Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results

Ratings of Teamwork and Perceptions of SIDR

As shown in Figure 1, a larger percentage of nurses rated the quality of communication and collaboration with hospitalists as high or very high on the intervention unit compared to the control unit (80% vs. 54%; P = 0.05).

Figure 1

Nurses' ratings of the teamwork and safety climate are summarized in Table 2. The median teamwork climate score was 85.7 (interquartile range [IQR], 75.092.9) for the intervention unit as compared to 61.6 (IQR, 48.283.9) for the control unit (P = 0.008). The median safety climate score was 75.0 (IQR, 70.581.3) for the intervention unit as compared to 61.1 (IQR, 30.281.3) for the control unit (P = 0.03).

Table 2.Nurses' Ratings of Teamwork and Patient Safety Climate by Unit

	Control Unit, n = 24	Intervention Unit, n = 25	P Value
Abbreviation: IQR, interquartile range.
Median Teamwork Climate Score (IQR)	75.0 (70.581.3)	61.6 (48.283.9)	0.008
Median Safety Climate Score (IQR)	85.7 (75.092.9)	61.1 (30.281.3)	0.03

Sixty‐five of 88 (74%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved the efficiency of their work day. Eighty of 88 (91%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved team collaboration. Seventy‐six of 88 (86%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved patient care. Sixty‐seven of 88 (76%) hospitalists and 22 of 25 (88%) nurses indicated that they wanted SIDR to continue indefinitely.

Discussion

We found that nurses working on a unit using SIDR rated the quality of communication and collaboration with hospitalists significantly higher as compared to a control unit. Notably, because hospitalists worked on both the intervention and control unit during their weeks on service, nurses on each unit were rating the quality of collaboration with the same hospitalists. Nurses also rated the teamwork and safety climate higher on the intervention unit. These findings are important because prior research has shown that nurses are often dissatisfied with the quality of collaboration and teamwork with physicians.68 Potential explanations include fundamental differences between nurses and physicians with regard to status/authority, gender, training, and patient care responsibilities.6 Unfortunately, a culture of poor teamwork may lead to a workplace in which team members feel unable to approach certain individuals and uncomfortable raising concerns. Not surprisingly, higher ratings of teamwork culture have been associated with nurse retention.22, 23 SIDR provided a facilitated forum for interdisciplinary discussion, exchange of critical clinical information, and collaboration on the plan of care.

Our findings are also important because poor communication represents a major etiology of preventable adverse events in hospitals.15 Higher ratings of collaboration and teamwork have been associated with better patient outcomes in observational studies.2426 Further research should evaluate the impact of improved interdisciplinary collaboration as a result of SIDR on the safety of care delivered on inpatient medical units.

The majority of providers agreed that SIDR improved patient care and that SIDR should continue indefinitely. Importantly, providers also felt that SIDR improved the efficiency of their workday and attendance was high among all disciplines. Prior studies on IDR either did not report attendance or struggled with attendance.11 Incorporating the input of frontline providers into the design of SIDR allowed us to create a sustainable intervention which fit into daily workflow.

Our bivariate analyses found significant patient case‐mix differences between the intervention and control unit, limiting our ability to perform direct comparisons in LOS and cost. Pre‐post analyses of LOS and cost may be affected by cyclical or secular trends. Because each approach has its own limitations, we felt that analyses using both an historic as well as a concurrent control would provide a more complete assessment of the effect of the intervention. We included case mix, among other variables, in out multivariable regression analyses and found no benefit to SIDR with regard to LOS and cost. Two prior studies have shown a reduction in LOS and cost with the use of IDR.12, 13 However, one study was conducted approximately 15 years ago and included patients with a longer mean LOS.12 The second study used a pre‐post study design which may not have accounted for unmeasured confounders affecting LOS and cost.13 A third, smaller study showed no effect on LOS and cost with the use of IDR.15 No prior study has evaluated the effect of IDR on LOS and cost in a nonteaching hospitalist service setting.

Our study has several limitations. First, our study reflects the experience of an intervention unit compared to a control unit in a single hospital. Larger studies will be required to test the reproducibility and generalizability of our findings. Second, we did not conduct preintervention provider surveys for comparison ratings of collaboration and teamwork. A prior study, conducted by our research group, found that nurses gave low ratings to the teamwork climate and the quality of collaboration with hospitalists.8 Because this baseline study showed consistently low nurse ratings of collaboration and teamwork across all medical units, and because the units in the current study were identical in size, structure, and staffing of nonphysician personnel, we did not repeat nurse surveys prior to the intervention. Third, as previously mentioned, our study did not directly assess the effect of improved teamwork and collaboration on patient safety. Further study is needed to evaluate this. Although we are not aware of any other interventions to improve interdisciplinary communication on the intervention unit, it is possible that other unknown factors contributed to our findings. We believe this is unlikely due to the magnitude of the improvement in collaboration and the high ratings of SIDR by nurses and physicians on the intervention unit.

In summary, SIDR had a positive effect on nurses' ratings of collaboration and teamwork on a nonteaching hospitalist unit. Future research efforts should assess whether improved teamwork as a result of SIDR also translates into safer patient care.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results

Ratings of Teamwork and Perceptions of SIDR

As shown in Figure 1, a larger percentage of nurses rated the quality of communication and collaboration with hospitalists as high or very high on the intervention unit compared to the control unit (80% vs. 54%; P = 0.05).

Figure 1

Nurses' ratings of the teamwork and safety climate are summarized in Table 2. The median teamwork climate score was 85.7 (interquartile range [IQR], 75.092.9) for the intervention unit as compared to 61.6 (IQR, 48.283.9) for the control unit (P = 0.008). The median safety climate score was 75.0 (IQR, 70.581.3) for the intervention unit as compared to 61.1 (IQR, 30.281.3) for the control unit (P = 0.03).

Table 2.Nurses' Ratings of Teamwork and Patient Safety Climate by Unit

	Control Unit, n = 24	Intervention Unit, n = 25	P Value
Abbreviation: IQR, interquartile range.
Median Teamwork Climate Score (IQR)	75.0 (70.581.3)	61.6 (48.283.9)	0.008
Median Safety Climate Score (IQR)	85.7 (75.092.9)	61.1 (30.281.3)	0.03

Sixty‐five of 88 (74%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved the efficiency of their work day. Eighty of 88 (91%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved team collaboration. Seventy‐six of 88 (86%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved patient care. Sixty‐seven of 88 (76%) hospitalists and 22 of 25 (88%) nurses indicated that they wanted SIDR to continue indefinitely.

Discussion

We found that nurses working on a unit using SIDR rated the quality of communication and collaboration with hospitalists significantly higher as compared to a control unit. Notably, because hospitalists worked on both the intervention and control unit during their weeks on service, nurses on each unit were rating the quality of collaboration with the same hospitalists. Nurses also rated the teamwork and safety climate higher on the intervention unit. These findings are important because prior research has shown that nurses are often dissatisfied with the quality of collaboration and teamwork with physicians.68 Potential explanations include fundamental differences between nurses and physicians with regard to status/authority, gender, training, and patient care responsibilities.6 Unfortunately, a culture of poor teamwork may lead to a workplace in which team members feel unable to approach certain individuals and uncomfortable raising concerns. Not surprisingly, higher ratings of teamwork culture have been associated with nurse retention.22, 23 SIDR provided a facilitated forum for interdisciplinary discussion, exchange of critical clinical information, and collaboration on the plan of care.

Our findings are also important because poor communication represents a major etiology of preventable adverse events in hospitals.15 Higher ratings of collaboration and teamwork have been associated with better patient outcomes in observational studies.2426 Further research should evaluate the impact of improved interdisciplinary collaboration as a result of SIDR on the safety of care delivered on inpatient medical units.

The majority of providers agreed that SIDR improved patient care and that SIDR should continue indefinitely. Importantly, providers also felt that SIDR improved the efficiency of their workday and attendance was high among all disciplines. Prior studies on IDR either did not report attendance or struggled with attendance.11 Incorporating the input of frontline providers into the design of SIDR allowed us to create a sustainable intervention which fit into daily workflow.

Our bivariate analyses found significant patient case‐mix differences between the intervention and control unit, limiting our ability to perform direct comparisons in LOS and cost. Pre‐post analyses of LOS and cost may be affected by cyclical or secular trends. Because each approach has its own limitations, we felt that analyses using both an historic as well as a concurrent control would provide a more complete assessment of the effect of the intervention. We included case mix, among other variables, in out multivariable regression analyses and found no benefit to SIDR with regard to LOS and cost. Two prior studies have shown a reduction in LOS and cost with the use of IDR.12, 13 However, one study was conducted approximately 15 years ago and included patients with a longer mean LOS.12 The second study used a pre‐post study design which may not have accounted for unmeasured confounders affecting LOS and cost.13 A third, smaller study showed no effect on LOS and cost with the use of IDR.15 No prior study has evaluated the effect of IDR on LOS and cost in a nonteaching hospitalist service setting.

Our study has several limitations. First, our study reflects the experience of an intervention unit compared to a control unit in a single hospital. Larger studies will be required to test the reproducibility and generalizability of our findings. Second, we did not conduct preintervention provider surveys for comparison ratings of collaboration and teamwork. A prior study, conducted by our research group, found that nurses gave low ratings to the teamwork climate and the quality of collaboration with hospitalists.8 Because this baseline study showed consistently low nurse ratings of collaboration and teamwork across all medical units, and because the units in the current study were identical in size, structure, and staffing of nonphysician personnel, we did not repeat nurse surveys prior to the intervention. Third, as previously mentioned, our study did not directly assess the effect of improved teamwork and collaboration on patient safety. Further study is needed to evaluate this. Although we are not aware of any other interventions to improve interdisciplinary communication on the intervention unit, it is possible that other unknown factors contributed to our findings. We believe this is unlikely due to the magnitude of the improvement in collaboration and the high ratings of SIDR by nurses and physicians on the intervention unit.

In summary, SIDR had a positive effect on nurses' ratings of collaboration and teamwork on a nonteaching hospitalist unit. Future research efforts should assess whether improved teamwork as a result of SIDR also translates into safer patient care.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results

Ratings of Teamwork and Perceptions of SIDR

As shown in Figure 1, a larger percentage of nurses rated the quality of communication and collaboration with hospitalists as high or very high on the intervention unit compared to the control unit (80% vs. 54%; P = 0.05).

Figure 1

Nurses' ratings of the teamwork and safety climate are summarized in Table 2. The median teamwork climate score was 85.7 (interquartile range [IQR], 75.092.9) for the intervention unit as compared to 61.6 (IQR, 48.283.9) for the control unit (P = 0.008). The median safety climate score was 75.0 (IQR, 70.581.3) for the intervention unit as compared to 61.1 (IQR, 30.281.3) for the control unit (P = 0.03).

Table 2.Nurses' Ratings of Teamwork and Patient Safety Climate by Unit

	Control Unit, n = 24	Intervention Unit, n = 25	P Value
Abbreviation: IQR, interquartile range.
Median Teamwork Climate Score (IQR)	75.0 (70.581.3)	61.6 (48.283.9)	0.008
Median Safety Climate Score (IQR)	85.7 (75.092.9)	61.1 (30.281.3)	0.03

Sixty‐five of 88 (74%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved the efficiency of their work day. Eighty of 88 (91%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved team collaboration. Seventy‐six of 88 (86%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved patient care. Sixty‐seven of 88 (76%) hospitalists and 22 of 25 (88%) nurses indicated that they wanted SIDR to continue indefinitely.

Discussion

We found that nurses working on a unit using SIDR rated the quality of communication and collaboration with hospitalists significantly higher as compared to a control unit. Notably, because hospitalists worked on both the intervention and control unit during their weeks on service, nurses on each unit were rating the quality of collaboration with the same hospitalists. Nurses also rated the teamwork and safety climate higher on the intervention unit. These findings are important because prior research has shown that nurses are often dissatisfied with the quality of collaboration and teamwork with physicians.68 Potential explanations include fundamental differences between nurses and physicians with regard to status/authority, gender, training, and patient care responsibilities.6 Unfortunately, a culture of poor teamwork may lead to a workplace in which team members feel unable to approach certain individuals and uncomfortable raising concerns. Not surprisingly, higher ratings of teamwork culture have been associated with nurse retention.22, 23 SIDR provided a facilitated forum for interdisciplinary discussion, exchange of critical clinical information, and collaboration on the plan of care.

Our findings are also important because poor communication represents a major etiology of preventable adverse events in hospitals.15 Higher ratings of collaboration and teamwork have been associated with better patient outcomes in observational studies.2426 Further research should evaluate the impact of improved interdisciplinary collaboration as a result of SIDR on the safety of care delivered on inpatient medical units.

The majority of providers agreed that SIDR improved patient care and that SIDR should continue indefinitely. Importantly, providers also felt that SIDR improved the efficiency of their workday and attendance was high among all disciplines. Prior studies on IDR either did not report attendance or struggled with attendance.11 Incorporating the input of frontline providers into the design of SIDR allowed us to create a sustainable intervention which fit into daily workflow.

Our bivariate analyses found significant patient case‐mix differences between the intervention and control unit, limiting our ability to perform direct comparisons in LOS and cost. Pre‐post analyses of LOS and cost may be affected by cyclical or secular trends. Because each approach has its own limitations, we felt that analyses using both an historic as well as a concurrent control would provide a more complete assessment of the effect of the intervention. We included case mix, among other variables, in out multivariable regression analyses and found no benefit to SIDR with regard to LOS and cost. Two prior studies have shown a reduction in LOS and cost with the use of IDR.12, 13 However, one study was conducted approximately 15 years ago and included patients with a longer mean LOS.12 The second study used a pre‐post study design which may not have accounted for unmeasured confounders affecting LOS and cost.13 A third, smaller study showed no effect on LOS and cost with the use of IDR.15 No prior study has evaluated the effect of IDR on LOS and cost in a nonteaching hospitalist service setting.

Our study has several limitations. First, our study reflects the experience of an intervention unit compared to a control unit in a single hospital. Larger studies will be required to test the reproducibility and generalizability of our findings. Second, we did not conduct preintervention provider surveys for comparison ratings of collaboration and teamwork. A prior study, conducted by our research group, found that nurses gave low ratings to the teamwork climate and the quality of collaboration with hospitalists.8 Because this baseline study showed consistently low nurse ratings of collaboration and teamwork across all medical units, and because the units in the current study were identical in size, structure, and staffing of nonphysician personnel, we did not repeat nurse surveys prior to the intervention. Third, as previously mentioned, our study did not directly assess the effect of improved teamwork and collaboration on patient safety. Further study is needed to evaluate this. Although we are not aware of any other interventions to improve interdisciplinary communication on the intervention unit, it is possible that other unknown factors contributed to our findings. We believe this is unlikely due to the magnitude of the improvement in collaboration and the high ratings of SIDR by nurses and physicians on the intervention unit.

In summary, SIDR had a positive effect on nurses' ratings of collaboration and teamwork on a nonteaching hospitalist unit. Future research efforts should assess whether improved teamwork as a result of SIDR also translates into safer patient care.

Malignant Otitis Externa (MOE) is a necrotizing infection of the external auditory canal characterized by extension into nearby soft tissue and bony structures that can potentially lead to mastoiditis, skull base osteomyelitis, cranial nerve palsies, and rarely, intracranial complications. MOE has been classically described as a disease affecting elderly diabetics1 and has been reported in immunocompromised patients with acquired immune deficiency syndrome (AIDS), malignancy, patients receiving chemotherapy, and neutropenic children.24 The incidence of MOE in the general population is estimated to be quite low and difficult to determine.5 However, over the past decades, the number of reported cases has been increasing, suggesting increased awareness of this syndrome by primary care physicians.6

Case Report

A 56‐year‐old white male was brought to the emergency department with altered mental status including decreased level of consciousness, bizarre behavior, headaches, and nausea for several weeks. He had a history of alcohol and cocaine abuse. He was homeless and a smoker. On examination, the patient was lethargic, disoriented with respect to time, place and person. Blood pressure was 107/72 mm Hg, heart rate 85 beats per minute; respirations were 16 per minute and temperature was 97.9F. Neurological examination was significant for loss of vision of the left eye and left facial peripheral nerve palsy. Examination of the left eye showed yellowish‐greenish discharge, a lower lid ectropium with upper lid ptosis, conjunctival erythema, and an 8 mm 6 mm abrasion in the medial half of the cornea. He had purulent drainage from the left ear with small vesicular lesions on the auricle, and a 3 cm 4 cm abscess on the right forearm. The remainder of the physical examination was unremarkable.

Laboratory‐test results showed white blood cell (WBC) count; 11.27 10⁹ cells/L with 76.6% neutrophils. A complete metabolic panel was within normal limits. Human immunodeficiency virus (HIV) and RPR testing were negative. Cerebrospinal fluid (CSF) studies demonstrated a WBC 39 cells/mm³ with lymphocytes predominance (85%), Red blood cell (RBC) 6 cells/mm³, protein 48 mg/dL, and glucose; 63 mg/dL. Computed tomographic scan of the head revealed an area of low attenuation with surrounding edema of the left temporal lobe and fracture of the temporal bone on the superior margin of the mastoid air cells extending into the left mastoid air cells (Figure 1). The fluid draining from the patient's left ear grew 2 different strains of Pseudomonas aeruginosa. Magnetic resonance imaging (MRI) of the brain demonstrated a 2.5 cm to 3.0 cm region of multiple loculations and edema in the left temporal lobe representing cerebritis with abscess and complete opacification of left mastoid air cell suggestive of mastoiditis (Figure 2). Piperacillin/tazobactam and tobramycin were initiated for suspected MOE with brain involvement. CSF and blood cultures were negative.

Figure 1

Figure 2

A repeat MRI at 3 weeks of therapy demonstrated interval improvement in the temporal lobe abscess and the edema surrounding the infection. At the time of discharge, after 6 weeks of antimicrobial therapy, the patient was alert and oriented with respect to person, place, and time.

Discussion

Pseudomonas aeruginosa is the most common organism cultured from MOE.4, 5 Other organisms such as Staphylococcus aureus,6 Proteus mirabilis, Klebsiella oxytocea,7 and Aspergillus species8 have been reported as well.

While the exact pathogenesis of MOE is poorly understood, accidental trauma from cotton swabs, exposure to lake water, swimming pool water, and repeated aural lavage have all been implicated as inciting factors.9 The current literature suggests that Pseudomonal otitis externa occurs due to abnormal host defense mechanisms rather than enhanced pathogen colonization.10

MOE typically presents with severe otalgia, headache, auricular tenderness, mastoid tenderness, or persistent otorrhea. The pain of MOE is usually severe, and the classic signs of infection such as fever, leukocytosis and neutrophil predominance (left shift) may not be present.5 The diagnosis can be confirmed by otoscopic exam which will demonstrate granulation tissue at the junction between the bony and cartilaginous tissues in the external auditory canal. MOE can produce certain physical findings that should raise red flags for local extension. Temporomandibular joint pain in the susceptible patient with otalgia could indicate MOE with joint invasion. Cranial nerve involvement, most commonly involves the seventh cranial nerve which results in a facial palsy. Other cranial neuropathies have been reported in MOE such as the glossopharyngeal, vagal, spinal accessory, and hypoglossal nerves.11 Confusion and nuchal rigidity should arouse suspicion of intracranial extension of the infection.

The diagnosis of MOE is usually made by a constellation of clinical, microbiological and radiological features. The first attempt at defining diagnostic criteria for MOE was in 1987, when Cohen and Friedman named several obligatory signs such as pain, exudate, edema, granulation tissue in the external ear canal, the presence of microabscesses if surgery is performed, and either a positive Tc‐99m bone scan or failure of local treatment for 1 week.12

Recent literature reviews emphasize that a positive bacterial or fungal culture of the external ear canal can help make the diagnosis of MOE.4 A recent study looking at diagnostic criteria noted that MOE may be present even without meeting all of these major criteria (clinical, microbiological, and radiological features).13 Some authors suggest that ear biopsy be considered if malignancy is a reasonable possibility.9

Other laboratory data can be within normal limits, such as a WBC count or differential and metabolic profiles.4 Erythrocyte sedimentation rate (ESR), while non‐specific, has been reported to be markedly increased in the setting of MOE.5 It is recommended that a baseline ESR be obtained, and then used to follow the response to treatment.14

Computed tomography (CT) scanning is considered the appropriate initial imaging study, however, there are mixed reports about whether a CT scan alone is enough to evaluate disease severity and its complications.15 While CT scan is quite sensitive for demonstrating bony destruction associated with MOE, MRI is better at detecting the soft tissue changes associated with MOE and more useful for following disease resolution after treatment.16

The treatment of MOE has evolved over time. Before the introduction of effective anti‐pseudomonal antibiotics, MOE had an associated mortality near 50%, and surgery was the recommended therapy.17 Currently, given the availability of effective anti‐pseudomonal therapy, there is usually no indication for surgery as a primary treatment in MOE. For sensitive pseudomonal species, oral Ciprofloxacin therapy for 6 to 8 weeks is considered the treatment of choice for MOE.18 Clinicians should be aware of the emergence of quinolone resistance in P. Aeruginosa,19 and antibiotic sensitivities should be performed on the culture to guide further treatment. In the setting of resistant or multi‐species infection, one should obtain external ear canal biopsy with wound debridement and begin long‐term intravenous therapy with an antipseudomonal beta‐lactam plus an aminoglycoside.18 In the setting of extension into the cranium causing cerebritis or abscess, it is recommended that a neurosurgeon be consulted immediately to determine whether the lesion is amenable to aspiration, excision, or watchful waiting with imaging follow up.

This case illustrates a serious complication from MOE, with ipsilateral facial nerve palsy, opthalmitis, mastoiditis, and cerebral abscess that was successfully treated with conservative medical management.

Malignant Otitis Externa (MOE) is a necrotizing infection of the external auditory canal characterized by extension into nearby soft tissue and bony structures that can potentially lead to mastoiditis, skull base osteomyelitis, cranial nerve palsies, and rarely, intracranial complications. MOE has been classically described as a disease affecting elderly diabetics1 and has been reported in immunocompromised patients with acquired immune deficiency syndrome (AIDS), malignancy, patients receiving chemotherapy, and neutropenic children.24 The incidence of MOE in the general population is estimated to be quite low and difficult to determine.5 However, over the past decades, the number of reported cases has been increasing, suggesting increased awareness of this syndrome by primary care physicians.6

Case Report

A 56‐year‐old white male was brought to the emergency department with altered mental status including decreased level of consciousness, bizarre behavior, headaches, and nausea for several weeks. He had a history of alcohol and cocaine abuse. He was homeless and a smoker. On examination, the patient was lethargic, disoriented with respect to time, place and person. Blood pressure was 107/72 mm Hg, heart rate 85 beats per minute; respirations were 16 per minute and temperature was 97.9F. Neurological examination was significant for loss of vision of the left eye and left facial peripheral nerve palsy. Examination of the left eye showed yellowish‐greenish discharge, a lower lid ectropium with upper lid ptosis, conjunctival erythema, and an 8 mm 6 mm abrasion in the medial half of the cornea. He had purulent drainage from the left ear with small vesicular lesions on the auricle, and a 3 cm 4 cm abscess on the right forearm. The remainder of the physical examination was unremarkable.

Laboratory‐test results showed white blood cell (WBC) count; 11.27 10⁹ cells/L with 76.6% neutrophils. A complete metabolic panel was within normal limits. Human immunodeficiency virus (HIV) and RPR testing were negative. Cerebrospinal fluid (CSF) studies demonstrated a WBC 39 cells/mm³ with lymphocytes predominance (85%), Red blood cell (RBC) 6 cells/mm³, protein 48 mg/dL, and glucose; 63 mg/dL. Computed tomographic scan of the head revealed an area of low attenuation with surrounding edema of the left temporal lobe and fracture of the temporal bone on the superior margin of the mastoid air cells extending into the left mastoid air cells (Figure 1). The fluid draining from the patient's left ear grew 2 different strains of Pseudomonas aeruginosa. Magnetic resonance imaging (MRI) of the brain demonstrated a 2.5 cm to 3.0 cm region of multiple loculations and edema in the left temporal lobe representing cerebritis with abscess and complete opacification of left mastoid air cell suggestive of mastoiditis (Figure 2). Piperacillin/tazobactam and tobramycin were initiated for suspected MOE with brain involvement. CSF and blood cultures were negative.

Figure 1

Figure 2

A repeat MRI at 3 weeks of therapy demonstrated interval improvement in the temporal lobe abscess and the edema surrounding the infection. At the time of discharge, after 6 weeks of antimicrobial therapy, the patient was alert and oriented with respect to person, place, and time.

Discussion

Pseudomonas aeruginosa is the most common organism cultured from MOE.4, 5 Other organisms such as Staphylococcus aureus,6 Proteus mirabilis, Klebsiella oxytocea,7 and Aspergillus species8 have been reported as well.

While the exact pathogenesis of MOE is poorly understood, accidental trauma from cotton swabs, exposure to lake water, swimming pool water, and repeated aural lavage have all been implicated as inciting factors.9 The current literature suggests that Pseudomonal otitis externa occurs due to abnormal host defense mechanisms rather than enhanced pathogen colonization.10

MOE typically presents with severe otalgia, headache, auricular tenderness, mastoid tenderness, or persistent otorrhea. The pain of MOE is usually severe, and the classic signs of infection such as fever, leukocytosis and neutrophil predominance (left shift) may not be present.5 The diagnosis can be confirmed by otoscopic exam which will demonstrate granulation tissue at the junction between the bony and cartilaginous tissues in the external auditory canal. MOE can produce certain physical findings that should raise red flags for local extension. Temporomandibular joint pain in the susceptible patient with otalgia could indicate MOE with joint invasion. Cranial nerve involvement, most commonly involves the seventh cranial nerve which results in a facial palsy. Other cranial neuropathies have been reported in MOE such as the glossopharyngeal, vagal, spinal accessory, and hypoglossal nerves.11 Confusion and nuchal rigidity should arouse suspicion of intracranial extension of the infection.

The diagnosis of MOE is usually made by a constellation of clinical, microbiological and radiological features. The first attempt at defining diagnostic criteria for MOE was in 1987, when Cohen and Friedman named several obligatory signs such as pain, exudate, edema, granulation tissue in the external ear canal, the presence of microabscesses if surgery is performed, and either a positive Tc‐99m bone scan or failure of local treatment for 1 week.12

Recent literature reviews emphasize that a positive bacterial or fungal culture of the external ear canal can help make the diagnosis of MOE.4 A recent study looking at diagnostic criteria noted that MOE may be present even without meeting all of these major criteria (clinical, microbiological, and radiological features).13 Some authors suggest that ear biopsy be considered if malignancy is a reasonable possibility.9

Other laboratory data can be within normal limits, such as a WBC count or differential and metabolic profiles.4 Erythrocyte sedimentation rate (ESR), while non‐specific, has been reported to be markedly increased in the setting of MOE.5 It is recommended that a baseline ESR be obtained, and then used to follow the response to treatment.14

Computed tomography (CT) scanning is considered the appropriate initial imaging study, however, there are mixed reports about whether a CT scan alone is enough to evaluate disease severity and its complications.15 While CT scan is quite sensitive for demonstrating bony destruction associated with MOE, MRI is better at detecting the soft tissue changes associated with MOE and more useful for following disease resolution after treatment.16

The treatment of MOE has evolved over time. Before the introduction of effective anti‐pseudomonal antibiotics, MOE had an associated mortality near 50%, and surgery was the recommended therapy.17 Currently, given the availability of effective anti‐pseudomonal therapy, there is usually no indication for surgery as a primary treatment in MOE. For sensitive pseudomonal species, oral Ciprofloxacin therapy for 6 to 8 weeks is considered the treatment of choice for MOE.18 Clinicians should be aware of the emergence of quinolone resistance in P. Aeruginosa,19 and antibiotic sensitivities should be performed on the culture to guide further treatment. In the setting of resistant or multi‐species infection, one should obtain external ear canal biopsy with wound debridement and begin long‐term intravenous therapy with an antipseudomonal beta‐lactam plus an aminoglycoside.18 In the setting of extension into the cranium causing cerebritis or abscess, it is recommended that a neurosurgeon be consulted immediately to determine whether the lesion is amenable to aspiration, excision, or watchful waiting with imaging follow up.

This case illustrates a serious complication from MOE, with ipsilateral facial nerve palsy, opthalmitis, mastoiditis, and cerebral abscess that was successfully treated with conservative medical management.

Malignant Otitis Externa (MOE) is a necrotizing infection of the external auditory canal characterized by extension into nearby soft tissue and bony structures that can potentially lead to mastoiditis, skull base osteomyelitis, cranial nerve palsies, and rarely, intracranial complications. MOE has been classically described as a disease affecting elderly diabetics1 and has been reported in immunocompromised patients with acquired immune deficiency syndrome (AIDS), malignancy, patients receiving chemotherapy, and neutropenic children.24 The incidence of MOE in the general population is estimated to be quite low and difficult to determine.5 However, over the past decades, the number of reported cases has been increasing, suggesting increased awareness of this syndrome by primary care physicians.6

Case Report

A 56‐year‐old white male was brought to the emergency department with altered mental status including decreased level of consciousness, bizarre behavior, headaches, and nausea for several weeks. He had a history of alcohol and cocaine abuse. He was homeless and a smoker. On examination, the patient was lethargic, disoriented with respect to time, place and person. Blood pressure was 107/72 mm Hg, heart rate 85 beats per minute; respirations were 16 per minute and temperature was 97.9F. Neurological examination was significant for loss of vision of the left eye and left facial peripheral nerve palsy. Examination of the left eye showed yellowish‐greenish discharge, a lower lid ectropium with upper lid ptosis, conjunctival erythema, and an 8 mm 6 mm abrasion in the medial half of the cornea. He had purulent drainage from the left ear with small vesicular lesions on the auricle, and a 3 cm 4 cm abscess on the right forearm. The remainder of the physical examination was unremarkable.

Laboratory‐test results showed white blood cell (WBC) count; 11.27 10⁹ cells/L with 76.6% neutrophils. A complete metabolic panel was within normal limits. Human immunodeficiency virus (HIV) and RPR testing were negative. Cerebrospinal fluid (CSF) studies demonstrated a WBC 39 cells/mm³ with lymphocytes predominance (85%), Red blood cell (RBC) 6 cells/mm³, protein 48 mg/dL, and glucose; 63 mg/dL. Computed tomographic scan of the head revealed an area of low attenuation with surrounding edema of the left temporal lobe and fracture of the temporal bone on the superior margin of the mastoid air cells extending into the left mastoid air cells (Figure 1). The fluid draining from the patient's left ear grew 2 different strains of Pseudomonas aeruginosa. Magnetic resonance imaging (MRI) of the brain demonstrated a 2.5 cm to 3.0 cm region of multiple loculations and edema in the left temporal lobe representing cerebritis with abscess and complete opacification of left mastoid air cell suggestive of mastoiditis (Figure 2). Piperacillin/tazobactam and tobramycin were initiated for suspected MOE with brain involvement. CSF and blood cultures were negative.

Figure 1

Figure 2

A repeat MRI at 3 weeks of therapy demonstrated interval improvement in the temporal lobe abscess and the edema surrounding the infection. At the time of discharge, after 6 weeks of antimicrobial therapy, the patient was alert and oriented with respect to person, place, and time.

Discussion

Pseudomonas aeruginosa is the most common organism cultured from MOE.4, 5 Other organisms such as Staphylococcus aureus,6 Proteus mirabilis, Klebsiella oxytocea,7 and Aspergillus species8 have been reported as well.

While the exact pathogenesis of MOE is poorly understood, accidental trauma from cotton swabs, exposure to lake water, swimming pool water, and repeated aural lavage have all been implicated as inciting factors.9 The current literature suggests that Pseudomonal otitis externa occurs due to abnormal host defense mechanisms rather than enhanced pathogen colonization.10

MOE typically presents with severe otalgia, headache, auricular tenderness, mastoid tenderness, or persistent otorrhea. The pain of MOE is usually severe, and the classic signs of infection such as fever, leukocytosis and neutrophil predominance (left shift) may not be present.5 The diagnosis can be confirmed by otoscopic exam which will demonstrate granulation tissue at the junction between the bony and cartilaginous tissues in the external auditory canal. MOE can produce certain physical findings that should raise red flags for local extension. Temporomandibular joint pain in the susceptible patient with otalgia could indicate MOE with joint invasion. Cranial nerve involvement, most commonly involves the seventh cranial nerve which results in a facial palsy. Other cranial neuropathies have been reported in MOE such as the glossopharyngeal, vagal, spinal accessory, and hypoglossal nerves.11 Confusion and nuchal rigidity should arouse suspicion of intracranial extension of the infection.

The diagnosis of MOE is usually made by a constellation of clinical, microbiological and radiological features. The first attempt at defining diagnostic criteria for MOE was in 1987, when Cohen and Friedman named several obligatory signs such as pain, exudate, edema, granulation tissue in the external ear canal, the presence of microabscesses if surgery is performed, and either a positive Tc‐99m bone scan or failure of local treatment for 1 week.12

Recent literature reviews emphasize that a positive bacterial or fungal culture of the external ear canal can help make the diagnosis of MOE.4 A recent study looking at diagnostic criteria noted that MOE may be present even without meeting all of these major criteria (clinical, microbiological, and radiological features).13 Some authors suggest that ear biopsy be considered if malignancy is a reasonable possibility.9

Other laboratory data can be within normal limits, such as a WBC count or differential and metabolic profiles.4 Erythrocyte sedimentation rate (ESR), while non‐specific, has been reported to be markedly increased in the setting of MOE.5 It is recommended that a baseline ESR be obtained, and then used to follow the response to treatment.14

Computed tomography (CT) scanning is considered the appropriate initial imaging study, however, there are mixed reports about whether a CT scan alone is enough to evaluate disease severity and its complications.15 While CT scan is quite sensitive for demonstrating bony destruction associated with MOE, MRI is better at detecting the soft tissue changes associated with MOE and more useful for following disease resolution after treatment.16

The treatment of MOE has evolved over time. Before the introduction of effective anti‐pseudomonal antibiotics, MOE had an associated mortality near 50%, and surgery was the recommended therapy.17 Currently, given the availability of effective anti‐pseudomonal therapy, there is usually no indication for surgery as a primary treatment in MOE. For sensitive pseudomonal species, oral Ciprofloxacin therapy for 6 to 8 weeks is considered the treatment of choice for MOE.18 Clinicians should be aware of the emergence of quinolone resistance in P. Aeruginosa,19 and antibiotic sensitivities should be performed on the culture to guide further treatment. In the setting of resistant or multi‐species infection, one should obtain external ear canal biopsy with wound debridement and begin long‐term intravenous therapy with an antipseudomonal beta‐lactam plus an aminoglycoside.18 In the setting of extension into the cranium causing cerebritis or abscess, it is recommended that a neurosurgeon be consulted immediately to determine whether the lesion is amenable to aspiration, excision, or watchful waiting with imaging follow up.

This case illustrates a serious complication from MOE, with ipsilateral facial nerve palsy, opthalmitis, mastoiditis, and cerebral abscess that was successfully treated with conservative medical management.

Pediatric patients with pneumonia frequently develop parapneumonic effusion (PNE),1 which account for 0.4 to 6 cases per 1000 pediatric admissions.2 The effusion initially is in a transudative, free‐flowing phase that may evolve to fibrino‐purulent phase and a later organizing phase.3 Hospital management includes antibiotic therapy, pain control, fluids, nutritional support, diagnostic imaging and most important is fluid drainage. Fluid drainage could be through thoracentesis, chest tubes,4 fibrinolysis,5 video‐assisted thoracoscopic surgery (VATS),6 or thoracotomy.7

During hospitalization, repeated phlebotomy and surgical procedures result in ongoing blood losses8, 9 while systemic inflammation and nutritional compromise may blunt erythropoiesis.10, 11 Both mechanisms may result in developing anemia and subsequent need for red blood cell transfusion (RBCT). Blood transfusions are associated with multiple complications including transfusion transmitted infections, acute lung injury, hemodynamic compromise, volume overload, hemolysis, and immune compromise.12, 13 Furthermore, suboptimal benefits,14 increased resource utilization,15 and risk of mortality16 have also been reported in Pediatric intensive care unit (ICU) patients who received blood transfusions.

A Pediatric Blood Conservation program was launched at Helen DeVos Children's Hospital in 1999, and since its inception the pediatric hospitalists have implemented blood conservation guidelines (BCG) in the management of some of the patients with PNE. The BCG incorporated into the care of the intervention group (group I) were orders for:

• Minimizing phlebotomy draws (without stating a specific frequency).

• Use of micro sampling blood collection tubes and reinfusion of any blood drawn prior to obtaining a blood sample (waste return).

• Hematinics use at managing physician's discretion (see Supporting Appendices 1 and 2 in the online version of this article).

No previous studies have addressed the impact of blood conservation strategies on the development of anemia in pediatric PNE. We hypothesized that BCG implementation resulted in smaller phlebotomy losses, lesser incidence of anemia, and lower transfusion requirements.

Methods

After obtaining an approval from the institutional review board, a retrospective medical records review was conducted of all pediatric patients (1 month‐18 years) admitted to Helen DeVos Children's Hospital with diagnoses of PNE from the period of January 1997 to December 2004.

Study Groups

Intervention group (group I) included all patients who were admitted with a diagnosis of PNE between the year 2000 to 2004 and had orders for BCG (as outlined above) written on or after admission to the hospital. That group included patients that were either solely managed by the hospitalists or comanaged by both the general pediatrician and the Hospitalist.

Simultaneous nonintervention group (group S) included patients with PNE who were admitted between 2000 to 2004 and did not have BCG orders on their record. Those patients were either managed solely by the general pediatricians or the Hospitalist may have been involved but no BCG orders were written. It was assumed that no intervention was implemented.

Historical nonintervention group (group H) included patients with PNE admitted between 1997 and 2000 prior to the implementation of the blood conservation program or the hospitalists service. Those patients were managed by the general pediatricians with the Intensivists help at times and no blood conservation measures were implemented.

Phlebotomy frequency and volume data were collected from the patient's medical record. When volume was not documented, an estimate was made based on the hospital actual practice and labs reported. If the child had central vascular access, a standard of 2 mL of blood was removed to clear the line prior to drawing the blood sample. In the S and H groups that volume was discarded and recorded as a blood loss. In Group I the blood used to clear the line was returned to the patients. Data regarding the patient's hemoglobin (Hgb) levels on admission and during hospitalization as well as RBCT frequency and volume were also collected. Other background data collected included, hospital stay, ICU admission, antibiotic use, isolated organisms, and PNE‐related interventions (thoracentesis, VATS and chest tube placement). A pediatric risk of mortality score (PRISM score17) was assigned for every patient based on data collected on the day of admission.

Statistical analysis was done using a Fisher exact test to compare qualitative data. For quantitative data Kruskal‐Wallis was used for comparison between the three groups while the Mann Whitney test was used for the pair wise comparisons. Odds Ratios and Confidence Intervals were calculated for variables associated with needing RBCTs.

Results

A total of 81 patients who were admitted to the hospital for medical and surgical management with PNE were included in the study. During the study period 24 patients with blood conservation orders on the chart were assigned to the intervention group. Another 28 patients were identified during the same period but did not have blood conservation orders and were assigned to the simultaneous no intervention group. A historical no intervention group of 29 patients were identified from a 3‐year period prior to the study period. Groups were similar in age, weight, and an overall low PRISM score. Group H tended to have lower acuity, longer hospital stay, more frequent pediatric intensive care unit (PICU) admissions, and tended to have more chest tube days compared to the (I) and (S) groups (Table 1).

All groups (I, S and H) had similar initial Hgb, in‐hospital decline in Hgb levels and time to reach a Hgb nadir. There was a trend toward a lower frequency of phlebotomy and significant difference in the phlebotomy volumes drawn even when corrected for patient weight and hospital stay, (I < S < H; P = 0.006), (Table 1).

All 3 groups had a similar pretransfusion Hgb trigger (7.7 1 gm/dL), timing of transfusions (7.9 1 day), volume of packed red blood cells (PRBCs) (19 15 mL/kg), and magnitude of Hgb rise following transfusions (3.9 1.5 gm/dL). There was a strong trend toward lower transfusion need in the intervention group though it did not reach statistical significance (8.3% [I], 17.9% [S]; and 31% [H]; P = 0.11) (Table 1 and Figure 1). Being in group (S) compared to (I) carried a relative risk of transfusion of 2.14 (confidence interval [CI], 0.4610.06).

Figure 1

Of all study patients, 19.8% received RBCT. Compared to those who did not require transfusions they were significantly younger, smaller (P = 0.001) and had a higher severity of illness score (PRISM) (P = 0.25). Transfused children had lower initial Hgb levels, more frequent phlebotomy, greater volume of blood drawn, and longer hospital stay (P = 0.001) (Table 2 and Figure 2).

Figure 2

A total of 36% of the patients were pretreated with antibiotics prior to obtaining pleural fluid cultures. Forty‐eight patients (59%) had negative cultures, 22 (27%) grew pneumococcus, 5 patients (6%) had streptococcus A, 2 patients had streptococcus viridans, 3 patients had staphylococci aureus, and 1 patient had Haemophilus influenzae. There was no difference between the study groups regarding the site of effusion, prior antibiotics therapy or culture results.

Discussion

This retrospective study showed that children with PNE had low Hgb upon admission to the hospital and after dropping an average of 2 gm/dL over the first week of hospitalization one‐fifth of the patients required transfusion. The phlebotomy volumes significantly decreased with BCG implementation, and transfusion frequency showed a strong trend toward decline. The fact that all 3 groups had similar pretransfusion Hgb and similar Hgb decline, despite differences in the phlebotomy volumes, may implicate other factors like bone marrow suppression, malnutrition, and procedural blood losses. All of these factors have been shown to contribute to the development of anemia in the critically ill patients10 and were not accounted for in this limited retrospective review.

Transfused patients were significantly smaller, younger, and had higher illness severity scores. They had lower initial Hgb levels, more phlebotomy, and longer hospital stay than nontransfused patients.

Pretransfusion Hgb was 7.5 gm/dL to 7.7 gm/dL in all groups, consistent with Lacroix et al's18 report on the safety of lower transfusion threshold in stable PICU patients. BCG resulted in a strong trend toward less transfusion but did not reach statistical significance likely due to the small sample size. It is tempting to hypothesize that aggressive erythropoietin therapy might augment that trend; however, given the relatively short hospital stay (1014 days), erythropoietin therapy may be less efficacious in the milder case with shorter hospital stay than those with longer hospitalization. After encouraging smaller studies19 Corwin et al.20 did not find a beneficial effect for erythropoietin in adult ICU patients nor did Jacobs et al.21 in ventilated children with bronchiolitis who had comparable length of hospitalization.

A specific benefit could not be attributed to iron/folate or erythropoietin therapy as neither the dosing, duration nor timing was controlled. Furthermore, given the limitations of retrospective reviews, the relative importance of the beneficial effect of limiting phlebotomy vs. hematinics use could not be determined.

The Hospitalist is focused on improving the quality and efficiency of caring for the inpatient.2225 The initiation of the hospitalist's service at our institution coincided with that of the blood conservation service. Consequently, the Hospitalist contributed to patient care as well as daily house staff and nursing education. For those children whose care was coordinated by the hospitalists, the study data showed a trend toward lesser admissions to the PICU and lower blood utilization. This trend further emphasizes the role a Hospitalist could play in adopting and implementing useful medical strategies lowering the cost of care. In this study, a change in patient care was observed over time with the hospitalists tending to employ more blood conservation measures when compared to the pediatrician.

In summary, children with PNE are at risk for developing severe anemia requiring transfusion. This retrospective study identified the characteristics of those likely to require transfusions. Blood conservation strategies seem to decrease the need for transfusions. The hospitalists played an important role in implementing the BCG. A prospective controlled study with adequate power is needed to examine both the various mechanisms for developing anemia and the impact of the individual components of the blood conservation strategies.

Pediatric patients with pneumonia frequently develop parapneumonic effusion (PNE),1 which account for 0.4 to 6 cases per 1000 pediatric admissions.2 The effusion initially is in a transudative, free‐flowing phase that may evolve to fibrino‐purulent phase and a later organizing phase.3 Hospital management includes antibiotic therapy, pain control, fluids, nutritional support, diagnostic imaging and most important is fluid drainage. Fluid drainage could be through thoracentesis, chest tubes,4 fibrinolysis,5 video‐assisted thoracoscopic surgery (VATS),6 or thoracotomy.7

During hospitalization, repeated phlebotomy and surgical procedures result in ongoing blood losses8, 9 while systemic inflammation and nutritional compromise may blunt erythropoiesis.10, 11 Both mechanisms may result in developing anemia and subsequent need for red blood cell transfusion (RBCT). Blood transfusions are associated with multiple complications including transfusion transmitted infections, acute lung injury, hemodynamic compromise, volume overload, hemolysis, and immune compromise.12, 13 Furthermore, suboptimal benefits,14 increased resource utilization,15 and risk of mortality16 have also been reported in Pediatric intensive care unit (ICU) patients who received blood transfusions.

A Pediatric Blood Conservation program was launched at Helen DeVos Children's Hospital in 1999, and since its inception the pediatric hospitalists have implemented blood conservation guidelines (BCG) in the management of some of the patients with PNE. The BCG incorporated into the care of the intervention group (group I) were orders for:

• Minimizing phlebotomy draws (without stating a specific frequency).

• Use of micro sampling blood collection tubes and reinfusion of any blood drawn prior to obtaining a blood sample (waste return).

• Hematinics use at managing physician's discretion (see Supporting Appendices 1 and 2 in the online version of this article).

No previous studies have addressed the impact of blood conservation strategies on the development of anemia in pediatric PNE. We hypothesized that BCG implementation resulted in smaller phlebotomy losses, lesser incidence of anemia, and lower transfusion requirements.

Methods

After obtaining an approval from the institutional review board, a retrospective medical records review was conducted of all pediatric patients (1 month‐18 years) admitted to Helen DeVos Children's Hospital with diagnoses of PNE from the period of January 1997 to December 2004.

Study Groups

Intervention group (group I) included all patients who were admitted with a diagnosis of PNE between the year 2000 to 2004 and had orders for BCG (as outlined above) written on or after admission to the hospital. That group included patients that were either solely managed by the hospitalists or comanaged by both the general pediatrician and the Hospitalist.

Simultaneous nonintervention group (group S) included patients with PNE who were admitted between 2000 to 2004 and did not have BCG orders on their record. Those patients were either managed solely by the general pediatricians or the Hospitalist may have been involved but no BCG orders were written. It was assumed that no intervention was implemented.

Historical nonintervention group (group H) included patients with PNE admitted between 1997 and 2000 prior to the implementation of the blood conservation program or the hospitalists service. Those patients were managed by the general pediatricians with the Intensivists help at times and no blood conservation measures were implemented.

Phlebotomy frequency and volume data were collected from the patient's medical record. When volume was not documented, an estimate was made based on the hospital actual practice and labs reported. If the child had central vascular access, a standard of 2 mL of blood was removed to clear the line prior to drawing the blood sample. In the S and H groups that volume was discarded and recorded as a blood loss. In Group I the blood used to clear the line was returned to the patients. Data regarding the patient's hemoglobin (Hgb) levels on admission and during hospitalization as well as RBCT frequency and volume were also collected. Other background data collected included, hospital stay, ICU admission, antibiotic use, isolated organisms, and PNE‐related interventions (thoracentesis, VATS and chest tube placement). A pediatric risk of mortality score (PRISM score17) was assigned for every patient based on data collected on the day of admission.

Statistical analysis was done using a Fisher exact test to compare qualitative data. For quantitative data Kruskal‐Wallis was used for comparison between the three groups while the Mann Whitney test was used for the pair wise comparisons. Odds Ratios and Confidence Intervals were calculated for variables associated with needing RBCTs.

Results

A total of 81 patients who were admitted to the hospital for medical and surgical management with PNE were included in the study. During the study period 24 patients with blood conservation orders on the chart were assigned to the intervention group. Another 28 patients were identified during the same period but did not have blood conservation orders and were assigned to the simultaneous no intervention group. A historical no intervention group of 29 patients were identified from a 3‐year period prior to the study period. Groups were similar in age, weight, and an overall low PRISM score. Group H tended to have lower acuity, longer hospital stay, more frequent pediatric intensive care unit (PICU) admissions, and tended to have more chest tube days compared to the (I) and (S) groups (Table 1).

All groups (I, S and H) had similar initial Hgb, in‐hospital decline in Hgb levels and time to reach a Hgb nadir. There was a trend toward a lower frequency of phlebotomy and significant difference in the phlebotomy volumes drawn even when corrected for patient weight and hospital stay, (I < S < H; P = 0.006), (Table 1).

All 3 groups had a similar pretransfusion Hgb trigger (7.7 1 gm/dL), timing of transfusions (7.9 1 day), volume of packed red blood cells (PRBCs) (19 15 mL/kg), and magnitude of Hgb rise following transfusions (3.9 1.5 gm/dL). There was a strong trend toward lower transfusion need in the intervention group though it did not reach statistical significance (8.3% [I], 17.9% [S]; and 31% [H]; P = 0.11) (Table 1 and Figure 1). Being in group (S) compared to (I) carried a relative risk of transfusion of 2.14 (confidence interval [CI], 0.4610.06).

Figure 1

Of all study patients, 19.8% received RBCT. Compared to those who did not require transfusions they were significantly younger, smaller (P = 0.001) and had a higher severity of illness score (PRISM) (P = 0.25). Transfused children had lower initial Hgb levels, more frequent phlebotomy, greater volume of blood drawn, and longer hospital stay (P = 0.001) (Table 2 and Figure 2).

Figure 2

A total of 36% of the patients were pretreated with antibiotics prior to obtaining pleural fluid cultures. Forty‐eight patients (59%) had negative cultures, 22 (27%) grew pneumococcus, 5 patients (6%) had streptococcus A, 2 patients had streptococcus viridans, 3 patients had staphylococci aureus, and 1 patient had Haemophilus influenzae. There was no difference between the study groups regarding the site of effusion, prior antibiotics therapy or culture results.

Discussion

This retrospective study showed that children with PNE had low Hgb upon admission to the hospital and after dropping an average of 2 gm/dL over the first week of hospitalization one‐fifth of the patients required transfusion. The phlebotomy volumes significantly decreased with BCG implementation, and transfusion frequency showed a strong trend toward decline. The fact that all 3 groups had similar pretransfusion Hgb and similar Hgb decline, despite differences in the phlebotomy volumes, may implicate other factors like bone marrow suppression, malnutrition, and procedural blood losses. All of these factors have been shown to contribute to the development of anemia in the critically ill patients10 and were not accounted for in this limited retrospective review.

Transfused patients were significantly smaller, younger, and had higher illness severity scores. They had lower initial Hgb levels, more phlebotomy, and longer hospital stay than nontransfused patients.

Pretransfusion Hgb was 7.5 gm/dL to 7.7 gm/dL in all groups, consistent with Lacroix et al's18 report on the safety of lower transfusion threshold in stable PICU patients. BCG resulted in a strong trend toward less transfusion but did not reach statistical significance likely due to the small sample size. It is tempting to hypothesize that aggressive erythropoietin therapy might augment that trend; however, given the relatively short hospital stay (1014 days), erythropoietin therapy may be less efficacious in the milder case with shorter hospital stay than those with longer hospitalization. After encouraging smaller studies19 Corwin et al.20 did not find a beneficial effect for erythropoietin in adult ICU patients nor did Jacobs et al.21 in ventilated children with bronchiolitis who had comparable length of hospitalization.

A specific benefit could not be attributed to iron/folate or erythropoietin therapy as neither the dosing, duration nor timing was controlled. Furthermore, given the limitations of retrospective reviews, the relative importance of the beneficial effect of limiting phlebotomy vs. hematinics use could not be determined.

The Hospitalist is focused on improving the quality and efficiency of caring for the inpatient.2225 The initiation of the hospitalist's service at our institution coincided with that of the blood conservation service. Consequently, the Hospitalist contributed to patient care as well as daily house staff and nursing education. For those children whose care was coordinated by the hospitalists, the study data showed a trend toward lesser admissions to the PICU and lower blood utilization. This trend further emphasizes the role a Hospitalist could play in adopting and implementing useful medical strategies lowering the cost of care. In this study, a change in patient care was observed over time with the hospitalists tending to employ more blood conservation measures when compared to the pediatrician.

In summary, children with PNE are at risk for developing severe anemia requiring transfusion. This retrospective study identified the characteristics of those likely to require transfusions. Blood conservation strategies seem to decrease the need for transfusions. The hospitalists played an important role in implementing the BCG. A prospective controlled study with adequate power is needed to examine both the various mechanisms for developing anemia and the impact of the individual components of the blood conservation strategies.

Pediatric patients with pneumonia frequently develop parapneumonic effusion (PNE),1 which account for 0.4 to 6 cases per 1000 pediatric admissions.2 The effusion initially is in a transudative, free‐flowing phase that may evolve to fibrino‐purulent phase and a later organizing phase.3 Hospital management includes antibiotic therapy, pain control, fluids, nutritional support, diagnostic imaging and most important is fluid drainage. Fluid drainage could be through thoracentesis, chest tubes,4 fibrinolysis,5 video‐assisted thoracoscopic surgery (VATS),6 or thoracotomy.7

During hospitalization, repeated phlebotomy and surgical procedures result in ongoing blood losses8, 9 while systemic inflammation and nutritional compromise may blunt erythropoiesis.10, 11 Both mechanisms may result in developing anemia and subsequent need for red blood cell transfusion (RBCT). Blood transfusions are associated with multiple complications including transfusion transmitted infections, acute lung injury, hemodynamic compromise, volume overload, hemolysis, and immune compromise.12, 13 Furthermore, suboptimal benefits,14 increased resource utilization,15 and risk of mortality16 have also been reported in Pediatric intensive care unit (ICU) patients who received blood transfusions.

A Pediatric Blood Conservation program was launched at Helen DeVos Children's Hospital in 1999, and since its inception the pediatric hospitalists have implemented blood conservation guidelines (BCG) in the management of some of the patients with PNE. The BCG incorporated into the care of the intervention group (group I) were orders for:

• Minimizing phlebotomy draws (without stating a specific frequency).

• Use of micro sampling blood collection tubes and reinfusion of any blood drawn prior to obtaining a blood sample (waste return).

• Hematinics use at managing physician's discretion (see Supporting Appendices 1 and 2 in the online version of this article).

No previous studies have addressed the impact of blood conservation strategies on the development of anemia in pediatric PNE. We hypothesized that BCG implementation resulted in smaller phlebotomy losses, lesser incidence of anemia, and lower transfusion requirements.

Methods

After obtaining an approval from the institutional review board, a retrospective medical records review was conducted of all pediatric patients (1 month‐18 years) admitted to Helen DeVos Children's Hospital with diagnoses of PNE from the period of January 1997 to December 2004.

Study Groups

Intervention group (group I) included all patients who were admitted with a diagnosis of PNE between the year 2000 to 2004 and had orders for BCG (as outlined above) written on or after admission to the hospital. That group included patients that were either solely managed by the hospitalists or comanaged by both the general pediatrician and the Hospitalist.

Simultaneous nonintervention group (group S) included patients with PNE who were admitted between 2000 to 2004 and did not have BCG orders on their record. Those patients were either managed solely by the general pediatricians or the Hospitalist may have been involved but no BCG orders were written. It was assumed that no intervention was implemented.

Historical nonintervention group (group H) included patients with PNE admitted between 1997 and 2000 prior to the implementation of the blood conservation program or the hospitalists service. Those patients were managed by the general pediatricians with the Intensivists help at times and no blood conservation measures were implemented.

Phlebotomy frequency and volume data were collected from the patient's medical record. When volume was not documented, an estimate was made based on the hospital actual practice and labs reported. If the child had central vascular access, a standard of 2 mL of blood was removed to clear the line prior to drawing the blood sample. In the S and H groups that volume was discarded and recorded as a blood loss. In Group I the blood used to clear the line was returned to the patients. Data regarding the patient's hemoglobin (Hgb) levels on admission and during hospitalization as well as RBCT frequency and volume were also collected. Other background data collected included, hospital stay, ICU admission, antibiotic use, isolated organisms, and PNE‐related interventions (thoracentesis, VATS and chest tube placement). A pediatric risk of mortality score (PRISM score17) was assigned for every patient based on data collected on the day of admission.

Statistical analysis was done using a Fisher exact test to compare qualitative data. For quantitative data Kruskal‐Wallis was used for comparison between the three groups while the Mann Whitney test was used for the pair wise comparisons. Odds Ratios and Confidence Intervals were calculated for variables associated with needing RBCTs.

Results

A total of 81 patients who were admitted to the hospital for medical and surgical management with PNE were included in the study. During the study period 24 patients with blood conservation orders on the chart were assigned to the intervention group. Another 28 patients were identified during the same period but did not have blood conservation orders and were assigned to the simultaneous no intervention group. A historical no intervention group of 29 patients were identified from a 3‐year period prior to the study period. Groups were similar in age, weight, and an overall low PRISM score. Group H tended to have lower acuity, longer hospital stay, more frequent pediatric intensive care unit (PICU) admissions, and tended to have more chest tube days compared to the (I) and (S) groups (Table 1).

All groups (I, S and H) had similar initial Hgb, in‐hospital decline in Hgb levels and time to reach a Hgb nadir. There was a trend toward a lower frequency of phlebotomy and significant difference in the phlebotomy volumes drawn even when corrected for patient weight and hospital stay, (I < S < H; P = 0.006), (Table 1).

All 3 groups had a similar pretransfusion Hgb trigger (7.7 1 gm/dL), timing of transfusions (7.9 1 day), volume of packed red blood cells (PRBCs) (19 15 mL/kg), and magnitude of Hgb rise following transfusions (3.9 1.5 gm/dL). There was a strong trend toward lower transfusion need in the intervention group though it did not reach statistical significance (8.3% [I], 17.9% [S]; and 31% [H]; P = 0.11) (Table 1 and Figure 1). Being in group (S) compared to (I) carried a relative risk of transfusion of 2.14 (confidence interval [CI], 0.4610.06).

Figure 1

Of all study patients, 19.8% received RBCT. Compared to those who did not require transfusions they were significantly younger, smaller (P = 0.001) and had a higher severity of illness score (PRISM) (P = 0.25). Transfused children had lower initial Hgb levels, more frequent phlebotomy, greater volume of blood drawn, and longer hospital stay (P = 0.001) (Table 2 and Figure 2).

Figure 2

A total of 36% of the patients were pretreated with antibiotics prior to obtaining pleural fluid cultures. Forty‐eight patients (59%) had negative cultures, 22 (27%) grew pneumococcus, 5 patients (6%) had streptococcus A, 2 patients had streptococcus viridans, 3 patients had staphylococci aureus, and 1 patient had Haemophilus influenzae. There was no difference between the study groups regarding the site of effusion, prior antibiotics therapy or culture results.

Discussion

This retrospective study showed that children with PNE had low Hgb upon admission to the hospital and after dropping an average of 2 gm/dL over the first week of hospitalization one‐fifth of the patients required transfusion. The phlebotomy volumes significantly decreased with BCG implementation, and transfusion frequency showed a strong trend toward decline. The fact that all 3 groups had similar pretransfusion Hgb and similar Hgb decline, despite differences in the phlebotomy volumes, may implicate other factors like bone marrow suppression, malnutrition, and procedural blood losses. All of these factors have been shown to contribute to the development of anemia in the critically ill patients10 and were not accounted for in this limited retrospective review.

Transfused patients were significantly smaller, younger, and had higher illness severity scores. They had lower initial Hgb levels, more phlebotomy, and longer hospital stay than nontransfused patients.

Pretransfusion Hgb was 7.5 gm/dL to 7.7 gm/dL in all groups, consistent with Lacroix et al's18 report on the safety of lower transfusion threshold in stable PICU patients. BCG resulted in a strong trend toward less transfusion but did not reach statistical significance likely due to the small sample size. It is tempting to hypothesize that aggressive erythropoietin therapy might augment that trend; however, given the relatively short hospital stay (1014 days), erythropoietin therapy may be less efficacious in the milder case with shorter hospital stay than those with longer hospitalization. After encouraging smaller studies19 Corwin et al.20 did not find a beneficial effect for erythropoietin in adult ICU patients nor did Jacobs et al.21 in ventilated children with bronchiolitis who had comparable length of hospitalization.

A specific benefit could not be attributed to iron/folate or erythropoietin therapy as neither the dosing, duration nor timing was controlled. Furthermore, given the limitations of retrospective reviews, the relative importance of the beneficial effect of limiting phlebotomy vs. hematinics use could not be determined.

The Hospitalist is focused on improving the quality and efficiency of caring for the inpatient.2225 The initiation of the hospitalist's service at our institution coincided with that of the blood conservation service. Consequently, the Hospitalist contributed to patient care as well as daily house staff and nursing education. For those children whose care was coordinated by the hospitalists, the study data showed a trend toward lesser admissions to the PICU and lower blood utilization. This trend further emphasizes the role a Hospitalist could play in adopting and implementing useful medical strategies lowering the cost of care. In this study, a change in patient care was observed over time with the hospitalists tending to employ more blood conservation measures when compared to the pediatrician.

In summary, children with PNE are at risk for developing severe anemia requiring transfusion. This retrospective study identified the characteristics of those likely to require transfusions. Blood conservation strategies seem to decrease the need for transfusions. The hospitalists played an important role in implementing the BCG. A prospective controlled study with adequate power is needed to examine both the various mechanisms for developing anemia and the impact of the individual components of the blood conservation strategies.