Hemodynamic effects of noradrenaline in neonatal septic shock: a prospective cohort study

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Hemodynamic effects of noradrenaline in neonatal septic shock: a prospective cohort study

https://doi.org/10.21203/rs.3.rs-2466983/v1

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BACKGROUND

Neonatal sepsis is the third most common cause of neonatal mortality. The incidence of neonatal septic shock in low-income countries is 26.8% with a mortality rate of 35.4%. The hemodynamic effects of noradrenaline on the pediatric population have been well documented, but studies in neonates are sparse. This research was carried out to evaluate the effects of noradrenaline on the clinical and hemodynamic parameters in neonates with septic shock.

METHODS

This was a single-center prospective cohort study in a level III Neonatal intensive care unit of a tertiary care hospital. Neonates with sepsis defined by Tollners criteria and with evidence of shock and those who received noradrenaline as a first-line vasoactive agent for treatment were included. At baseline, demographic and clinical data and hemodynamic parameters were recorded and entered in a pre-designed case record form. The primary outcome measured was the response at the end of one hour of infusion of noradrenaline and the mortality rate.

RESULTS

A total of 21 babies received noradrenaline infusion for neonatal septic shock. The cohort comprised 17 preterm neonates (mean GA of 36.1 Weeks) with a median birth weight of 1.957. Resolution of shock at one hour of starting noradrenaline was achieved in 76.2% of cases. The median NICU stay was 5.5 days, and the median duration of hospital stay was 14 days. The mean blood pressure improved significantly after the initiation of noradrenaline infusion from a baseline of 30.6 mm of Hg (SD-6.1) to 37.8 mm of Hg (SD- 8.22, p < 0.001) at 1 hour after initiation of noradrenaline. Fractional shortening improved significantly after noradrenaline initiation from 29% (SD-13.5) at baseline to 45.1% (SD-21.1, p < 0.001) after 1 hour of noradrenaline. There was a mortality rate of 28.6% in our study.

CONCLUSION

Noradrenaline is a relatively safe and effective drug to use in the treatment of neonatal septic shock. Noradrenaline is effective in increasing blood pressure and improves left ventricular systolic function. Further studies with a larger sample size are needed to confirm our findings before it can be recommended as a first-line therapy in infants with neonatal shock.

Noradrenaline

Neonatal Septic shock

Hemodynamics

Preterm neonates

Neonatal sepsis is the third most common cause of neonatal mortality, accounting for approximately 15% of all neonatal deaths globally [1]. A hospital-based collaborative network study from India demonstrated that neonatal sepsis accounted for 14.3% of neonatal intensive care unit (NICU) admissions and contributed to 24% of neonatal deaths. [3] This is in contrast to the findings from developed countries where incidence is as low as 0.98 cases per 1000 live births [4]. Sepsis is a common cause of multifactorial shock in neonates. Globally, the reported incidence of neonatal sepsis with shock is around 1.3% of all NICU admissions and it is associated with high mortality [5]. The incidence is higher in low-income countries with an incidence of 26.8% and a mortality of 35.4% [6]. Hypotensive preterm neonates are more likely to develop complications, death, and adverse neurodevelopmental outcomes [7, 8]. Mainstay therapy for septic shock includes prompt diagnosis, hemodynamic assessment, administration of empiric antibiotics, fluid resuscitation, vasopressor support if shock persists, and hydrocortisone for refractory shock. Traditionally, dopamine and adrenaline have been used as the initial vasopressor agent for the management of neonatal shock, with comparable efficacy and safety [9, 10]. Although dopamine and adrenaline have been used extensively, recent guidelines by the American college of critical care medicine (ACCM) standards, suggest that adrenaline should be used as the first treatment for shock, with the drug being tailored further depending on the kind of shock - warm shock (noradrenaline) or cold shock (adrenaline) [11]. Noradrenaline stimulates beta 1-adrenergic and alpha-adrenergic receptors, causing increased contractility and heart rate and, thereby increasing systemic blood pressure and coronary blood flow. In clinical practice, alpha effects (vasoconstriction) are greater than beta effects (inotropic and chronotropic effects), especially on higher doses [12]. Additionally, noradrenaline has a pulmonary vasodilatation effect in neonates with high pulmonary vascular resistance (PVR) [13, 14]. Noradrenaline has been demonstrated to be effective in the management of pediatric septic shock [15, 16]. The hemodynamic effects of noradrenaline on the pediatric population have been well documented, but studies in neonates are sparse. Improvement in blood pressure, urine output, decreased oxygen requirement after noradrenaline initiation, and reversal of shock in term neonate’s refractory to dopamine and dobutamine have been reported [13, 17]. These studies have focused on clinical parameters and there is a gap in knowledge related to the hemodynamic effects of noradrenaline in infants with neonatal shock. This research was carried out to evaluate the effects of noradrenaline on the clinical and hemodynamic parameters in neonates with septic shock.

Study settings and subjects

This was a single-center prospective cohort study carried out in a level III NICU of a tertiary care teaching hospital. Neonates with sepsis defined by Tollners criteria and with clinical evidence of shock and those who received noradrenaline infusion as a first-line vasoactive agent for treatment were included [18]. Neonates with major congenital malformations, hypovolemic shock (blood loss, shock due to other fluid loss), hemodynamically significant patent ductus arteriosus (hsPDA), and moderate to severe hypoxic-ischemic encephalopathy were excluded [19, 20]. Written informed consent was obtained from the parents of the neonate. Data were recorded in a case record form (CRF). At baseline, demographic and clinical data and hemodynamic status were recorded and entered in a pre-designed case record form. Blood pressure (BP) was monitored by a non-invasive oscillometric method, using the Nihon Kohden, VISMO multipara monitor. Cuff sizes of 1 to 3 (cuff 1 for arm circumference 1-4cm, cuff 2 for arm circumference 4–6 cm, and cuff 3 for 6–11 cm) were used, so as to cover at least two-thirds of the right upper arm length and entire arm circumference. Three successive readings at two-minute intervals were taken and the average of these three readings was taken and rounded to the nearest mmHg. Septic shock was defined by systemic hypotension (Mean blood pressure (MBP) < 10th percentile of the normal range for birth weight and postnatal age(21)), with at least three of the following criteria for decreased perfusion: (i)tachycardia (heart rate > 20 above baseline), (ii) weak peripheral pulses, (iii) prolonged capillary refill time > 3 sec and (iv) urine output < 1 mL/kg/h. Left ventricular systolic functions (left ventricular output (LVO) and fractional shortening (FS) (both in parasternal long and short axis views) and right ventricular systolic (right ventricular output (RVO), tricuspid annular plane systolic excursion (TAPSE)) were measured twice using echocardiography - once after fluid bolus and again after sixty minutes of starting noradrenaline infusion. All eligible patients received a fluid bolus of 10mL/kg of crystalloids, then noradrenaline was administered at 0.2–0.5 mcg/kg/min through central or midline venous catheters. The resolution of shock was defined as improvement in MBP > 10th centile of the normal range for birth weight and postnatal age along with capillary refilling time duration of < 3 seconds. If an optimal response was not present, the selection of the next vasoactive drug was left to the discretion of the neonatologist.

Outcome measures

The primary outcome measured was the response noted at the end of one hour of infusion of noradrenaline, whether the shock had resolved or unresolved and if there was a need for increasing the dose. The mortality rate was also measured as a primary outcome. Secondary outcomes included (i) ventricular systolic function assessment by echocardiography, (ii) requirement of additional vasopressors, (iii) vitals (heart rate, blood pressure) and acid-base parameters at 0- and 60-minute, (iv) duration of ventilation, (v) neonatal morbidities during hospital stay like intraventricular hemorrhage (IVH), acute kidney injury (AKI), necrotizing enterocolitis (NEC stage 2/3)

Statistics

Statistical analyses were performed with SPSS software (version 23.0. IBM Corp., Armonk, NY, USA). Continuous variables were described as mean and variation of each observation from the mean value (standard deviation) represented as mean ± SD or median and interquartile range if they failed to follow a normal distribution. Categorical variables were described by taking percentages. Paired data were analyzed using Paired T-test or Wilcoxon Signed Rank test and a p-value < 0.05 was considered statistically significant.

During the study period from March 2020 to January 2022, there were a total of 854 NICU admissions needing level 3 care. Out of these, 197 were diagnosed with sepsis and 65 babies were diagnosed to have septic shock, out of which 21 babies received noradrenaline infusion. (Fig. 1) The cohort comprised 17 preterm neonates (mean GA of 36.1 Weeks, range of 28.2 Weeks to 38.3 Weeks) with a median birth weight of 1.957 (IQR range 1.335–2.287) (Table 1). The mean duration of time for which shock persisted [mean (SD)] was 8.19 (10.6) hours with a median (IQR) of 6 (2.5–10) hours. Resolution of shock at one hour of starting noradrenaline was achieved in 76.2% (16 neonates) cases and 23.8% (5 neonates) of cases required additional inotrope support. The median NICU stay was 5.5 days (IQR range 3.25–9.5 days), and the median duration of hospital stay was 14 days (IQR range 6-17.5 days). Mechanical ventilation was required in 71.4% of cases and the mortality rate was 28.6%. The MBP improved significantly after the initiation of noradrenaline infusion from a baseline of 30.6 mm of Hg (SD-6.1) to 37.8 mm of Hg (SD- 8.22, p < 0.001) at 1 hour after initiation of noradrenaline infusion. (Table 2) There was no significant change in heart rate, serum lactate, or other blood gas parameters. (Table 3) Fractional shortening improved significantly after noradrenaline initiation from 29% (SD-13.5) at baseline to 45.1% (SD-21.1, p < 0.001) after 1 hour of noradrenaline infusion although there was no statistically significant increase in LVO. (Fig. 2) Although there was an improvement in all the echocardiographic parameters including left ventricular output and left ventricular outflow velocity time integral (VTI), right ventricular output, right ventricular outflow VTI, and TAPSE, this improvement was not statistically significant. (Fig. 3) The only adverse reaction noted was tachycardia, which was present in 4 (19%) babies. Six neonates died leading to a mortality rate of 28.6%. Five of the six neonates did not respond to noradrenaline infusion and required additional inotropic support. The cause of death was refractory septic shock.

Table 1

Characteristics of the cohort
Variable	Cases (n = 21)
Maternal Parameters
Primigravida, n (%)	12 (57.1%)
Pregnancy-induced hypertension, n (%)	02 (9.5%)
Maternal Covid infection, n (%)	02 (9.5%)
Mode of delivery- Vaginal delivery, n (%)	08 (38%)
Neonatal Parameters
Gestational age (Weeks) [Mean (SD)]	36.1 (4.2)
Gestational age < 37 Weeks, n (%)	17 (80.9%)
Birth weight, gram, mean (SD) Median (IQR)	1852 (2000) 1.957 (1.335–2.287)
Small for gestational age (< 10th centile), n (%)	16 (76.1%)
Male, n (%)	17 (80.9%)
APGAR at 1 min [Mean (SD)]	5.85 (1.9)
APGAR at 5 min [Mean (SD)]	7.3 (1.8)
Blood culture positive, n (%)	04 (19%)
Duration of Shock [Mean (SD)]	8.19 (10.6)
Resolution of shock at one hour of starting the drug, n (%)	16 (76.2%)
Mechanical ventilation (days), [Mean (SD)]	15 (71.4)
Intraventricular hemorrhage (IVH), n (%)	07 (33.3%)
Grade 1 Grade 2 Grade 3 Grade 4	04 (19%) 01 (4.76%) 02 (9.52%) 00
Acute kidney injury, n (%)	03 (14.3%)
Necrotising enterocolitis, n (%)	01 (4.8%)
NICU stay (days) [Median (IQR)]	5.5 (3.25–9.5)
Hospital stays (days) [Median (IQR)]	14 (6-17.5)
Mortality, n (%)	06 (28.6%)
SD = Standard deviation, IQR-Interquartile range

Table 2

Echocardiographic parameters of the cohort
Variables	Parameters at the initiation of noradrenaline	Parameters one hour later	Changes at one hour	P value
Left ventricular parameter
HR; Mean (SD)	148.6(16.6)	152.6 (22.3)	4.0 (5.7)	0.437
VTI; Mean (SD)	9.4(2.6)	10.0 (3.2)	0.6 (0.6)	0.384
OCSA; Mean (SD)	6.0(1.2)	6.3 (1.4)	0.3 (0.2)	0.170
VO; Mean (SD)	208.8(83.5)	292.2 (163.9)	83.4 (80.4)	0.109
FS; Mean (SD)	29.0(13.5)	45.1 (21.1)	16.1 (7.6)	< 0.001
Right ventricular parameter
HR; Mean (SD)	147.19(16.5)	154.1 (21.9)	6.9 (5.4)	0.172
VTI; Mean (SD)	9.9(3)	11.3 (3.5)	1.4 (0.5)	0.087
OCSA; Mean (SD)	6.3(1.2)	6.4 (1.4)	0.1 (0.2)	0.281
VO; Mean (SD)	237(134.1)	329.5 (145.3)	37.3 (18.6)	0.059
TAPSE; Mean (SD)	9.0(2.6)	9.8 (2.5)	0.8 (0.1)	0.476
HR-Heart Rate, VTI-Velocity Time Integral, OCSA-Outflow cross-sectional
Area, VO-Ventricular output, FS-Fractional Shortening, TAPSE-Tricuspid annular plane systolic excursion, SD-Standard deviation

Table 3

Vital and acid-base parameters of the cohort at one hour of starting noradrenaline
Vital parameters and blood gases	Before Noradrenaline	After Noradrenaline	p-value
Heart Rate (beats per minute), Mean (SD)	154.13 ± 13.88	152.38 ± 21.78	0.75
Mean Blood Pressure (mm of HG), Mean (SD	30.65 ± 6.11	37.82 ± 8.22	< 0.001
Capillary Filling Time(seconds), Mean (SD)	2.22 ± 0.42	1.78 ± 0.73	0.028
pH, Mean (SD)	7.3 ± 0.08	7.29 ± 0.11	0.552
pCO2 in mm Hg, Mean (SD)	37.4 ± 8.87	37.47 ± 10.5	0.982
pO2 in mm Hg, Median (IQR)	67 (39.5–100.5)	67 (47–91.5)	0.945
HCO3 mmol/L, Mean (SD)	18.5 ± 3.72	17.5 ± 2.68	0.113
Base deficit mmol/L, Median (IQR)	-7.1 (-9.5 – -5.05)	-7 (-10.75 - -5.45)	0.575
Lactate, Median (IQR)	3.55 (2.32–5.32)	2.3 (1.35–4.9)	0.173

This prospective study showed that the use of noradrenaline in the management of neonatal septic shock improves left ventricular function and mean blood pressure. Although there was improvement seen in the left ventricular output and left ventricular velocity time integral (VTI), right ventricular output, right ventricular VTI, and TAPSE, they were not statistically significant (p > 0.1). In our cohort, there were no significant adverse effects of noradrenaline. Our study demonstrates that noradrenaline positively affects cardiac function and is a safe drug to use in neonatal septic shock. However, this needs to be validated with a larger sample size. This study demonstrates the effectiveness of noradrenaline as a first-line inotropic agent in neonatal septic shock. As of 2017, the ACCM standards recommend dopamine or adrenaline as the first-line medication for the treatment of neonatal septic shock [11]. Dopamine has a potential adverse effect of increased pulmonary vascular resistance and pulmonary hypertension in new-born [22, 23]. Recent physiology-based approaches to the management of hemodynamic instability and expert opinion have questioned the selection of dopamine as a first-line inotropic agent in neonatal septic shock [24]. Adrenaline has potent inotropic and chronotropic action but has an endocrine stress response causing hyperglycemia, an increase in plasma lactate along with a fall in arterial pH and base excess [25, 26]. In contrast, increasing evidence has demonstrated that noradrenaline may be an ideal inotrope in the management of septic shock – acting both as an inotropic agent and also decreasing pulmonary vascular resistance as needed in warm shock. Tournex P et al [13] observed in a prospective observational study of 22 neonates that noradrenaline was effective in increasing systolic blood pressure, urine output, and a decrease in blood lactate. The same findings were noted by Gupta S et al in a retrospective cohort study of 53 neonates [17]. Moreover, experimental studies exhibited that noradrenaline has a pulmonary vasodilatory effect [27, 28]. It has also been proven to have a pulmonary vasodilatory effect with improved oxygenation and reduced fractional inspired oxygen (FIO2) requirement in neonates [13, 14]. These pharmacological effects of noradrenaline make it an ideal inotropic agent in neonatal shock, especially in an infant with vasodilatation or those with high PVR or pulmonary hypertension. Noradrenaline is a widely acceptable first-line inotropic agent in adults with septic shock [29]. Guidelines have been developed for the use of noradrenaline as a first-line therapeutic agent in the management of pediatric vasodilatory shock [30, 31]. Noradrenaline raises systemic blood pressure, cardiac output, oxygen delivery, consumption, and regional blood flow, including mesenteric and renal blood flow, and improves survival [32]. Our findings are in accordance with the published findings on the effects of noradrenaline in neonates. Similar to studies by Tourneux et al [13] and Gupta et al [17] in neonatal shock, a retrospective done by Rizk et al [14] in preterm neonates with refractory septic shock showed good improvement in MBP. These findings are consistent with our study, with a good response to noradrenaline in increasing MBP and reducing the need for other inotropes. Neonates in our study showed rapid improvement in blood pressure with a significant response within one hour of initiation of noradrenaline. The response was more rapid as compared to other studies done by Torunex et al [13], Rizk et al [14], and Gupta et al [17] where the response was seen within 3h, 8h, and 6h of initiation of noradrenaline.

Six neonates (28.6%) died in our study. This was higher compared to Torunex et al [13] and Gupta et al [17] with a mortality rate of 18% and 16%, respectively.

This is the first study describing the impact of noradrenaline on clinical hemodynamic and echocardiographic parameters in a study population including both term and preterm neonates with septic shock. We assessed the effects of noradrenaline on both right and left ventricular systolic functions, with a significant effect on fractional shortening of the left ventricle, a common echocardiographic parameter used to assess left ventricular systolic function.

We acknowledge the limitations of our study, especially a small sample size, and that results from a cohort of 21 neonates from a single tertiary care center may not be generalized to other populations. Only four neonates (19%) had confirmed culture-positive sepsis. Other neonates had clinical and supportive laboratory evidence for neonatal sepsis. Diastolic function assessment using echocardiography was not included in the study design. Long-term outcomes were not evaluated.

Noradrenaline is effective in increasing blood pressure and improves left ventricular systolic function as assessed by echocardiography. It is a relatively safe and effective drug to use in the treatment of neonatal septic shock with minimal adverse effects. Further studies with larger sample size and echocardiographic assessment of all ventricular parameters are needed to confirm our findings before it can be recommended as a first-line therapy in infants with neonatal shock.

ACCM- American college of critical care medicine, CRF- Case record form, FIO2- Fractional-inspired oxygen, FS- Fractional shortening, HsPDA- Hemodynamically significant patent ductus arteriosus, IVH- Intraventricular hemorrhage, IQR- Interquartile range, LVO- Left ventricular output, MBP- Mean blood pressure, NEC- Necrotising enterocolitis, NICU- Neonatal intensive care unit, PVR- Pulmonary vascular resistance, RVO- Right ventricular output, SD- Standard deviation, TAPSE- Tricuspid plane systolic excursion, VTI- Velocity time integral.

Acknowledgments

Not applicable

Author’s contribution

RG, SP, and PS contributed to the study conception and design. Data collection and analysis were done by RG. AK and RG wrote the main manuscript. YS and NS revised the manuscript. All authors reviewed and approved the final manuscript.

Funding

No funding was done for the research or publication.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

The study was started after approval by the Bharati Vidyapeeth (Deemed to be University) Medical College institutional ethics committee (DCGI Reg. No. ECR 518/ Inst/MH/2014RR-17). All methods were carried out in accordance with relevant guidelines, regulations, and hospital policy. Informed consent was obtained from all legal guardians of the subjects enrolled in the study for study participation.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Author Details

¹Department of Neonatology, Bharati University Medical College, Pune-Satara Road, Pune, Maharastra-411043, India. ²Division of Neonatology, Loma Linda University School of Medicine, 11175 Anderson Street Rm 11121, Coleman Avenue, Loma Linda 92345, USA.³Departement of Neonatology, Sidra Medicine, 26999 Doha, Qatar.

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No competing interests reported.

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Hemodynamic effects of noradrenaline in neonatal septic shock: a prospective cohort study

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