Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study

Abstract

Objective: Remote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation. The feasibility and safety of RIC in preterm infants with NEC are unknown. The study aimed to assess the feasibility and safety of RIC in preterm infants with suspected or confirmed NEC.

Design: Phase I non-randomised pilot study conducted in three steps: step A to determine the safe duration of limb ischaemia (up to 4 min); step B to assess the safety of 4 repeated cycles of ischaemia-reperfusion at the maximum tolerated duration of ischaemia determined in step A; step C to assess the safety of applying 4 cycles of ischaemia-reperfusion on two consecutive days.

Setting: Level III neonatal intensive care unit, The Hospital for Sick Children (Toronto, Canada).

Patients: Fifteen preterm infants born between 22 and 33 weeks gestational age.

Intervention: Four cycles of ischaemia (varying duration) applied to the limb via a manual sphygmomanometer, followed by reperfusion (4 min) and rest (5 min), repeated on two consecutive days.

Outcomes: The primary outcomes were (1) feasibility defined as RIC being performed as planned in the protocol, and (2) safety defined as perfusion returning to baseline within 4 min after cuff deflation.

Results: Four cycles/day of limb ischaemia (4 min) followed by reperfusion (4 min) and a 5 min gap, repeated on two consecutive days was feasible and safe in all neonates with suspected or confirmed NEC.

Conclusions: This study is pivotal for designing a future randomised controlled trial to assess the efficacy of RIC in preterm infants with NEC.

Trial registration number: NCT03860701.

Keywords: gastroenterology; neonatology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Physiological variables recorded to assess the safety of remote ischaemic conditioning (RIC) in step A (n=5). (A) Peripheral oxygen (O2) saturation and (B) capillary refill time (CRT in s) were assessed before and after every cycle of ischaemia. (C) Pain was assessed according to the Premature Infant Pain Profile (PIPP score) and measured before the first RIC cycle, 30 s after each cycle and 6 hours after the last cycle of ischaemia. (D) Urine output (mL/kg/hour) was measured 24 hours before and after RIC. Data are represented as median with range. A two-way analysis of variance with main effects only and post hoc Tukey’s multiple comparisons test was used to compare pre-RIC and post-RIC oxygen saturation, CRT (s) and PIPP score. A paired non-parametric Wilcoxon test was used to compare pre-RIC and post-RIC urine output (mL/kg/hour). There was no significant difference between pre-RIC and post-RIC values of any of the listed parameters.

Figure 2

Physiological variables recorded to assess the safety of remote ischaemic conditioning (RIC) in step B (n=5). (A) Peripheral oxygen (O2) saturation and (B) capillary refill time (CRT in s) were assessed before and after every cycle of ischaemia. (C) Pain was assessed according to the Premature Infant Pain Profile (PIPP score) and measured before the first RIC cycle, 30 s after each cycle and 6 hours after the last cycle of ischaemia. (D) Urine output (mL/kg/hour) was measured 24 hours before and after RIC. Data are represented as median with range. A two-way analysis of variance with main effects only and post hoc Tukey’s multiple comparisons test was used to compare pre-RIC and post-RIC oxygen saturation, CRT (s) and PIPP score. A paired non-parametric Wilcoxon test was used to compare pre-RIC and post-RIC urine output (mL/kg/hour). There was no significant difference between pre-RIC and post-RIC values of any of the listed parameters.

Figure 3

Physiological variables recorded to assess the safety of remote ischaemic conditioning (RIC) in step C day 1 and 2 (n=5 in each day). (A, E) Peripheral oxygen (O2) saturation and (B, F) capillary refill time (CRT in s) were assessed before and after every cycle of ischaemia. The day 2 CRT for all patients is reported, although lines are superimposed. (C, G) Pain was assessed according to the Premature Infant Pain Profile (PIPP score) and measured before the first RIC cycle, 30 s after each cycle and 6 hours after the last cycle of ischaemia. (D, H) Urine output (mL/kg/hour) was measured 24 hours before and after RIC. Data are represented as median with range. A two-way analysis of variance with main effects only and post hoc Tukey’s multiple comparisons test was used to compare pre-RIC and post-RIC oxygen saturation, CRT (s) and PIPP score. A paired non-parametric Wilcoxon test was used to compare pre-RIC and post-RIC urine output (mL/kg/hour). There was no significant difference between pre-RIC and post-RIC values of any of the listed parameters.