Adverse Outcomes Associations with chronic opiate exposure in VLBW neonates.

1
Adverse Outcomes Associations with chronic opiate
exposure in VLBW neonates.
Fahad Al-Sufayan MD , Ibrahim Ali MD , R J Baier
MD Department of Pediatrics and Child Health,
University of Manitoba
Abstract Background Morphine is widely used
frequently in mechanically ventilated VLBW
infants. The pharmacokinetics of morphine in VLBW
infants is different than pediatrics and adult
patients. There are still unanswered questions
about the safety of morphine in such vulnerable
group of infants. Hypotension, requiring volume
resuscitation or inotropes use ,is frequently
encountered in VLBW infants exposed to morphine.
There is a growing concern about the potential
negative impact of chronic morphine use on the
host immunity system and increased risk of
infection. Objective We sought to determine if
ventilated VLBW infants who are chronically
exposed to higher doses of morphine during the
first 2 weeks of life have a significant increase
in the incidence of adverse outcome namely BPD,
IVH, ROP, NEC and sepsis. Design/Methods A
retrospective study of 60 VLBW infants ( BW 937
227 g, GA 26.5 1.4 wks ) who required
ventilation for more than 7 days and admitted to
NICU from January 2000 through December 2005.
Cumulative morphine exposure (mg/kg) was recorded
daily for the duration of hospitalization.
Outcomes were analyzed according to cumulative
morphine exposure during the first 2 weeks of
life. Group 1 received lt 1.68 mg /kg /wk during
the first two weeks of life ( equivalent to lt
0.01 mg/kg/hr ) ,group 2 gt 1.68 mg / kg
/wk. Results There were no significant
differences between the 2 groups with regards to
gestation , BW, incidence of RDS , need for
surfactant, and incidence of PDA. SNAPPE II
scores were higher in group 2 ( 44.4 5.5 vs.
24.7 2.9 p 0.002 ).There was no differences
in the incidence of survival to discharge , the
use of oxygen at 28 days, ROP , any IVH ,Hospital
length of stay or bacteremia. However higher
exposure was significantly associated with use of
oxygen at 36 weeks corrected gestational age ( 10
vs. 8 p0.03 ) , time to achieve full feeding (
17 vs. 36 p0.006 ) , any NEC , NEC stage II
III ( 14 vs. 3 p lt0.001 ) , hypotension ( 22
vs. 26 p0.02 ) , use of volume expansion for
hypotension ( 22 vs. 20 plt0.001 ) , inotrope
use ( 21 vs. 23 p 0.016 ) , steroids to treat
hypotension ( 19 vs. 12 plt0.001 ) , and
multiple bacteremia ( 6 vs. 1 p 0.024 ).There
were trend toward sepsis related mortality ( 4
vs. 1 p 0.06 ) , severe IVH ( 10 vs. 26
p0.058 ).Using multivariate (logistic regression
) analysis , comparing effects of BW, GA and
SNAPPE II score , the cumulative morphine
exposure remained a significant predictor of NEC
, delayed achievement of full feeding ,
hypotension , volume and steroids for
hypotension. Conclusion Use of higher morphine
during the first 2 weeks of life is associated
with increased risk of NEC, hypotension and
multiple bacteremia, independent of BW , GA , and
SNAPPE II score. In VLBW,chronic use of morphine
greater than 0.01 mg / kg / hour for long periods
may not be recommended.

• Statistical Analysis
• Infants divided into 2 groups according to opiate
  exposure (High Exposure)gt1.68mg/kg/week (Low
  Exposure) lt1.68mg/kg/week.
• Cumulative opiate exposure expressed as mg/kg
  morphine equivalents.
• Univariate analysis consist of Chi-square,
  student t test, and Mann-Whitney U test .
• Multivariate regression analysis used to adjust
  for confounders (birth weight, gestational age,
  and SNAPPE score).
• Data expressed as mean SEM.
• P lt 0.05 was deemed statistically significant.
• Data analysis done by SPSS version 15.0 (SPSS,
  Chicago, IL)

Effects of Opiate Exposure on CNS outcomes
Organisms Causing sepsis
Effects of Opiate Exposure on Survival
Results
Characteristics of High and Low Opiate Exposure
groups
Effects of Opiate Exposure on Infectious
Complications

• Introduction
• Premature infants experience and sense pain
• Morphine and other opiates are widely used as
  sedative/analgesics in many NICUs
• Very little is known about the safety of
  prolonged morphine use
• Opiates have significant immuno-modulatory effects

• Conclusions
• Chronic use of morphine in a dose higher than
  1.68 mg/kg/week (equivalent to 0.01mg/kg/hour) is
  associated with
• Increased incidence of multiple bacteremia
• Increased sepsis related mortality
• Increased incidence of hypotension and need
  for inotrope support
• Increased incidence of severe IVH
• Increased incidence ofl aser for ROP
• Delay in establishing enteral feeds feeding
  intolerance
• Increased incidence of stage II III NEC
• Recommendation
• The benefits of chronic morphine use in VLBW
  infants in a dose gt 0.01mg/kg/hour need to be
  balanced against the risks of increased
  complications.
• Acknowledgments
• We are grateful for the support of Manitoba
  Institute of Child Health Inc.

Effects of Opiate Exposure on Hypotension

• Methods
• Retrospective study of 60 very low birth weight
  (VLBW) infants admitted to 2 level III NICUs
  Over a 3-year period (2002 to 2005 )
• Inclusion criteria
• Birth weight lt1500 grams.
• Between 24 and 32 weeks of gestation
• Mechanical Ventilation for 7 days.
• Exclusion Criteria
• Major congenital anomalies
• Primary immune deficiency
• Maternal history of opioid addiction
• Cumulative opiate ( morphine equivalent) exposure
  was calculated daily for first 8 weeks if life