IV acetaminophen lowered postop morphine need in neonates, infants

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.

Neonates and infants given intravenous acetaminophen as the primary analgesic during the 48 hours after major surgery required a 66% lower cumulative morphine dose than did those given a continuous morphine infusion as the primary analgesic, according to a report in the Jan. 9 issue of JAMA.

Patients given IV acetaminophen (paracetamol) achieved a level of analgesia similar to that of patients given a morphine infusion, judging by their equivalent need for rescue doses of morphine and their equivalent scores on two rating scales of pain and discomfort, reported Dr. Ilse Ceelie of the departments of intensive care and pediatric surgery at Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, and her associates.

"These results suggest that IV paracetamol may be an interesting alternative as primary analgesic in neonates and infants," they said.

Acetaminophen’s opioid-sparing effect has been demonstrated in older children and adults, but only two studies have assessed the drug’s opioid-sparing effect following surgery in the infant age group. Both of these studies used acetaminophen as an add-on therapy rather than as the primary analgesic, and they yielded conflicting results.

So Dr. Ceelie and her colleagues performed a single-center, randomized clinical trial to determine whether IV acetaminophen would reduce the cumulative morphine dose by at least 30%. They assessed 74 children younger than 1 year who were undergoing major abdominal or thoracic (but noncardiac) surgery during a 2-year period.

All the study subjects had been born at 37 weeks or later and weighed more than 1,500 g at the time of surgery. The most frequent procedures were closures of congenital diaphragmatic hernia, repair of intestinal atresia, and repair of esophageal atresia. All patients were given a loading dose of morphine 30 minutes before their surgery was expected to conclude. After the procedure they were transferred to the ICU, where the study medication was begun within 5 minutes.

Patients were randomly assigned in a double-blind fashion to receive either IV acetaminophen plus a placebo infusion mimicking morphine infusion (35 subjects) or a morphine infusion plus a placebo IV mimicking an acetaminophen drip (39 subjects). They were closely monitored for pain and distress by ICU nurses using the Numeric Rating Scale-11 and COMFORT-Behavior Scale. In addition, the surgeons computed a surgical stress score for each patient.

If discomfort was noted, midazolam was initiated. If pain was noted, rescue morphine boluses were administered as needed; if they were not sufficient, the maximum dose of morphine was given or the patient was switched to fentanyl.

The primary endpoint of the study was the cumulative dose of morphine – the sum of the intraoperative loading dose, the study dose of morphine (if applicable), and any rescue doses of morphine (if applicable).

The mean cumulative dose of morphine was 121 mcg/kg per 48 hours in the acetaminophen group, which was 66% lower than the mean cumulative dose of 357 mcg/kg per 48 hours in the morphine group, Dr. Ceelie and her associates reported (JAMA 2013;309;149-54).

The investigators also analyzed the data after dividing the study subjects into two age groups: those aged 0-10 days and those aged 11 days to 1 year. This was because "there are major changes in the pharmacokinetics of morphine during the first 10 days of life," but only minor changes thereafter.

In this analysis, the cumulative dose of morphine in the acetaminophen group (median, 111 mcg/kg per 48 hours) was 49% lower than that in the morphine group (median, 218 mcg/kg per 48 hours) among the neonates (aged 0-10 days). Among patients aged 11 days to 1 year, the difference in the cumulative dose of morphine was even more striking: The median was 152 mcg/kg/48 hours in the acetaminophen group and 553 in the morphine group, a difference of 73%.

The acetaminophen and morphine groups did not differ significantly in the total dose of rescue morphine, the number of morphine rescue doses, or the number of patients requiring rescue doses. In addition, the median scores on the two measures of pain and discomfort were similar between the two groups.

The overall rate of adverse effects was higher, but not significantly so, for morphine (34.2%) than for acetaminophen (27.3%). However, naloxone was administered to three infants in the morphine group because of respiratory depression, whereas none of the patients in the acetaminophen group developed respiratory depression.

"Despite the lack of statistical significance for this and other adverse effects, this observation does suggest a potential reduction in respiratory depression with use of acetaminophen," the researchers noted.

There were no cases of seizures, hypotension, or gastrointestinal adverse effects, they added.

Neonates have a lower risk of acetaminophen-induced hepatotoxicity than do older children and adults because the enzymes, such as CYP2E1, necessary for the hepatotoxic metabolite to develop are still immature, the researchers noted.

This study was limited in that it involved a strictly defined patient population at a single medical center, so the findings may not be widely generalizable. Moreover, liver function was not monitored in the acetaminophen group, and the study was underpowered to detect a difference in adverse effects, which "limits our ability to determine which treatment was safest," Dr. Ceelie and her colleagues said.

The study was supported by a grant from ZonMw Priority Medicines for Children. The authors reported no potential conflicts of interest.