EBNEO Commentary: Permissive hypotension in preterm infants- Is masterly inactivity the right approach?

October 04, 2025

MANUSCRIPT CITATION

Alderliesten T, Arasteh E, van Alphen A, Groenendaal F, Dudink J, Benders MJ, van Bel F, Lemmers P. Treatment of Hypotension of Prematurity: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2025 May 24:fetalneonatal-2024-328253. doi: 10.1136/archdischild-2024-328253. Epub ahead of print. PMID: 40413017.

REVIEWED BY

Deepika Sankaran, MD (corresponding author)
University of California, Davis, Sacramento
dsankaran@health.ucdavis.edu

Satyan Lakshminrusimha, MD
University of California, Davis, Sacramento
slakshmi@health.ucdavis.edu

Heather Siefkes, MD
University of California, Davis, Sacramento
hsiefkes@health.ucdavis.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

P: Preterm infants born at gestational age (GA) of 24 0/7 to 29 6/7 weeks with idiopathic arterial hypotension.
I: In the permissive hypotension (PH) group, treatment was initiated if one of the criteria were met (figure 1, regional cerebral oxygen saturation (rScO2) <50% for 30 min despite optimal respiratory support, urine output of < 0.6 mL/kg/h evaluated every 4 hours, capillary refill time (CRT) > 3 seconds on 2 consecutive measurements evaluated every 4 hours, plasma lactate > 6 mM/L evaluated every 4 hours, mean arterial blood pressure (MABP) 5 mm Hg below GA in weeks).
C: In the standard treatment (ST) group, treatment was initiated when the MABP in mm Hg was < GA in weeks. In both groups, when criteria were met, treatment consisted of the following in escalating order: 1) a fluid bolus of saline or fresh frozen plasma, 2) dopamine up to 10 mcg/kg/min, 3) dobutamine in addition to dopamine, and 4) epinephrine. Hydrocortisone may be considered on escalation of inotropic support beyond dopamine monotherapy.
O: Primary outcome: Neurodevelopmental outcome (NDO) assessment at 24 months of age corrected for prematurity using Bayley Scale for Infant and Toddler Development, 3rd Dutch version to calculate a Cognitive and Motor Index Score (BSITD-III-NL, mean=100, SD=15) by blinded outcome assessors.
T: 24 months

Figure 1

METHODS

• Design: Randomized controlled clinical trial
• Allocation: Randomized, 1:1 allocation sequence, by means of hosted service, stratified by gestational age (27 weeks) and birth weight (<10th percentile) • Blinding: No, except for NDO and ultrasound assessors • Follow-up period: 24 months • Setting: Single center, Neonatal intensive care unit at Wilhelmina Children’s Hospital, Utrecht, the Netherlands. • Patients: Preterm infants born at GA 24+0 weeks to 29+6 weeks with idiopathic arterial hypotension, defined as a MABP in mm Hg lower than the infant’s GA in weeks. Exclusion criteria were: (1) Clinically suspected or microbiologically proven sepsis at admission, (2) Major congenital abnormalities, (3) Postnatal age at the time of development of arterial hypotension >72 hours, (4) No arterial line, or (5) Evidence of poor organ/tissue perfusion before inclusion.
• Intervention: Permissive hypotension (treatment for hypotension reserved to infants meeting criteria for poor perfusion – low cerebral rScO2, decrease urine output, prolonged CRT, increased plasma lactate, MABP > 5 mm Hg < GA), compared to standard treatment (treatment for hypotension if MABP in mm Hg < GA in weeks)
• Outcomes:
Primary outcome: Neurodevelopmental outcome (NDO) assessment at 24 months of age corrected for prematurity using Bayley Scale for Infant and Toddler Development, 3rd Dutch version to calculate a Cognitive and Motor Index Score (BSITD-III-NL, mean=100, SD=15) by blinded outcome assessors.
• Secondary outcomes:
1. All-cause mortality.
2. Composite adverse outcomes defined as BSITD-III-NL cognitive and or motor score <85 Below -1SD) or death.
3. Others: occurrence of IVH <7 days by cranial USG, reviewed by blinded assessor; perforated NEC, cystic PVL, scaled Fine and Gross Motor Scores using the BSITD-III-NL (mean=10, SD=3).
• Enrolment : 57% of projected
• Analysis and Sample Size: Intention-to-treat, blinded for group allocsation. Two-sided student t test for parametric and Mann-Whitney U test for non-parametric, ordinalmlogistic regression for binary and ordinal outcome variables, no adjustment for multiple testing, 0.05 significance level, analyzed using R Studio.
• Patient follow-up: % included in analysis

Figure 2 TOHOP Sankaran Siefkes Permissive hypotension

MAIN RESULTS

Primary outcome not different between ST and PH groups. Infants in PH group had less frequent need for initiation of inotropes and shorter duration of inotrope in the setting of MABP being not different. Relative risks for death (1.4 (0.6 to 3.7)) and composite adverse outcome (0.8 (0.5 to 1.3)) were not different between the 2 treatment strategies. The percentage of time spent with an rScO2 <50% was higher in the PH group 36–42 hours (ST median 0%, IQR (0 – 0.7) vs PH 0.5% (0.0 – 5.3), p 0.04) and 0–72 hours after randomization (ST median 0.9%, IQR (0.4–3.8) vs PH 2.4% (0.9–7.3), p = 0.04).

CONCLUSION

Permissive hypotension approach in treatment of systemic hypotension in premature infants < 30 weeks was associated with a lower duration of inotrope use while attaining similar blood pressure levels. The study did not see negative effects of permissive hypotension approach in terms of risk of death, necrotizing enterocolitis, grade III IVH/PVHI, or NDO, but was underpowered for the outcomes.

COMMENTARY

Cerebral autoregulation is the ability to maintain stable cerebral blood flow (CBF) despite fluctuations in mean arterial blood pressure (MABP). The critical closing pressure (CrCP) represents the MABP threshold below which CBF decreases. In preterm infants, autoregulatory capacity is limited, and MABP often approximates the CrCP. Consequently, CBF in this population is highly sensitive to both hypotension and blood pressure fluctuations induced by vasoactive agents(1). Lower regional cerebral oxygen saturation (rScO₂), measured by near-infrared spectroscopy (NIRS), may indicate cerebral hypoperfusion. Whether hypotension should be treated universally, or only when accompanied by evidence of hypoperfusion, remains an ongoing debate.

 

Treatment of Hypotension of Prematurity (TOHOP) is a randomized trial by Alderlisten et al that compared standard treatment (ST) (solely based on MABP< gestational age, GA in weeks in mmHg) to perfusion-based permissive hypotension (PH) approach in preterm infants (24 0/7- 29 6/7 weeks GA)(2). Treatment was initiated in the PH group if there were signs of hypoperfusion (figure 1) or MABP was <GA−5 in weeks. Interestingly, the indication for initiation of treatment was MABP <GA−5 in weeks in majority of the infants in the PH group rather than markers of poor perfusion (figure 2). Essentially, this trial compared initiation of treatment for hypotension for MABP in mmHg These findings are similar to a recent trial. The Hypotension in Preterm Infants (HIP) trial included infants <28 weeks GA who were randomized to receive a saline bolus followed by dopamine infusion or 5% dextrose (figure 3). The HIP trial reported no difference in survival to 36 weeks PMA without severe brain injury(3). However, on long term follow-up, survival without neurodevelopmental impairment was observed in 48% in dopamine group and 25% in placebo group with an odds ratio 2.79 (95%CI 0.89, 8.72), p=0.078.(4) This study was also not adequately powered.

Figure 3 HIP Siefkes Sankaran HIP trial graphic abstract

While the PH approach in the management of systemic hypotension in the first 72h after birth is feasible and facilitates individualized care, its safety is uncertain with possible risk of cerebral hypoperfusion and hypoxemia. After excluding causes such as blood loss and sepsis, stratifying “idiopathic” hypotension by chronological age at onset (≤6, 6-24, and 24-72h) may be valuable when evaluating treatment strategies. In addition to weighing the risks of untreated hypotension, iatrogenic risks of blood pressure fluctuations associated with vasoactive medications should be carefully considered (5, 6). Pending performance of adequately powered trials evaluating PH vs ST approach in preterm infants, the use of GA in weeks as a MABP (in mmHg) cut-off for initiating dopamine appears to be a reasonable approach and is not associated with increased risk of death or negative long-term outcomes in TOHOP and HIP trials.

 

REFERENCES

1. Noori S, Seri I. Hemodynamic antecedents of peri/intraventricular hemorrhage in very preterm neonates. Semin Fetal Neonatal Med. 2015;20(4):232-7.
2. Alderliesten T, Arasteh E, van Alphen A, Groenendaal F, Dudink J, Benders MJ, et al. Treatment of Hypotension of Prematurity: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2025.
3. Dempsey EM, Barrington KJ, Marlow N, O’Donnell CPF, Miletin J, Naulaers G, et al. Hypotension in Preterm Infants (HIP) randomised trial. Arch Dis Child Fetal Neonatal Ed. 2021;106(4):398-403.
4. Marlow N, Barrington KJ, ODonnell CPF, Miletin J, Naulaers G, Cheung P-Y, et al. Outcomes of extremely preterm infants who participated in a randomised trial of dopamine for treatment of hypotension (the HIP trial) at 2 years corrected age. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2025:fetalneonatal-2024-327894.
5. Munro MJ, Walker AM, Barfield CP. Hypotensive extremely low birth weight infants have reduced cerebral blood flow. Pediatrics. 2004;114(6):1591-6.
6. Soul JS, Hammer PE, Tsuji M, Saul JP, Bassan H, Limperopoulos C, et al. Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatr Res. 2007;61(4):467-73.

Figure 1: Graphic summary of the TOHOP trial. The green boxes represent the characteristics and outcomes in the standard treatment arm and the red boxes represent the characteristics and outcomes of the permissive hypotension arm. Although the primary outcome of neurodevelopmental outcome at 24 months was not different between the 2 arms, more infants in the permissive hypotension ram had lower cerebral regional oxygen saturation along with a non-significant trend towards higher mortality (13% in permissive hypotension arm vs 7% in standard treatment arm). GA, gestational age, MABP, mean arterial blood pressure. rScO2 regional cerebral mixed venous oxygen saturation, sIVH III severe intraventricular hemorrhage, PVHI, periventricular hemorrhagic infarction, CA corrected age, NEC, necrotizing enterocolitis. Copyright Satyan Lakshminrusimha.

Figure 2: Permissive hypotension in TOHOP trial. For infants in the permissive hypotension arm, a decrease in cerebral oxygenation or urine output, or an increase in serum lactate or delayed capillary refill time, were considered in the decision making for initiating treatment of hypotension when the MABP was 5 mm Hg less than the GA in weeks. GA, gestational age. MABP, mean arterial blood pressure. rScO2, cerebra regional mixed venous oxygen saturation. Copyright Satyan Lakshminrusimha.

Figure 3: Graphic summary of the HIP trial. The green boxes represent the standard treatment arm and the red boxes represent the restrictive management arm. The primary outcome of survival to 36 weeks postmenstrual age without severe brain injury was not different between the 2 arms. Interestingly, on long term follow up, survival without neurodevelopmental disability was 48% with standard treatment compared to 25% with restrictive treatment (OR 2.79 (0.89,8.72), p=0.078). GA, gestational age in weeks, MABP, mean arterial blood pressure, PMA, postmenstrual age, sIVH, severe IVH, PVL, periventricular leukomalacia. NEC, necrotizing enterocolitis, SIP, spontaneous intestinal perforation, head C, head circumference, Cap refill, capillary refill time. Copyright Satyan Lakshminrusimha.

FUNDING

This work has been supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institutes of Health HD109443 (D.S), HD072929 (S.L.) and 5K23HD108353-03 (H.S.), and National Heart, Lung, Brain Institute (NHLBI) 1K08HL181183-01 (D.S.) . The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR001860 and linked award 5KL2TR001859 (D.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funder/ sponsor did not participate in planning or devising this work.

CONFLICTS OF INTEREST

None

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