Revisions of clinical protocols using the Plan Do Check Act cycle improved outcomes of extremely preterm infants at 2 years (2024)

Abbreviations

CI

confidence interval

NICU

neonatal intensive care unit

OR

odds ratio

PDCA

Plan Do Check Act

Key Notes

• Filling gaps between the standard of care and existing protocols is challenging, which might be accelerated using iteration cycles.

• Protocols for surfactant replacement, respiratory gas humidity, indomethacin, antibiotics, narcotics, parenteral nutrition and catheterisation were revised using Plan Do Check Act cycle, which improved outcomes of extremely preterm infants at 2years.

• Plan Do Check Act cycle may help reach a consensus when optimising clinical protocols.

2.1. Study population

Between January 2006 and December 2015, a total of 2,690 newborn infants were admitted to our NICU, which is a tertiary, referral NICU. Of these, 174 infants were born between 22+0weeks and 27+6weeks. All infants born at greater than 22 gestational weeks were provided with full intensive care options, whereas those born at 22weeks of gestation were resuscitated upon request from their parents. The study cohort comprised of 162 extremely preterm infants, excluding 10 outborn infants and two infants with chromosomal abnormalities (Figure ​(Figure11).

2.2. Clinical strategy for quality improvement

In July 2007, a working group was formed with nine consultant neonatologists, neonatal nurse practitioners, NICU nurses and paediatric registrars to improve the outcomes in extremely preterm infants. Clinical records were reviewed every six months to inspect the relevance of therapeutic regimens during the first 28days of life, referring to recommendations published in Cochrane Reviews (Cochrane Collaboration, London, UK) and UpToDate (UpToDate Inc), with extended searches through other search engines. Adverse events at a corrected age of 40weeks were reviewed to identify the incidence of death, endotracheal tube reintubation, culture‐positive or clinically diagnosed septicaemia, grade III/IV intraventricular haemorrhage, dependence on oxygen/respiratory support and grade III retinopathy of prematurity. Ductus arteriosus, necrotising enterocolitis and intestinal perforation requiring surgical intervention were also noted. The working group proposed a list of possible protocol changes based on the clinical appraisal and literature review. A set of major protocol revisions were chosen and agreed upon at six‐monthly multidisciplinary quality improvement meetings. To avoid strategy drift, protocols were changed only when attendees of the meeting regarded the revision as relevant based on sufficient accumulated data. Short term adverse events were closely monitored to run the PDCA cycle. Subsequently, major changes in the clinical protocol were made on 1st January 2008 and 1st January 2012, which divided the study period into three periods of January 2006 to December 2007, January 2008 to December 2011 and January 2012 to December 2015.

2.3. Clinical background variables

Clinical variables before, during and after birth were collected from patient records (Table1).

2.4. Data analysis

The primary outcome was assessed by death or neurological impairments, defined by Gross Motor Function Classification Score greater than II, deafness or blindness at a corrected age of two years. Death or grade III/IV intraventricular haemorrhage by a corrected age of 40weeks and death by a corrected age of 2years were also used as secondary outcomes. Association between the study periods and outcomes was assessed using logistic regression analysis, controlling for sex, gestational age and Apgar score at 5min. Univariate logistic regression analysis was also performed to estimate the crude effects of clinical backgrounds on the outcome of infants.

This retrospective analysis was conducted in compliance with the Declaration of Helsinki under the approval of the Ethics Committee of the Kurume University School of Medicine. Informed consent was not required for the use of anonymised data obtained for clinical reasons.

3.1. Appraisal for period 2006–2007

Of the 24 infants born during this period, those with respiratory failure were intubated immediately after birth. Peripheral or peripherally inserted central catheters were inserted at 100±38min after birth (Table1). Surfactant was replaced at 180 (150–195) min after birth only after confirming the depth of the endotracheal tube using a radiograph (Table1), which was relatively later than clinically recommended.⁹ Intravenous indomethacin was considered only for patients with significant ductal shunt. Prophylactic ampicillin (100mg/kg/day) and cefotaxime (100mg/kg/day) were administered to infants born at less than 26weeks of gestation and those with suspicion of infection. A relatively low humidity setting was used for the ventilator circuit, with the humidifier chamber outlet temperature of 35°C and Y‐piece temperature of 37°C. Nasal continuous positive airway pressure (CPAP) was routinely used at 5cmH₂O after weaning from invasive respiratory support. We also encouraged minimum handling approach and developmental care, such as positioning of limbs, quiet environment and dim lighting.

In terms of adverse events at 40weeks postconceptional age, eight infants died of immaturity after failing to respond to the maximum cardiac/respiratory support, each on days zero, one, two, three, three, four, 13 and 21. In addition, three infants died of septicaemia due to ampicillin/cefotaxime resistant gram‐negative rods, each on days six, six and 40. Endotracheal tube reintubation was required in eight infants; tube obstruction was confirmed in four cases. None of the infants required a bowel surgery for necrotising enterocolitis or intestinal perforation. Grade III/IV intraventricular haemorrhage and dependence on oxygen/respiratory support were observed in three and 14 infants, respectively (Table2).

At the quality improvement meeting, the working group proposed early surfactant replacement and early catheterisation to promote early stabilisation of infants. High humidifier setting for the respiratory gases, prophylactic indomethacin, routine use of narcotics, early parenteral nutrition and prophylactic ampicillin/gentamicin was also proposed. Attendees of the meeting agreed that early stabilisation of infants and prevention of systemic infection and endotracheal tube blockage must be prioritised. Subsequently, protocols were changed to administer surfactant in less than 30min after birth and use the standard humidifier setting with humidifier chamber outlet 37°C and Y‐piece 40°C.^{10, 11} The use of prophylactic indomethacin of 0.1mg/kg/dose,¹² ampicillin/gentamicin instead of ampicillin/cefotaxime,^{13, 14, 15, 16, 17} continuous intravenous fentanyl of 1µg/kg/h ^{18, 19} and parenteral nutrition with amino acid infusion ^{12, 20} within 24h of birth was also implemented.

3.2. Appraisal for period 2008–2011

For all the 55 infants born during this period, surfactant was replaced precisely at 15min after birth (Table1). Catheters were inserted at 109±40min after birth. Intravenous indomethacin was administered within 6h after birth in 70.9% of the infants. The standard high humidifier setting was used for all 55 infants during the study period. Prophylactic gentamicin was administered to 76.4% of infants. From the period 2006–2007 to 2008–2011, there was an upward trend of administering narcotics and amino acid infusion within 24h of birth (Table1). Maternal glucocorticoid exposure also tended to increase although no protocol change was made with respect to this treatment (Table1). No significant change was noted for the minimum handling approach, developmental care and use of CPAP devices.

Of the 55 infants born during the period 2008–2011, three died of immaturity without responding to the cardiac and respiratory support on days one, two and five. Deaths from septicaemia occurred in two infants on days one and five, respectively. Their blood cultures were positive for Escherichia coli and Staphylococcus aureus, respectively, both of which were resistant to ampicillin, cefotaxime and gentamicin. Deaths due to necrotising enterocolitis and bronchopulmonary dysplasia were also noted in one each infant on days eight and 35, respectively. Endotracheal tube reintubation was required in 13 infants; tube obstruction was confirmed in two infants. Bowel surgery for necrotising enterocolitis or intestinal perforation, grade III/IV intraventricular haemorrhage and dependence on oxygen/respiratory support were observed in two, 13 and 49 infants, respectively (Table2).

The working group proposed to speed‐up the administration of prophylactic indomethacin and commencement of narcotics and parenteral nutrition via very early insertion of vascular catheters. Attendees of the quality improvement meeting agreed that the incidence of intraventricular haemorrhage should be reduced via an even earlier stabilisation of infants. Protocols were changed to encourage very early completion of catheterisation within 1h after birth using umbilical catheters. The catheters were used to administer indomethacin within 6h of birth, and subsequently, administration of narcotics and parental nutrition was also initiated.

3.3. Appraisal for period 2012–2015

For 83 infants born during this period, surfactant was replaced precisely at 15min after birth (Table1). The standard humidifier settings and prophylactic gentamicin were used in all infants. Catheterisation was completed at 79±33min after birth. Intravenous indomethacin was administered within 6h after birth in 91.6% of the infants. Between periods 2008–2011 and 2012–2015, there was a trend towards increased maternal glucocorticoid exposure. However, no marked changes were observed in the use of narcotics and amino acid infusion within 24h of birth and the minimum handling approach, developmental care and use of CPAP devices (Table1).

Of the 83 infants born during this period, one infant born at 23.3weeks of gestation died on day zero because of immaturity after failing to respond to the cardiac/respiratory support. Thirteen infants required endotracheal tube reintubation, none of which was confirmed as tube obstruction. Bowel surgery, grade III/IV intraventricular haemorrhage and dependence on oxygen/respiratory support were seen in three, 11 and 64 infants, respectively (Table2).

3.4. Independent variables of the primary outcome

At a corrected age of two years, 20 infants died, 35 developed cerebral palsy and 16 were diagnosed as deaf or blind (Table2). Univariate analysis revealed that death or neurological impairments were associated with gestational age, birth weight, Apgar scores at 1 and 5min, the requirement for inotropes on day zero, surgical ductus closure and delayed establishment of enteral feeding (p<0.001, p=0.006, p<0.001, p<0.001, p=0.001, p=0.040 and p<0.001, respectively) (Table3). Reduction in death or neurological impairments was associated with the therapeutic regimen for periods 2008–2011 and 2012–2015 even after adjusting for gestational age, Apgar scores at 5min and sex (vs. period 2006–2007; p=0.013 and 0.035, respectively) (Table1).

3.5. Independent variables of the secondary outcomes

At a corrected age of 40weeks, death (n=19) or survival with intraventricular haemorrhage (n=19) was associated with period 2012–2015 (vs. period 2006–2007; p=0.001), antenatal glucocorticoid (p=0.003), gestational age (p<0.001), birth weight (p=0.002), Apgar scores at 1 and 5min (both p<0.001), surfactant replacement within 30min after birth (p=0.024), requirement for inotropes on day zero (p=0.005), indomethacin administration within 6h after birth (p=0.001), high humidifier setting (p=0.019) and delayed establishment of enteral feeding (p<0.001) (TableS1). In the multivariate model, death or survival with intraventricular haemorrhage was associated with the therapeutic regimen for periods 2008–2011 and 2012–2015, even after adjusting for gestational age, Apgar scores at 5min and sex (vs. period 2006–2007, p=0.009 and p<0.001, respectively) (Table4A).

Death before a corrected age of 2years was associated with periods 2008–2011 and 2012–2015 (vs. period 2006–2007, p=0.002 and p<0.001, respectively), antenatal glucocorticoid (p=0.004), gestational age (p<0.001), birth weight (p=0.008), Apgar scores at 1 and 5min (p=0.005 and p=0.003, respectively), early surfactant replacement (p<0.001), the requirement for inotropes on day zero (p=0.049), high humidifier setting (p<0.001), necrotising enterocolitis or intestinal perforation (p=0.002), use of gentamicin (vs. cefotaxime, p=0.004) and early commencement of parenteral nutrition (p<0.001, Fisher's exact test) (TableS2). In the multivariate model, death was dependent on the therapeutic regimen for periods 2008–2011 and 2012–2015 even after adjusting for gestational age, Apgar scores at 5min and male sex (vs. period 2006–2007, both p<0.001) (Table4B).

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