angiography to image small pulmonary vessels showed that these microscopic abnormalities were associated with multiple filling defects in the distal pulmonary vasculature 17. This study showed a higher PVR and pulmonary pressure among non survivors, this was identical with Bull et al. (2010) 18 who noted that PVR was statistically higher in patients who died versus who lived. They also noted that survivors had progressive decreases in PVR as the disease evolved, whereas non survivors tended to maintain or increase PVR. These observations raised hope that treatment directed at the pulmonary vascular component of ARDS might improve outcome. Also Tinubu et al. (1993) 19 reported that PVR tended to be higher in patients with respiratory failure and ARDS than those with respiratory failure but without ARDS. The present study showed a higher median of PVR and RVSP in patients on HFOV when compared to those conventionally ventilated, but this was statistically insignificant mostly due to small number of patients. Kornecki et al. (2002) 20 reported that the use of HFOV did not result in an increase in the PVR in a small study of 5 children after Fontan cardiac surgery. Our results showed a significant positive correlation between PVR and PIP which can be explained by the more the severe the lung injury is, the more the pressure needed for the patient. Also there was a significant positive correlations between (FIO2 and TRV) and (FIO2 and PAEDP) but to our knowledge there was no available data assessing this correlation in patients with ARDS. The overall mortality rate among patients was 85%. Lippmann et al. (1995) 21 reported that 4 patients of all their 26 bronchopneumonic patients included in the study performed in community teaching hospital; Albert Einstein Medical Center, USA, developed ARDS, three of these survived. Fialkow et al. (2002) 22, reported a mortality rate of 48% in their study. Dahlem et al. (2003) 10 detected 31.4% mortality rate among their ARDS pediatric patients. However Flori et al. (2005) 23 stated that the mortality rates have varied between 20-75% among several studies, but they are difficult to interpret because of inconsistent diagnostic criteria and due to the small number of patients. Moreover, Sigurdsson et al. (2013) 24 stated that the hospital mortality of their cohort study was 37% which is similar to reported results both in Europe and in the United States 25. In conclusion, Hypoxemia resulted from ARDS can adversely affect the pulmonary vascular bed and hence, management of pulmonary vascular dysfunction could represent a future therapeutic target for those patients. Vol. 2 - No.3 July - September 2015 70