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Interleukin-6 concentrations in neonatal sepsis
CORRESPONDENCE
5
midazolam for sedation of anxious children undergoing laceration repair. Ann Emerg Med 1994; 24: 1074–79. Scheepers M, Scheepers B. Clough P. Midazolam via the intranasal route: an effective rescue medication for severe epilepsy in adults with a learning disability. Seizure 1998; 6: 509–13.
Sir—R C Scott and colleagues1 show that buccal administration of midazolam is easy and safe and has no substantial adverse effects. We have been prescribing midazolam for buccal use for the past 18 months. Midazolam was dispensed in ampoules (10 mg in 2 mL), which is recommended for intravenous or intramuscular use. We have conducted a retrospective study (November, 1997, to October, 1998) of the community use of buccal midazolam in children, aged 1–17 years, with prolonged or serial epileptic seizures. Data were obtained by questionnaire, and additional information was gathered from the case notes. Ten patients had been given 5–10 mg of buccal midazolam at least once (range one to 13 times per child). 78 episodes were treated with buccal midazolam, which was given 2–60 minutes after the onset of continuous or serial seizures by the child’s parent or guardian. In 68/78 (87%) episodes, seizures stopped within 2–20 min. The mean time from administration to the end of seizure was 6 min. In 61 (78%) episodes, seizures stopped within 10 min; the mean time to clinical response was 5 min for these episodes. An ambulance was called on 11/78 (14%) occasions. The child was taken to hospital on 13 occasions (17%) and admitted on nine occasions (12%). Nine of ten parents found buccal midazolam effective, all ten found it convenient to administer, but seven found drawing the midazolam up from the ampoule to be difficult. On seven occasions (9%) parents were concerned about poor respiratory effort. There were no serious adverse events. All patients had previously used rectal diazepam and seven of ten encountered difficulties on at least one occasion with rectal diazepam. Rectal diazepam is the most commonly used treatment for continuous or serial seizures before admission. It has its drawbacks: it is embarrassing to use in public places, and can be difficult to administer. Use of buccal midazolam, therefore, has a clear social and practical advantage over rectal diazepam. In our experience buccal midazolam is a safe, effective and popular home treatment for prolonged or serial epileptic seizures. Buccal administration of midazolam may become the preferred treatment for seizures that occur outside hospital.
1798
A ready-to-administer preparation of liquid midazolam for buccal use might overcome the difficulty of drawing up of midazolam from ampoules. *Arijit Chattopadhyay, Bernie Morris, Louise Blackburn, Evangeline Wassmer, William Whitehouse Department of Paediatric Neurosciences, Diana, Princess of Wales Children’s Hospital, Birmingham B4 6NH, UK 1
Scott RC, Besag FMC, Neville BGR. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 1999; 353: 623–26.
Interleukin-6 concentrations in neonatal sepsis Sir—In their study of neonatal infection E E Önal and colleagues (Jan 16, p 239)1 report that interleukin6 was 74% sensitive, 91% specific, and had a positive predictive value (PPV) and negative predictive value (NPV) of 77% and 89%, respectively. There seems to be a mistake in these numbers and the only way to reconstruct a 2⫻2 table is if the values for PPV and NPV are transposed. They conclude that the measurement of interleukin-6 alone would be sufficiently sensitive to diagnose neonatal infection. We suggest that the sensitivity and NPV need to be much higher, particularly if the results of the interleukin-6 assay are meant to guide a decision to treat with antibiotics. In neonatal infection, it is vital that definite cases are not missed, and hence the NPV (and the sensitivity) should be as high as possible. Önal and colleagues report the 95% CI for NPV of 77% as 62–89%. The chance that a baby had infection before interleukin-6 was measured was 50%, the prevalence of infection in their cohort. There remained a chance of up to 38% that a baby who was negative for interleukin6 could still have had infection, an increase in diagnostic accuracy that is clinically marginal. Interleukin-6 is a rapid-response inflammatory protein with a short Undetectable plasma half-life. 2 concentrations may be measured in septic neonates at the time of suspected infection onset because the interleukin-6 concentration has already returned to baseline. By contrast, Creactive protein, an acute phase protein stimulated by interleukin-6 rises to abnormal concentrations in neonates 24–48 h after the onset of infection— time when interleukin-6 concentrations
may have already fallen to within the normal range. The combination of interleukin-6, an early marker of infection, with C-reactive protein (CRP), a later sepsis marker, may allow the clinician to monitor the evolution of neonatal infection and detect more accurately infected neonates. Studies that have measured interleukin-6 and CRP together show that the combination is more sensitive than either marker alone, with little change in the specificity, and hence few falsepositive results.3–5 Interleukin-6 alone is not sufficiently sensitive to make a diagnosis of neonatal infection; sensitivity can be increased by the addition of another sepsis marker, C-reactive protein. *S Mehr, L Doyle Division of Newborn Services, Royal Women’s Hospital, Melbourne, Carlton Victoria 3053, Australia 1
Önal EE, Kitapci F, Dilmen U, et al. Interleukin-6 concentration in neonatal sepsis. Lancet 1999; 353: 239–40. 2 Ng PC, Cheng SH, Chui KM, et al. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and Creactive protein in preterm very low birthweight infants. Arch Dis Child 1997; 77: F221–27. 3 Edgar JDM, Wilson DC, McMillan SA, et al. Predictive value of soluble immunological mediators in neonatal infection. Clin Sci 1994; 87: 165–71. 4 Messer J, Eyer D, Donato L, et al. Evaluation of interleukin-6 and soluble receptors of tumour necrosis factor for early diagnosis of neonatal infection. J Pediatr 1996; 129: 574–80. 5 Doellner H, Arntzen KJ, Haereid PE, et al. Interleukin-6 concentrations in neonates evaluated for sepsis. J Pediatr 1998; 132: 295–99.
Authors’ reply Sir—We reviewed our statistical analysis, and the cross table of our data is shown below: Interleukin-6 (pg/mL)
Sepsis
No sepsis
Total
肁20 <20 Total
31 3 34
9 25 34
40 28 68
From this cross table sensitivity (true positivity) which means the ratio of a positive test in the patient with sepsis is 92%. Specificity (false positivity), which means the ratio of negative test in patients without sepsis is 73·5%. Negative predictive value is the probability of the true result of the negative test. If interleukin-6 concentration is below 20 pg/mL (negative test), the probability that the patient does not have sepsis is 89% (25/28). Interleukin-6 is produced by Thelper type 2 cells, monocytes, macrophages, and endothelial cells,
THE LANCET • Vol 353 • May 22, 1999
5
midazolam for sedation of anxious children undergoing laceration repair. Ann Emerg Med 1994; 24: 1074–79. Scheepers M, Scheepers B. Clough P. Midazolam via the intranasal route: an effective rescue medication for severe epilepsy in adults with a learning disability. Seizure 1998; 6: 509–13.
Sir—R C Scott and colleagues1 show that buccal administration of midazolam is easy and safe and has no substantial adverse effects. We have been prescribing midazolam for buccal use for the past 18 months. Midazolam was dispensed in ampoules (10 mg in 2 mL), which is recommended for intravenous or intramuscular use. We have conducted a retrospective study (November, 1997, to October, 1998) of the community use of buccal midazolam in children, aged 1–17 years, with prolonged or serial epileptic seizures. Data were obtained by questionnaire, and additional information was gathered from the case notes. Ten patients had been given 5–10 mg of buccal midazolam at least once (range one to 13 times per child). 78 episodes were treated with buccal midazolam, which was given 2–60 minutes after the onset of continuous or serial seizures by the child’s parent or guardian. In 68/78 (87%) episodes, seizures stopped within 2–20 min. The mean time from administration to the end of seizure was 6 min. In 61 (78%) episodes, seizures stopped within 10 min; the mean time to clinical response was 5 min for these episodes. An ambulance was called on 11/78 (14%) occasions. The child was taken to hospital on 13 occasions (17%) and admitted on nine occasions (12%). Nine of ten parents found buccal midazolam effective, all ten found it convenient to administer, but seven found drawing the midazolam up from the ampoule to be difficult. On seven occasions (9%) parents were concerned about poor respiratory effort. There were no serious adverse events. All patients had previously used rectal diazepam and seven of ten encountered difficulties on at least one occasion with rectal diazepam. Rectal diazepam is the most commonly used treatment for continuous or serial seizures before admission. It has its drawbacks: it is embarrassing to use in public places, and can be difficult to administer. Use of buccal midazolam, therefore, has a clear social and practical advantage over rectal diazepam. In our experience buccal midazolam is a safe, effective and popular home treatment for prolonged or serial epileptic seizures. Buccal administration of midazolam may become the preferred treatment for seizures that occur outside hospital.
1798
A ready-to-administer preparation of liquid midazolam for buccal use might overcome the difficulty of drawing up of midazolam from ampoules. *Arijit Chattopadhyay, Bernie Morris, Louise Blackburn, Evangeline Wassmer, William Whitehouse Department of Paediatric Neurosciences, Diana, Princess of Wales Children’s Hospital, Birmingham B4 6NH, UK 1
Scott RC, Besag FMC, Neville BGR. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 1999; 353: 623–26.
Interleukin-6 concentrations in neonatal sepsis Sir—In their study of neonatal infection E E Önal and colleagues (Jan 16, p 239)1 report that interleukin6 was 74% sensitive, 91% specific, and had a positive predictive value (PPV) and negative predictive value (NPV) of 77% and 89%, respectively. There seems to be a mistake in these numbers and the only way to reconstruct a 2⫻2 table is if the values for PPV and NPV are transposed. They conclude that the measurement of interleukin-6 alone would be sufficiently sensitive to diagnose neonatal infection. We suggest that the sensitivity and NPV need to be much higher, particularly if the results of the interleukin-6 assay are meant to guide a decision to treat with antibiotics. In neonatal infection, it is vital that definite cases are not missed, and hence the NPV (and the sensitivity) should be as high as possible. Önal and colleagues report the 95% CI for NPV of 77% as 62–89%. The chance that a baby had infection before interleukin-6 was measured was 50%, the prevalence of infection in their cohort. There remained a chance of up to 38% that a baby who was negative for interleukin6 could still have had infection, an increase in diagnostic accuracy that is clinically marginal. Interleukin-6 is a rapid-response inflammatory protein with a short Undetectable plasma half-life. 2 concentrations may be measured in septic neonates at the time of suspected infection onset because the interleukin-6 concentration has already returned to baseline. By contrast, Creactive protein, an acute phase protein stimulated by interleukin-6 rises to abnormal concentrations in neonates 24–48 h after the onset of infection— time when interleukin-6 concentrations
may have already fallen to within the normal range. The combination of interleukin-6, an early marker of infection, with C-reactive protein (CRP), a later sepsis marker, may allow the clinician to monitor the evolution of neonatal infection and detect more accurately infected neonates. Studies that have measured interleukin-6 and CRP together show that the combination is more sensitive than either marker alone, with little change in the specificity, and hence few falsepositive results.3–5 Interleukin-6 alone is not sufficiently sensitive to make a diagnosis of neonatal infection; sensitivity can be increased by the addition of another sepsis marker, C-reactive protein. *S Mehr, L Doyle Division of Newborn Services, Royal Women’s Hospital, Melbourne, Carlton Victoria 3053, Australia 1
Önal EE, Kitapci F, Dilmen U, et al. Interleukin-6 concentration in neonatal sepsis. Lancet 1999; 353: 239–40. 2 Ng PC, Cheng SH, Chui KM, et al. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and Creactive protein in preterm very low birthweight infants. Arch Dis Child 1997; 77: F221–27. 3 Edgar JDM, Wilson DC, McMillan SA, et al. Predictive value of soluble immunological mediators in neonatal infection. Clin Sci 1994; 87: 165–71. 4 Messer J, Eyer D, Donato L, et al. Evaluation of interleukin-6 and soluble receptors of tumour necrosis factor for early diagnosis of neonatal infection. J Pediatr 1996; 129: 574–80. 5 Doellner H, Arntzen KJ, Haereid PE, et al. Interleukin-6 concentrations in neonates evaluated for sepsis. J Pediatr 1998; 132: 295–99.
Authors’ reply Sir—We reviewed our statistical analysis, and the cross table of our data is shown below: Interleukin-6 (pg/mL)
Sepsis
No sepsis
Total
肁20 <20 Total
31 3 34
9 25 34
40 28 68
From this cross table sensitivity (true positivity) which means the ratio of a positive test in the patient with sepsis is 92%. Specificity (false positivity), which means the ratio of negative test in patients without sepsis is 73·5%. Negative predictive value is the probability of the true result of the negative test. If interleukin-6 concentration is below 20 pg/mL (negative test), the probability that the patient does not have sepsis is 89% (25/28). Interleukin-6 is produced by Thelper type 2 cells, monocytes, macrophages, and endothelial cells,
THE LANCET • Vol 353 • May 22, 1999