Neonatal Intensive Care
Hemodynamic Changes in Preterm Neonates With Septic Shock: A Prospective Observational Study* Shiv Sajan Saini, DM1; Praveen Kumar, DM1; Rohit Manoj Kumar, DM2
Objective: We evaluated hemodynamic changes in preterm neonates with septic shock using functional echocardiography and studied the effects of vasoactive drugs on hemodynamic variables. Design: Prospective observational study. Setting: Level III neonatal ICU. Subjects and Patients: We enrolled 52 preterm neonates with septic shock (shock group) and an equal number of gestation and postnatal age-matched healthy neonates (control group). Interventions: We measured functional hemodynamic variables (left and right ventricular output, ejection fraction, isovolumetric relaxation time, and early passive to late active peak velocity ratio) by echocardiography in the shock group during initial fluid resuscitation, before initiation of vasoactive drugs, and again 30–40 minutes after initiation of vasoactive drug infusion. Control group underwent a single assessment after enrollment. We compared various hemodynamic variables between shock group and control group using paired t test or Wilcoxon signed-rank test. *See also p. 494. 1 Neonatal Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India. 2 Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. This work was performed at Post Graduate Institute of Medical Education and Research, Chandigarh, India. The study was registered with Clinical Trial Registry of India (CTRI/2011/091/000012). Dr. Saini conceptualized and designed the study, collected and analyzed the data, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Praveen Kumar helped in designing the study, supervised the data collection and data analysis, reviewed and revised the manuscript, critically evaluated the manuscript for scientific content, and approved the final manuscript as submitted. Dr. Manoj Kumar c ross-checked the data collection, image quality, and interpretation; helped in preparation of the manuscript; and approved the final manuscript as submitted. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ pccmjournal). Dr Saini has received salary support from Council of Scientific and Industrial Research, New Delhi, India. The sponsor had no role in planning, conduct, analysis, or publication of the study. Dr. Saini received salary support and Drs. P. Kumar and R. M. Kumar received partial salary support. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000115
Pediatric Critical Care Medicine
Measurements and Main Results: The baseline left ventricular output was significantly higher in neonates with septic shock as compared with controls (median [interquartile range], 305 mL/kg/ min [204, 393] vs 233 mL/kg/min [204, 302]; p < 0.001), but ejection fraction was similar between the two groups (55% ± 12% vs 55% ± 5%, p = 0.54). Other hemodynamic variables were comparable between the two groups. After vasoactive drug infusion, there was a significant increase in heart rate (152 ± 18 to 161 ± 18 beats/min, p ≤ 0.001) and right ventricular output (median [interquartile range], 376 [286, 468] to 407 [323, 538] mL/kg/min; p = 0.018) compared with the baseline, but left ventricular output and ejection fraction did not change significantly. Conclusions: We found an elevated left ventricular output but normal ejection fraction in preterm neonates with septic shock. This suggests that septic shock in preterm neonates is predominantly due to vasoregulatory failure. Vasoactive drugs significantly increased right ventricular output, which was predominantly due to increase in heart rate. (Pediatr Crit Care Med 2014; 15:443–450) Key Words: functional echocardiography; hemodynamic changes; myocardial dysfunction; neonate; septic shock; vasoregulatory failure
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nternational pediatric sepsis consensus statement defines septic shock as cardiovascular organ dysfunction in presence of sepsis (1). Shock is a state of cellular energy failure, which is an end result of various pathogenetic mechanisms like hypovolemia, vasoregulatory failure, and/or myocardial dysfunction. The hemodynamic changes in neonatal septic shock are not understood completely. As a result, the treatment of neonatal septic shock is empirical and is largely based on pediatric and adult data (2, 3). In adult septic shock, predominant hemodynamic alteration is decreased systemic vascular resistance and elevated cardiac indices (4). In pediatric septic shock, nonhyperdynamic (2, 5–7) and hyperdynamic states with decreased systemic vascular resistance (8) have been described. The limited data about hemodynamic changes in neonatal septic shock mainly come from animal models (9–12). In these models, decreased peripheral vascular resistance (9, 12), as well as decreased myocardial performance, has been found (10, 11). Recently, hemodynamic changes have been described in neonates with late onset neonatal sepsis (13), www.pccmjournal.org
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but human data for hemodynamic changes in neonatal septic shock are scanty (2, 3). Conventionally, hemodynamic assessment is obtained by inserting arterial catheters and pulmonary vascular catheters. Due to technical challenges in establishing these catheters, it had been difficult to measure hemodynamics in sick neonates. Furthermore, limited time is available for establishing these catheters and doing hemodynamic assessment before initiation of vasoactive drugs. Recently, functional echocardiography has proven to be a useful alternative to overcome these difficulties. It is being increasingly used as a point-of-care hemodynamic assessment tool in a variety of neonatal conditions. We planned this study to evaluate hemodynamic changes in preterm neonates presenting with septic shock, utilizing functional echocardiography. In addition, we evaluated the effects of vasoactive drugs on hemodynamic variables.
METHODS Study Design and Setting We conducted this prospective observational study in a level III neonatal ICU from March 2010 to August 2012. The study was approved by the Institute’s Ethics Committee and registered with Clinical Trial Registry of India (CTRI/2011/091/000012). We obtained an informed written consent from one of the parents of neonates before enrolling them. Study Population We prospectively screened all inborn infants for occurrence of shock. From among infants with shock, consecutive preterm infants fulfilling criteria for “septic shock” were enrolled as “cases.” Septic shock was diagnosed, if in addition to evidence of sepsis, both of the following criteria according to modified International Pediatric Consensus Conference statement on sepsis and organ dysfunction in Pediatrics (1) were satisfied, that is, 1) either hypotension or any two of the following— delayed capillary refill time (> 3 s), feeble pulses, core-periphery temperature difference more than 3°C, urine output less than 0.5 mL/kg/hr, or presence of unexplained metabolic acidosis (base excess > –5.0); and 2) persistence of shock even after two saline boluses of 10 mL/kg each (2, 14). Hypotension was defined as systolic blood pressure (BP) or diastolic BP less than fifth percentile for the postmenstrual age (15). We considered a diagnosis of sepsis if either blood or cerebrospinal fluid culture was positive in a symptomatic neonate or if the clinical course and sepsis screen variables were clearly compatible with the diagnosis. Positive sepsis screen was defined as presence of any two of the following: C-reactive protein more than 10 mg/L, microerythrocyte sedimentation rate more than 10 mm after first hour, total leukocyte and absolute neutrophil counts outside the reference range (16), or immature to total neutrophil ratio more than 0.2. Neonates with 1) moderate-to-severe hypoxic ischemic encephalopathy, 2) diagnosed or suspected congenital heart disease including isolated patent ductus arteriosus (PDA), 3) possible cardiogenic shock including transitional circulation, with no setting of sepsis, 4) clinically defined 444
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hypovolemic shock, 5) already initiated vasoactive drug infusion, and 6) lethal congenital malformations were excluded. We selected the controls randomly from the same birth cohort by the following criteria: 1) apparently healthy neonates not requiring any respiratory support, or any drugs for maintenance of circulation, and receiving gestational and postnatal age appropriate enteral feeds; and 2) matched to cases for gestation (± 1 wk) and postnatal age (± 1 d). Protocol for Management of Septic Shock All enrolled neonates were monitored continuously by a multichannel vital signs monitor. The BP was measured by invasive intra-arterial catheters or noninvasively by oscillometry, if arterial catheter could not be established. Septic shock was managed initially by two normal saline boluses, 10 mL/kg each, given over 10–15 minutes. If signs of septic shock persisted, vasoactive drugs were instituted. Dopamine was started in hypotensive neonates (15) at 10 μg/kg/min and hiked by 5 μg/ kg/min every 15–20 minutes in case of nonresponse. Dobutamine was started at 10 μg/kg/min in normotensive neonates with signs of poor peripheral perfusion and hiked by 5 μg/kg/ min every 15–20 minutes. The decision to start and modify vasoactive drugs was taken by the bedside physicians. Echocardiography Protocol In shock group, the hemodynamic assessments were performed at baseline during the infusion of saline bolus but before starting vasoactive drugs. Repeat assessment was performed 30–40 minutes after starting infusion of vasoactive drugs. In control group, functional hemodynamic assessment was performed only once. The functional echocardiography was performed by a single investigator (S.S.S.) using the MicroMaxx ultrasound system (SonoSite, Bothell, WA) using an 8-4 MHz (P 10) highfrequency phased array transducer probe as per standard published literature (17–23). The images were stored in hard disc and cross-checked by the pediatric cardiologist (R.M.K.). Left and right ventricular outputs (LVO, RVO) were calculated by measuring internal diameter of artery, velocity time integral (VTI), and heart rate (HR) and using following formula: ventricular output = 3.14 × (Diameter2/4) × VTI × HR/ weight of the baby (17). Ejection fraction (EF) was calculated by measuring left ventricle end-diastolic volume (LVEDV) and left ventricle end-systolic volume (LVESV) (measured in apical four-chamber view) and using Simpson’s method (LVEDV – LVESV/LVEDV) (18, 22, 23). Ratio of peak velocities of early passive wave (E wave) and the late active wave (A wave) (E/A ratio) and isovolumetric relaxation time (IVRT) interval were evaluated from pulse wave Doppler interrogation of transmitral flow in apical four-chamber view (21–23). Left atrium to aortic root ratio was measured in long-axis parasternal view (19). An estimation of organ blood flows was done by evaluating peak systolic and mean flows (using pulse wave Doppler) in middle cerebral artery and celiac artery (20, 23). Further details of the echocardiography protocol can be accessed in the supplemental data (Supplemental Digital Content 1, http://links.lww.com/PCC/A97). June 2014 • Volume 15 • Number 5
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Statistical Analysis We used paired t test or Wilcoxon signed-rank test to compare demographic and hemodynamic variables between shock and control groups. For categorical outcomes, we used Fisher exact or chi-square tests with Yates correction. We compared hemodynamic variables before and after initiation of vasoactive drugs by paired t test or Wilcoxon signed-rank test. Analysis was performed using SPSS version 17.0 (SPSS, Chicago, IL). Since no data were available for the pathophysiology of septic shock in preterm human neonates, we recruited a convenient sample size of 52 neonates with septic shock and 52 controls.
of 10 neonates could not be recorded before initiation of fluid bolus. The diagnosis of sepsis was based on p ositive-blood cultures in 26 patients (50%), a positive sepsis screen with compatible clinical course in 22 patients (42%), and frank clinical signs of sepsis along with sclerema in four neonates. Majority of culture-proven sepsis was due to Gram-negative organisms: Klebsiella pneumoniae (n = 5), Enterobacter aerogenes (n = 5), Acinetobacter baumannii (n = 3), Escherichia coli (n = 3), lactose-fermenting Gram-negative bacilli (n = 1), and non–lactose-fermenting Gram-negative bacilli (n = 1). There were six Gram-positive isolates, Staphylococcus aureus and Coagulasenegative Staphylococcus (n = 3 each), and two Candida species. Of 52 preterm neonates with septic shock, 10 survived. RESULTS The baseline LVO in neonates with septic shock was sigWe enrolled 52 preterm infants with septic shock and a simi- nificantly elevated as compared with that in controls (median lar number of gestation and postnatal age-matched controls [interquartile range, IQR], 305 mL/kg/min [204, 393] vs (Fig. 1). The demographic profile and baseline characteristics of 233 mL/kg/min [204, 302]; p < 0.001) while the EF was comthe two groups were comparable (Table 1). Among infants with parable (Table 2). IVRT was significantly shorter in the infants septic shock, 33 were hypotensive, nine had normal BP, and BP with shock as compared with controls. Other hemodynamic variables including celiac and middle cerebral artery blood flow velocities were not different between the two groups (Table 2). We also analyzed hemodynamic variables in the subset of neonates with shock and culture-positive sepsis (n = 26) and their controls (n = 26). In this subgroup also, neonates with shock had elevated LVO as compared with controls (mean ± sd, 349 ± 150 vs 261 ± 85; p = 0.001) but had comparable EFs (mean ± sd, 52 ± 12 vs 55 ± 4, respectively; p = 0.658). The presence of PDA was confirmed on echocardiography in 31 neonates with septic shock (60%) and 12 controls (23%) (p = 0.005). In neonates with septic shock and PDA (n = 31), baseline LVO was significantly higher as compared with controls (median [IQR] LVO, 328 [217–400] vs 256 [208–316], respectively; p < 0.001), whereas EF was comparable (58 ± 9 vs 55 ± 4, respectively; p = 0.155). However, in neonates with septic shock but no PDA (n = 21), the baseline LVO was not significantly different from that of controls (median [IQR] LVO, 295 [207– 412] vs 242 [204–310], respecFigure 1. Flow of patients and subjects in the study. HIE = hypoxic ischemic encephalopathy, PDA - patent tively; p = 0.182). ductus arteriosus. Pediatric Critical Care Medicine
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Table 1.
Demographic Profile and Baseline Variables
Characteristics
Shock Group (n = 52)
Control Group (n = 52)
31.1 ± 2.8
31.2 ± 2.3
1,293 (1,000, 1,536)
1,214 (999, 1,532)
Gestation (wk)a Birth weight (g)
b
4 (3, 7)
Postnatal age (d)b
3 (3, 6)
Male sex (%)c
30 (58)
26 (50)
Small for gestation (%)c
18 (35)
21 (40)
Patent ductus arteriosus (%)c
31 (60)
12 (23)d
Patent foramen ovale (%)c
38 (73)
35 (64)
Culture proven
26 (50)
Not applicable
Screen positive
22 (42)
Sepsis type (%)c
Other
4 (8)
Clinical features of shock (%)
c
Blood pressure < fifth percentile
33 (64)
Capillary filling time ≥ 3 s
40 (78)
Poor peripheral pulses
41 (79)
Cool peripheries
32 (62)
Not applicable
Acid base status
a
pH
7.18 ± 0.14
Base excess
Not applicable
–13.2 ± 5.6
Values are presented as mean ± sd. Values are presented as median (interquartile range). c Values are presented as proportions n (%). d p = 0.005; rest of column p > 0.05. a
b
We also compared the hemodynamic variables before and 30–40 minutes after start of vasoactive drug infusion (either dopamine or dobutamine). We were able to record post-vasoactive drug hemodynamic variables in 41 of 52 neonates with septic shock. The mean dose of each of these drugs at the time of functional hemodynamic assessment was 15 ± 5 μg/kg/min. As per unit protocol, the maximum dose of each of drugs was 20 μg/kg/min. There was statistically significant increase in heart rate and RVO after initiation of vasoactive drugs. However, LVO, EF, E/A ratio, IVRT, and organ blood flows did not change significantly (Table 3). Of these 41 neonates, 27 received dopamine, 11 received dobutamine, and three received both dobutamine and dopamine as initial vasoactive drugs. We separately analyzed changes in hemodynamic variables among neonates who received dopamine and dobutamine as a primary vasoactive drug for management of shock (Table 4). The neonates who received dopamine had lower gestation and BP as compared with those who received dobutamine. Among neonates who received dopamine, the heart rate increased significantly. However, there was no significant change in LVO and RVO. There was a significant decrease in EF (mean ± sd, 61% ± 10% to 53% ± 9%; p = 0.004) and IVRT 446
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(median [IQR], 40 [20, 55] to 30 [25, 40]; p = 0.032). Among a limited sample of neonates who received dobutamine, there was no change in heart rate, LVO, RVO, and other hemodynamic variables (Table 4).
DISCUSSION In this prospective observational study, we found a significantly elevated LVO but similar EF in preterm neonates with septic shock as compared with healthy controls, suggesting vasoregulatory failure as the predominant pathophysiological change. After initiation of vasoactive drugs in shock group, we observed significantly increased heart rates but no difference in cardiac contractility. In adult septic shock, the predominant pathophysiology is decreased systemic vascular resistance and vasodilatation (2, 4). Pediatric septic shock is believed to be predominantly due to myocardial dysfunction (2, 5–7, 24). However, recent data suggest vasodilatation as the major hemodynamic change early in course of pediatric septic shock (8). There is very limited human literature about pathophysiology of neonatal septic shock. Similar to our findings, de Waal and Evans (13) June 2014 • Volume 15 • Number 5
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Table 2.
Hemodynamic Variables in Preterm Neonates With Septic Shock and Controls
Characteristics
p
Shock Group (n = 52)
Control Group (n = 52)
Heart rate (per min)
153 ± 22
140 ± 14
0.004a
Velocity time integral
11 ± 3
10 ± 2
0.001a
2.5 (2.0, 3.0)
2.3 (1.7, 2.8)
0.005a
305 (204, 393)
233 (204, 302)
150 ± 21
141 ± 16
0.044a
Left ventricle
Stroke volume (mL) Left ventricular output (mL/kg/min)
< 0.001a
Right ventricle Heart rate (per min) Velocity time integral
10 (9, 12)
11 (11, 13)
0.024a
Stroke volume (mL)
3.3 (2.6, 4.1)
3.7 (2.8, 4.4)
0.238
386 (286, 517)
383 (294, 490)
0.756
55 ± 5
0.537
Right ventricular output (mL/kg/min) Ejection fraction (%)
55 ± 12
Early passive wave and late active wave ratio
1.0 (0.9, 1.4)
1.0 (1.0, 1.2)
0.232
Isovolumetric relaxation time (ms)
35 (20, 55)
55 (43, 68)
0.014a
Peak
72 (58, 99)
65 (52, 79)
0.568
Mean
39 (27, 58)
31 (26, 40)
0.646
Celiac artery systolic blood flow velocity (cm/s)
Middle cerebral artery systolic blood flow velocity (cm/s) Peak
51 ± 19
Mean
21 (16, 34)
45 ± 12 26 (19, 30)
0.315 0.586
p < 0.05. Values are mean ± sd; median (interquartile range).
a
also found elevated cardiac output and low systemic vascular resistance among preterm neonates with clinical sepsis. It is hypothesized that neonates with septic shock have dysregulated cytokine and chemokine production, leading to peripheral vasodilatation (2, 4, 25). We found an elevated LVO and normal EF (hyperdynamic circulation) in preterm neonates with septic shock. Since BP is a product of cardiac output and systemic vascular resistance, an elevated LVO in presence of low BP suggests decreased systemic vascular resistance. We did not find differences in RVO as the VTI of right ventricular outflow tract was significantly less in neonates with septic shock (Table 2), which was opposite to the changes in heart rate. This finding could be due to elevated pulmonary arterial pressure, which is common in sick neonates. However, we could not measure markers of pulmonary artery hypertension at the baseline, as the time frame available for assessment was very limited. In addition to vasoregulatory failure, myocardial dysfunction could coexist in neonates with septic shock. The EF was comparable between neonates with shock and controls. Although widely used, EF is not a very reliable measure of myocardial contractility due to a variety of reasons. It is dependent on preload and afterload and limited contractile movement of the ventricular septum. Hence, EF could fail to pick up myocardial dysfunction in presence of decreased systemic Pediatric Critical Care Medicine
vascular resistance. Additionally, we had three neonates with LVO less than 150 mL/kg/min despite vasoregulatory failure. Hence, myocardial dysfunction could coexist or appear in due course in preterm neonatal septic shock. A significantly higher proportion of neonates with septic shock had PDA. Similar hemodynamic changes have been described among nonseptic premature neonates with PDA (26). Although PDA per se could explain the hyperdynamic circulation, it is reasonable to speculate that the patency of ductus among neonates with septic shock could be an important mechanism of hyperdynamic circulation. Infection promotes patency of PDA by increased cyclooxygenase expression and prostaglandin levels (27). The LVO in neonates with septic shock but without PDA was numerically higher than that in controls, but the difference was statistically not significant, possibly because of small number of neonates in this subgroup. Vasoactive drugs significantly increased the RVO and heart rate from the baseline. It appears that the increase in RVO was predominantly due to increase in heart rate, although increase in VTI might have also contributed. This observation suggests that in routinely used doses up to 20 μg/kg/min, the vasoactive drugs increase cardiac output mainly by increasing heart rate rather than myocardial contractility. The neonatal heart normally contracts at its maximum capacity and has got very little reserve www.pccmjournal.org
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Table 3. Hemodynamic Variables in Preterm Neonates With Septic Shock at Baseline and 30–40 Minutes After Initiation of Vasoactive Drugs Before Vasoactive Drugs (n = 41)
After Vasoactive Drugs (n = 41)
Heart rate (per min)
152 ± 18
161 ± 18
0.005a
Velocity time integral
12 ± 3
11 ± 3
0.392
Stroke volume (mL)
2.5 (2.1, 3.0)
2.5 (2.1, 2.9)
0.586
313 (212, 396)
358 (239, 422)
0.175
Characteristics
p
Left ventricle
Left ventricular output (mL/kg/min) Right ventricle Heart rate (per min)
150 ± 19
161 ± 19
< 0.001a
Velocity time integral
10 (9, 12)
11 (9, 12)
0.805
Stroke volume (mL)
3.2 (2.6, 3.7)
3.3 (2.5, 3.8)
0.833
376 (286, 468)
407 (323, 538)
0.018a
Right ventricular output (mL/kg/min) Ejection fraction (%)
57 ± 12
53 ± 8
0.231
Early passive wave and late active wave ratio
1.0 (0.9, 1.3)
1.1 (1.0, 1.6)
0.837
Isovolumetric relaxation time (ms)
40 (20, 55)
30 (25, 50)
0.076
1.9 ± 0.6
2.1 ± 0.5
0.962
Peak
81 ± 32
84 ± 29
0.327
Mean
43 ± 20
47 ± 21
0.533
Peak
51 (43, 68)
54 (42, 73)
0.552
Mean
23 (16, 35)
30 (19, 46)
0.379
Left atrium to aortic root ratio Celiac artery systolic blood flow velocity (cm/s)
Middle cerebral artery systolic blood flow velocity (cm/s)
p < 0.05. Values are mean ± sd or median (interquartile range).
a
(28). RVO is believed to be a better measure of systemic blood flow in neonates with open PDA and no intracardiac shunts. This is especially true in first few days of life as there is minimal shunt across patent foramen ovale (23). The lack of significant increase in LVO may have been due to the small sample size. Nevertheless, this generates a hypothesis that there might be a role of higher pressor doses of dopamine or alternative drugs like norepinephrine in management of septic shock. Although standard textbooks mention doses of dopamine up to 20 μg/ kg/min in neonatal septic shock (29), Noori and Seri (30) and Perez et al (31) have suggested that the dose of dopamine can be increased to 15–40 μg/kg/min in absence of any appreciable side effects (3). We found that EF decreased after dopamine infusion, which could indicate possible myocardial involvement or increased systemic vascular resistance secondary to vasopressor doses of dopamine. It should be noted that the dopamine was given to hypotensive neonates while dobutamine was given to normotensive neonates with signs of peripheral circulatory failure. Hence, these findings should be interpreted cautiously. Our study describes functional echocardiographic findings in neonatal septic shock and generates hypotheses for 448
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future analytical studies. The saline bolus infusions during functional hemodynamic assessment could have per se affected the measurements. However, this type of study is not feasible otherwise, as it would be unethical to delay treatment. For the assessment of myocardial systolic functions, we used EF, which is dependent on afterload. In the presence of decreased afterload in vasoregulatory failure, the myocardial contractility might appear falsely normal. We need afterload independent variables to study the myocardial dysfunction, for example, dP/dT or left ventricular end-systolic wall stress velocity of fiber shortening relation. However, dP/ dT measurement is possible only in neonates with mitral regurgitation.
CONCLUSIONS In preterm neonates presenting with septic shock in first week of life, elevated LVO and normal EF suggest that vasoregulatory failure is the predominant pathophysiology, although myocardial dysfunction could be contributing in some. Vasoactive drugs increase the RVO in these neonates mainly by increasing the heart rate. June 2014 • Volume 15 • Number 5
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Table 4. Changes in Hemodynamic Variables After Dopamine and Dobutamine in Preterm Neonates With Septic Shock Dopamine (n = 27) Characteristics
Post Dopamine
Baseline
Gestation (wk)
Dobutamine (n = 11) p
Baseline
30 ± 3
Weight (g)
33 ± 3
1,235 (982, 1,471)
Postnatal age (d)
Post Dobutamine
0.026a
1,460 (1,163, 1,777)
4 (3, 6)
p
3 (2, 10)
0.082 0.568
Blood pressure Systolic (mm Hg)
38 ± 7
60 ± 16
0.003a
Diastolic (mm Hg)
18 ± 3
34 ± 14
0.002a
Left ventricle Heart rate (per min)
148 ± 16
162 ± 17
Velocity time integral
12 ± 3
11 ± 3
Stroke volume (mL)
2.5 (2.1, 3.0)
< 0.001a
159 ± 16
161 ± 22
0.751
0.236
12 ± 4
12 ± 3
0.986
2.5 (2.0, 2.9)
0.367
2.7 ± 0.9
2.7 ± 0.8
0.855
336 ± 142
349 ± 127
0.312
297 ± 112
311 ± 130
0.322
Heart rate (per min)
147 ± 18
160 ± 17
< 0.001a
154 ± 12
162 ± 23
0.281
Velocity time integral
10 (9, 12)
11 (8, 12)
0.346
10 ± 2
11 ± 3
0.293
Stroke volume (mL)
3.2 (2.6, 4.0)
3.3 (2.5, 4.1)
0.551
3.1 ± 0.6
3.3 ± 0.9
0.304
388 (305, 477)
433 (343, 550)
0.201
343 ± 116
381 ± 141
0.059
61 ± 10
53 ± 9
0.004
53 (45, 57)
56 (53, 59)
0.207
Early passive wave and late active wave ratio
1.1 (0.9, 1.3)
1.1 (1.0, 1.5)
0.683
1.0 (0.8, 1.7)
1.3 (0.9, 1.7)
0.465
Isovolumetric relaxation time (ms)
40 (20, 55)
30 (25, 40)
0.032a
38 ± 15
39 ± 21
0.890
2.1 ± 0.5
0.769
2.1 ± 0.6
2.0 ± 0.5
0.560
76 (61, 92)
0.394
89 ± 42
107 ± 45
0.141
42 ± 15
0.759
—
—
—
Left ventricle output (mL/kg/min) Right ventricle
Right ventricle output (mL/kg/min) Ejection fraction (%)
Left atrium to aortic root ratio
1.9 ± 0.6
a
Celiac artery systolic blood flow velocity (cm/s) Peak
67 (57, 96)
Mean
43 ± 18
Middle cerebral artery systolic blood flow velocity (cm/s) Peak
49 (41, 65)
61 (47, 81)
0.033a
67 (49, 83)
49 (16, 58)
0.050
Mean
19 (16, 30)
31 (19, 53)
0.158
—
—
—
p < 0.05. Values are mean ± sd or median (interquartile range). Dashes indicate data not available.
a
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4. Landry DW, Oliver JA: The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345:588–595 5. Ceneviva G, Paschall JA, Maffei F, et al: Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics 1998; 102:e19 6. Pollack MM, Fields AI, Ruttimann UE: Sequential cardiopulmonary variables of infants and children in septic shock. Crit Care Med 1984; 12:554–559 7. Pollack MM, Fields AI, Ruttimann UE: Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985; 13:454–459 www.pccmjournal.org
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20. Low JA, Froese AB, Galbraith RS, et al: Middle cerebral artery blood flow velocity in the newborn following delivery. Clin Invest Med 1993; 16:29–37 21. Schmitz L, Stiller B, Pees C, et al: Doppler-derived parameters of diastolic left ventricular function in preterm infants with a birth weight
Hemodynamic Changes in Preterm Neonates With Septic Shock: A Prospective Observational Study* Shiv Sajan Saini, DM1; Praveen Kumar, DM1; Rohit Manoj Kumar, DM2
Objective: We evaluated hemodynamic changes in preterm neonates with septic shock using functional echocardiography and studied the effects of vasoactive drugs on hemodynamic variables. Design: Prospective observational study. Setting: Level III neonatal ICU. Subjects and Patients: We enrolled 52 preterm neonates with septic shock (shock group) and an equal number of gestation and postnatal age-matched healthy neonates (control group). Interventions: We measured functional hemodynamic variables (left and right ventricular output, ejection fraction, isovolumetric relaxation time, and early passive to late active peak velocity ratio) by echocardiography in the shock group during initial fluid resuscitation, before initiation of vasoactive drugs, and again 30–40 minutes after initiation of vasoactive drug infusion. Control group underwent a single assessment after enrollment. We compared various hemodynamic variables between shock group and control group using paired t test or Wilcoxon signed-rank test. *See also p. 494. 1 Neonatal Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India. 2 Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. This work was performed at Post Graduate Institute of Medical Education and Research, Chandigarh, India. The study was registered with Clinical Trial Registry of India (CTRI/2011/091/000012). Dr. Saini conceptualized and designed the study, collected and analyzed the data, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Praveen Kumar helped in designing the study, supervised the data collection and data analysis, reviewed and revised the manuscript, critically evaluated the manuscript for scientific content, and approved the final manuscript as submitted. Dr. Manoj Kumar c ross-checked the data collection, image quality, and interpretation; helped in preparation of the manuscript; and approved the final manuscript as submitted. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ pccmjournal). Dr Saini has received salary support from Council of Scientific and Industrial Research, New Delhi, India. The sponsor had no role in planning, conduct, analysis, or publication of the study. Dr. Saini received salary support and Drs. P. Kumar and R. M. Kumar received partial salary support. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000115
Pediatric Critical Care Medicine
Measurements and Main Results: The baseline left ventricular output was significantly higher in neonates with septic shock as compared with controls (median [interquartile range], 305 mL/kg/ min [204, 393] vs 233 mL/kg/min [204, 302]; p < 0.001), but ejection fraction was similar between the two groups (55% ± 12% vs 55% ± 5%, p = 0.54). Other hemodynamic variables were comparable between the two groups. After vasoactive drug infusion, there was a significant increase in heart rate (152 ± 18 to 161 ± 18 beats/min, p ≤ 0.001) and right ventricular output (median [interquartile range], 376 [286, 468] to 407 [323, 538] mL/kg/min; p = 0.018) compared with the baseline, but left ventricular output and ejection fraction did not change significantly. Conclusions: We found an elevated left ventricular output but normal ejection fraction in preterm neonates with septic shock. This suggests that septic shock in preterm neonates is predominantly due to vasoregulatory failure. Vasoactive drugs significantly increased right ventricular output, which was predominantly due to increase in heart rate. (Pediatr Crit Care Med 2014; 15:443–450) Key Words: functional echocardiography; hemodynamic changes; myocardial dysfunction; neonate; septic shock; vasoregulatory failure
I
nternational pediatric sepsis consensus statement defines septic shock as cardiovascular organ dysfunction in presence of sepsis (1). Shock is a state of cellular energy failure, which is an end result of various pathogenetic mechanisms like hypovolemia, vasoregulatory failure, and/or myocardial dysfunction. The hemodynamic changes in neonatal septic shock are not understood completely. As a result, the treatment of neonatal septic shock is empirical and is largely based on pediatric and adult data (2, 3). In adult septic shock, predominant hemodynamic alteration is decreased systemic vascular resistance and elevated cardiac indices (4). In pediatric septic shock, nonhyperdynamic (2, 5–7) and hyperdynamic states with decreased systemic vascular resistance (8) have been described. The limited data about hemodynamic changes in neonatal septic shock mainly come from animal models (9–12). In these models, decreased peripheral vascular resistance (9, 12), as well as decreased myocardial performance, has been found (10, 11). Recently, hemodynamic changes have been described in neonates with late onset neonatal sepsis (13), www.pccmjournal.org
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but human data for hemodynamic changes in neonatal septic shock are scanty (2, 3). Conventionally, hemodynamic assessment is obtained by inserting arterial catheters and pulmonary vascular catheters. Due to technical challenges in establishing these catheters, it had been difficult to measure hemodynamics in sick neonates. Furthermore, limited time is available for establishing these catheters and doing hemodynamic assessment before initiation of vasoactive drugs. Recently, functional echocardiography has proven to be a useful alternative to overcome these difficulties. It is being increasingly used as a point-of-care hemodynamic assessment tool in a variety of neonatal conditions. We planned this study to evaluate hemodynamic changes in preterm neonates presenting with septic shock, utilizing functional echocardiography. In addition, we evaluated the effects of vasoactive drugs on hemodynamic variables.
METHODS Study Design and Setting We conducted this prospective observational study in a level III neonatal ICU from March 2010 to August 2012. The study was approved by the Institute’s Ethics Committee and registered with Clinical Trial Registry of India (CTRI/2011/091/000012). We obtained an informed written consent from one of the parents of neonates before enrolling them. Study Population We prospectively screened all inborn infants for occurrence of shock. From among infants with shock, consecutive preterm infants fulfilling criteria for “septic shock” were enrolled as “cases.” Septic shock was diagnosed, if in addition to evidence of sepsis, both of the following criteria according to modified International Pediatric Consensus Conference statement on sepsis and organ dysfunction in Pediatrics (1) were satisfied, that is, 1) either hypotension or any two of the following— delayed capillary refill time (> 3 s), feeble pulses, core-periphery temperature difference more than 3°C, urine output less than 0.5 mL/kg/hr, or presence of unexplained metabolic acidosis (base excess > –5.0); and 2) persistence of shock even after two saline boluses of 10 mL/kg each (2, 14). Hypotension was defined as systolic blood pressure (BP) or diastolic BP less than fifth percentile for the postmenstrual age (15). We considered a diagnosis of sepsis if either blood or cerebrospinal fluid culture was positive in a symptomatic neonate or if the clinical course and sepsis screen variables were clearly compatible with the diagnosis. Positive sepsis screen was defined as presence of any two of the following: C-reactive protein more than 10 mg/L, microerythrocyte sedimentation rate more than 10 mm after first hour, total leukocyte and absolute neutrophil counts outside the reference range (16), or immature to total neutrophil ratio more than 0.2. Neonates with 1) moderate-to-severe hypoxic ischemic encephalopathy, 2) diagnosed or suspected congenital heart disease including isolated patent ductus arteriosus (PDA), 3) possible cardiogenic shock including transitional circulation, with no setting of sepsis, 4) clinically defined 444
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hypovolemic shock, 5) already initiated vasoactive drug infusion, and 6) lethal congenital malformations were excluded. We selected the controls randomly from the same birth cohort by the following criteria: 1) apparently healthy neonates not requiring any respiratory support, or any drugs for maintenance of circulation, and receiving gestational and postnatal age appropriate enteral feeds; and 2) matched to cases for gestation (± 1 wk) and postnatal age (± 1 d). Protocol for Management of Septic Shock All enrolled neonates were monitored continuously by a multichannel vital signs monitor. The BP was measured by invasive intra-arterial catheters or noninvasively by oscillometry, if arterial catheter could not be established. Septic shock was managed initially by two normal saline boluses, 10 mL/kg each, given over 10–15 minutes. If signs of septic shock persisted, vasoactive drugs were instituted. Dopamine was started in hypotensive neonates (15) at 10 μg/kg/min and hiked by 5 μg/ kg/min every 15–20 minutes in case of nonresponse. Dobutamine was started at 10 μg/kg/min in normotensive neonates with signs of poor peripheral perfusion and hiked by 5 μg/kg/ min every 15–20 minutes. The decision to start and modify vasoactive drugs was taken by the bedside physicians. Echocardiography Protocol In shock group, the hemodynamic assessments were performed at baseline during the infusion of saline bolus but before starting vasoactive drugs. Repeat assessment was performed 30–40 minutes after starting infusion of vasoactive drugs. In control group, functional hemodynamic assessment was performed only once. The functional echocardiography was performed by a single investigator (S.S.S.) using the MicroMaxx ultrasound system (SonoSite, Bothell, WA) using an 8-4 MHz (P 10) highfrequency phased array transducer probe as per standard published literature (17–23). The images were stored in hard disc and cross-checked by the pediatric cardiologist (R.M.K.). Left and right ventricular outputs (LVO, RVO) were calculated by measuring internal diameter of artery, velocity time integral (VTI), and heart rate (HR) and using following formula: ventricular output = 3.14 × (Diameter2/4) × VTI × HR/ weight of the baby (17). Ejection fraction (EF) was calculated by measuring left ventricle end-diastolic volume (LVEDV) and left ventricle end-systolic volume (LVESV) (measured in apical four-chamber view) and using Simpson’s method (LVEDV – LVESV/LVEDV) (18, 22, 23). Ratio of peak velocities of early passive wave (E wave) and the late active wave (A wave) (E/A ratio) and isovolumetric relaxation time (IVRT) interval were evaluated from pulse wave Doppler interrogation of transmitral flow in apical four-chamber view (21–23). Left atrium to aortic root ratio was measured in long-axis parasternal view (19). An estimation of organ blood flows was done by evaluating peak systolic and mean flows (using pulse wave Doppler) in middle cerebral artery and celiac artery (20, 23). Further details of the echocardiography protocol can be accessed in the supplemental data (Supplemental Digital Content 1, http://links.lww.com/PCC/A97). June 2014 • Volume 15 • Number 5
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Statistical Analysis We used paired t test or Wilcoxon signed-rank test to compare demographic and hemodynamic variables between shock and control groups. For categorical outcomes, we used Fisher exact or chi-square tests with Yates correction. We compared hemodynamic variables before and after initiation of vasoactive drugs by paired t test or Wilcoxon signed-rank test. Analysis was performed using SPSS version 17.0 (SPSS, Chicago, IL). Since no data were available for the pathophysiology of septic shock in preterm human neonates, we recruited a convenient sample size of 52 neonates with septic shock and 52 controls.
of 10 neonates could not be recorded before initiation of fluid bolus. The diagnosis of sepsis was based on p ositive-blood cultures in 26 patients (50%), a positive sepsis screen with compatible clinical course in 22 patients (42%), and frank clinical signs of sepsis along with sclerema in four neonates. Majority of culture-proven sepsis was due to Gram-negative organisms: Klebsiella pneumoniae (n = 5), Enterobacter aerogenes (n = 5), Acinetobacter baumannii (n = 3), Escherichia coli (n = 3), lactose-fermenting Gram-negative bacilli (n = 1), and non–lactose-fermenting Gram-negative bacilli (n = 1). There were six Gram-positive isolates, Staphylococcus aureus and Coagulasenegative Staphylococcus (n = 3 each), and two Candida species. Of 52 preterm neonates with septic shock, 10 survived. RESULTS The baseline LVO in neonates with septic shock was sigWe enrolled 52 preterm infants with septic shock and a simi- nificantly elevated as compared with that in controls (median lar number of gestation and postnatal age-matched controls [interquartile range, IQR], 305 mL/kg/min [204, 393] vs (Fig. 1). The demographic profile and baseline characteristics of 233 mL/kg/min [204, 302]; p < 0.001) while the EF was comthe two groups were comparable (Table 1). Among infants with parable (Table 2). IVRT was significantly shorter in the infants septic shock, 33 were hypotensive, nine had normal BP, and BP with shock as compared with controls. Other hemodynamic variables including celiac and middle cerebral artery blood flow velocities were not different between the two groups (Table 2). We also analyzed hemodynamic variables in the subset of neonates with shock and culture-positive sepsis (n = 26) and their controls (n = 26). In this subgroup also, neonates with shock had elevated LVO as compared with controls (mean ± sd, 349 ± 150 vs 261 ± 85; p = 0.001) but had comparable EFs (mean ± sd, 52 ± 12 vs 55 ± 4, respectively; p = 0.658). The presence of PDA was confirmed on echocardiography in 31 neonates with septic shock (60%) and 12 controls (23%) (p = 0.005). In neonates with septic shock and PDA (n = 31), baseline LVO was significantly higher as compared with controls (median [IQR] LVO, 328 [217–400] vs 256 [208–316], respectively; p < 0.001), whereas EF was comparable (58 ± 9 vs 55 ± 4, respectively; p = 0.155). However, in neonates with septic shock but no PDA (n = 21), the baseline LVO was not significantly different from that of controls (median [IQR] LVO, 295 [207– 412] vs 242 [204–310], respecFigure 1. Flow of patients and subjects in the study. HIE = hypoxic ischemic encephalopathy, PDA - patent tively; p = 0.182). ductus arteriosus. Pediatric Critical Care Medicine
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Table 1.
Demographic Profile and Baseline Variables
Characteristics
Shock Group (n = 52)
Control Group (n = 52)
31.1 ± 2.8
31.2 ± 2.3
1,293 (1,000, 1,536)
1,214 (999, 1,532)
Gestation (wk)a Birth weight (g)
b
4 (3, 7)
Postnatal age (d)b
3 (3, 6)
Male sex (%)c
30 (58)
26 (50)
Small for gestation (%)c
18 (35)
21 (40)
Patent ductus arteriosus (%)c
31 (60)
12 (23)d
Patent foramen ovale (%)c
38 (73)
35 (64)
Culture proven
26 (50)
Not applicable
Screen positive
22 (42)
Sepsis type (%)c
Other
4 (8)
Clinical features of shock (%)
c
Blood pressure < fifth percentile
33 (64)
Capillary filling time ≥ 3 s
40 (78)
Poor peripheral pulses
41 (79)
Cool peripheries
32 (62)
Not applicable
Acid base status
a
pH
7.18 ± 0.14
Base excess
Not applicable
–13.2 ± 5.6
Values are presented as mean ± sd. Values are presented as median (interquartile range). c Values are presented as proportions n (%). d p = 0.005; rest of column p > 0.05. a
b
We also compared the hemodynamic variables before and 30–40 minutes after start of vasoactive drug infusion (either dopamine or dobutamine). We were able to record post-vasoactive drug hemodynamic variables in 41 of 52 neonates with septic shock. The mean dose of each of these drugs at the time of functional hemodynamic assessment was 15 ± 5 μg/kg/min. As per unit protocol, the maximum dose of each of drugs was 20 μg/kg/min. There was statistically significant increase in heart rate and RVO after initiation of vasoactive drugs. However, LVO, EF, E/A ratio, IVRT, and organ blood flows did not change significantly (Table 3). Of these 41 neonates, 27 received dopamine, 11 received dobutamine, and three received both dobutamine and dopamine as initial vasoactive drugs. We separately analyzed changes in hemodynamic variables among neonates who received dopamine and dobutamine as a primary vasoactive drug for management of shock (Table 4). The neonates who received dopamine had lower gestation and BP as compared with those who received dobutamine. Among neonates who received dopamine, the heart rate increased significantly. However, there was no significant change in LVO and RVO. There was a significant decrease in EF (mean ± sd, 61% ± 10% to 53% ± 9%; p = 0.004) and IVRT 446
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(median [IQR], 40 [20, 55] to 30 [25, 40]; p = 0.032). Among a limited sample of neonates who received dobutamine, there was no change in heart rate, LVO, RVO, and other hemodynamic variables (Table 4).
DISCUSSION In this prospective observational study, we found a significantly elevated LVO but similar EF in preterm neonates with septic shock as compared with healthy controls, suggesting vasoregulatory failure as the predominant pathophysiological change. After initiation of vasoactive drugs in shock group, we observed significantly increased heart rates but no difference in cardiac contractility. In adult septic shock, the predominant pathophysiology is decreased systemic vascular resistance and vasodilatation (2, 4). Pediatric septic shock is believed to be predominantly due to myocardial dysfunction (2, 5–7, 24). However, recent data suggest vasodilatation as the major hemodynamic change early in course of pediatric septic shock (8). There is very limited human literature about pathophysiology of neonatal septic shock. Similar to our findings, de Waal and Evans (13) June 2014 • Volume 15 • Number 5
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Table 2.
Hemodynamic Variables in Preterm Neonates With Septic Shock and Controls
Characteristics
p
Shock Group (n = 52)
Control Group (n = 52)
Heart rate (per min)
153 ± 22
140 ± 14
0.004a
Velocity time integral
11 ± 3
10 ± 2
0.001a
2.5 (2.0, 3.0)
2.3 (1.7, 2.8)
0.005a
305 (204, 393)
233 (204, 302)
150 ± 21
141 ± 16
0.044a
Left ventricle
Stroke volume (mL) Left ventricular output (mL/kg/min)
< 0.001a
Right ventricle Heart rate (per min) Velocity time integral
10 (9, 12)
11 (11, 13)
0.024a
Stroke volume (mL)
3.3 (2.6, 4.1)
3.7 (2.8, 4.4)
0.238
386 (286, 517)
383 (294, 490)
0.756
55 ± 5
0.537
Right ventricular output (mL/kg/min) Ejection fraction (%)
55 ± 12
Early passive wave and late active wave ratio
1.0 (0.9, 1.4)
1.0 (1.0, 1.2)
0.232
Isovolumetric relaxation time (ms)
35 (20, 55)
55 (43, 68)
0.014a
Peak
72 (58, 99)
65 (52, 79)
0.568
Mean
39 (27, 58)
31 (26, 40)
0.646
Celiac artery systolic blood flow velocity (cm/s)
Middle cerebral artery systolic blood flow velocity (cm/s) Peak
51 ± 19
Mean
21 (16, 34)
45 ± 12 26 (19, 30)
0.315 0.586
p < 0.05. Values are mean ± sd; median (interquartile range).
a
also found elevated cardiac output and low systemic vascular resistance among preterm neonates with clinical sepsis. It is hypothesized that neonates with septic shock have dysregulated cytokine and chemokine production, leading to peripheral vasodilatation (2, 4, 25). We found an elevated LVO and normal EF (hyperdynamic circulation) in preterm neonates with septic shock. Since BP is a product of cardiac output and systemic vascular resistance, an elevated LVO in presence of low BP suggests decreased systemic vascular resistance. We did not find differences in RVO as the VTI of right ventricular outflow tract was significantly less in neonates with septic shock (Table 2), which was opposite to the changes in heart rate. This finding could be due to elevated pulmonary arterial pressure, which is common in sick neonates. However, we could not measure markers of pulmonary artery hypertension at the baseline, as the time frame available for assessment was very limited. In addition to vasoregulatory failure, myocardial dysfunction could coexist in neonates with septic shock. The EF was comparable between neonates with shock and controls. Although widely used, EF is not a very reliable measure of myocardial contractility due to a variety of reasons. It is dependent on preload and afterload and limited contractile movement of the ventricular septum. Hence, EF could fail to pick up myocardial dysfunction in presence of decreased systemic Pediatric Critical Care Medicine
vascular resistance. Additionally, we had three neonates with LVO less than 150 mL/kg/min despite vasoregulatory failure. Hence, myocardial dysfunction could coexist or appear in due course in preterm neonatal septic shock. A significantly higher proportion of neonates with septic shock had PDA. Similar hemodynamic changes have been described among nonseptic premature neonates with PDA (26). Although PDA per se could explain the hyperdynamic circulation, it is reasonable to speculate that the patency of ductus among neonates with septic shock could be an important mechanism of hyperdynamic circulation. Infection promotes patency of PDA by increased cyclooxygenase expression and prostaglandin levels (27). The LVO in neonates with septic shock but without PDA was numerically higher than that in controls, but the difference was statistically not significant, possibly because of small number of neonates in this subgroup. Vasoactive drugs significantly increased the RVO and heart rate from the baseline. It appears that the increase in RVO was predominantly due to increase in heart rate, although increase in VTI might have also contributed. This observation suggests that in routinely used doses up to 20 μg/kg/min, the vasoactive drugs increase cardiac output mainly by increasing heart rate rather than myocardial contractility. The neonatal heart normally contracts at its maximum capacity and has got very little reserve www.pccmjournal.org
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Table 3. Hemodynamic Variables in Preterm Neonates With Septic Shock at Baseline and 30–40 Minutes After Initiation of Vasoactive Drugs Before Vasoactive Drugs (n = 41)
After Vasoactive Drugs (n = 41)
Heart rate (per min)
152 ± 18
161 ± 18
0.005a
Velocity time integral
12 ± 3
11 ± 3
0.392
Stroke volume (mL)
2.5 (2.1, 3.0)
2.5 (2.1, 2.9)
0.586
313 (212, 396)
358 (239, 422)
0.175
Characteristics
p
Left ventricle
Left ventricular output (mL/kg/min) Right ventricle Heart rate (per min)
150 ± 19
161 ± 19
< 0.001a
Velocity time integral
10 (9, 12)
11 (9, 12)
0.805
Stroke volume (mL)
3.2 (2.6, 3.7)
3.3 (2.5, 3.8)
0.833
376 (286, 468)
407 (323, 538)
0.018a
Right ventricular output (mL/kg/min) Ejection fraction (%)
57 ± 12
53 ± 8
0.231
Early passive wave and late active wave ratio
1.0 (0.9, 1.3)
1.1 (1.0, 1.6)
0.837
Isovolumetric relaxation time (ms)
40 (20, 55)
30 (25, 50)
0.076
1.9 ± 0.6
2.1 ± 0.5
0.962
Peak
81 ± 32
84 ± 29
0.327
Mean
43 ± 20
47 ± 21
0.533
Peak
51 (43, 68)
54 (42, 73)
0.552
Mean
23 (16, 35)
30 (19, 46)
0.379
Left atrium to aortic root ratio Celiac artery systolic blood flow velocity (cm/s)
Middle cerebral artery systolic blood flow velocity (cm/s)
p < 0.05. Values are mean ± sd or median (interquartile range).
a
(28). RVO is believed to be a better measure of systemic blood flow in neonates with open PDA and no intracardiac shunts. This is especially true in first few days of life as there is minimal shunt across patent foramen ovale (23). The lack of significant increase in LVO may have been due to the small sample size. Nevertheless, this generates a hypothesis that there might be a role of higher pressor doses of dopamine or alternative drugs like norepinephrine in management of septic shock. Although standard textbooks mention doses of dopamine up to 20 μg/ kg/min in neonatal septic shock (29), Noori and Seri (30) and Perez et al (31) have suggested that the dose of dopamine can be increased to 15–40 μg/kg/min in absence of any appreciable side effects (3). We found that EF decreased after dopamine infusion, which could indicate possible myocardial involvement or increased systemic vascular resistance secondary to vasopressor doses of dopamine. It should be noted that the dopamine was given to hypotensive neonates while dobutamine was given to normotensive neonates with signs of peripheral circulatory failure. Hence, these findings should be interpreted cautiously. Our study describes functional echocardiographic findings in neonatal septic shock and generates hypotheses for 448
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future analytical studies. The saline bolus infusions during functional hemodynamic assessment could have per se affected the measurements. However, this type of study is not feasible otherwise, as it would be unethical to delay treatment. For the assessment of myocardial systolic functions, we used EF, which is dependent on afterload. In the presence of decreased afterload in vasoregulatory failure, the myocardial contractility might appear falsely normal. We need afterload independent variables to study the myocardial dysfunction, for example, dP/dT or left ventricular end-systolic wall stress velocity of fiber shortening relation. However, dP/ dT measurement is possible only in neonates with mitral regurgitation.
CONCLUSIONS In preterm neonates presenting with septic shock in first week of life, elevated LVO and normal EF suggest that vasoregulatory failure is the predominant pathophysiology, although myocardial dysfunction could be contributing in some. Vasoactive drugs increase the RVO in these neonates mainly by increasing the heart rate. June 2014 • Volume 15 • Number 5
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Table 4. Changes in Hemodynamic Variables After Dopamine and Dobutamine in Preterm Neonates With Septic Shock Dopamine (n = 27) Characteristics
Post Dopamine
Baseline
Gestation (wk)
Dobutamine (n = 11) p
Baseline
30 ± 3
Weight (g)
33 ± 3
1,235 (982, 1,471)
Postnatal age (d)
Post Dobutamine
0.026a
1,460 (1,163, 1,777)
4 (3, 6)
p
3 (2, 10)
0.082 0.568
Blood pressure Systolic (mm Hg)
38 ± 7
60 ± 16
0.003a
Diastolic (mm Hg)
18 ± 3
34 ± 14
0.002a
Left ventricle Heart rate (per min)
148 ± 16
162 ± 17
Velocity time integral
12 ± 3
11 ± 3
Stroke volume (mL)
2.5 (2.1, 3.0)
< 0.001a
159 ± 16
161 ± 22
0.751
0.236
12 ± 4
12 ± 3
0.986
2.5 (2.0, 2.9)
0.367
2.7 ± 0.9
2.7 ± 0.8
0.855
336 ± 142
349 ± 127
0.312
297 ± 112
311 ± 130
0.322
Heart rate (per min)
147 ± 18
160 ± 17
< 0.001a
154 ± 12
162 ± 23
0.281
Velocity time integral
10 (9, 12)
11 (8, 12)
0.346
10 ± 2
11 ± 3
0.293
Stroke volume (mL)
3.2 (2.6, 4.0)
3.3 (2.5, 4.1)
0.551
3.1 ± 0.6
3.3 ± 0.9
0.304
388 (305, 477)
433 (343, 550)
0.201
343 ± 116
381 ± 141
0.059
61 ± 10
53 ± 9
0.004
53 (45, 57)
56 (53, 59)
0.207
Early passive wave and late active wave ratio
1.1 (0.9, 1.3)
1.1 (1.0, 1.5)
0.683
1.0 (0.8, 1.7)
1.3 (0.9, 1.7)
0.465
Isovolumetric relaxation time (ms)
40 (20, 55)
30 (25, 40)
0.032a
38 ± 15
39 ± 21
0.890
2.1 ± 0.5
0.769
2.1 ± 0.6
2.0 ± 0.5
0.560
76 (61, 92)
0.394
89 ± 42
107 ± 45
0.141
42 ± 15
0.759
—
—
—
Left ventricle output (mL/kg/min) Right ventricle
Right ventricle output (mL/kg/min) Ejection fraction (%)
Left atrium to aortic root ratio
1.9 ± 0.6
a
Celiac artery systolic blood flow velocity (cm/s) Peak
67 (57, 96)
Mean
43 ± 18
Middle cerebral artery systolic blood flow velocity (cm/s) Peak
49 (41, 65)
61 (47, 81)
0.033a
67 (49, 83)
49 (16, 58)
0.050
Mean
19 (16, 30)
31 (19, 53)
0.158
—
—
—
p < 0.05. Values are mean ± sd or median (interquartile range). Dashes indicate data not available.
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