Clinical Profile of Neonatal Admissions at Prince Rashid bin Al-Hassan Hospital

ABSTRACT

Objective: To determine the indications, clinical profile, and outcomes of neonatal admissions at Prince Rashid bin Al-Hassan Hospital.

Methods: Retrospective study of all neonates admitted to the neonatal intensive care unit (NICU) between January 1, 2016, and September 30, 2017. Collected data included gender, gestational age, birth weight, mode of delivery, clinical indication for admission, and discharge outcomes. All data was entered into a Microsoft Excel spreadsheet and analyzed using IBM (SPSS) Statistics version 26.

Results: A total of 2120 newborns were admitted to the NICU during the study period; 1551 (73.2%) were inborn and 569 (26.8%) out born. Of the 2120, 1117 (52.6%) were male and 1003 (47.3%) were female;1172 (55.3%) were term neonates and 948 (44.7%)preterm neonates; 55 were neonates with extreme low birth weight (ELBW), 153 were very low birth weight (VLBW), and 662 were low birth weight (LBW). Cesarean section delivery accounted for 60.6% of all admitted neonates. The most frequent clinical indications leading to admission were preterm and respiratory distress syndrome (43%), transient tachypnea of newborn(TTN) (16%), neonatal sepsis (15%), birth asphyxia (9.1%), and neonatal jaundice (7.2%). Early onset sepsis (EOS) and late onset sepsis (LOS) represented (56.4%) and (43.6%), respectively, of all proved cultures. Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli were the most common isolated organisms leading to sepsis.Prematurity, neonatal respiratory distress syndrome (RDS), and neonatal sepsis were the most common risk factorsleading to death. The mortality rate was (7.5%) of all admitted newborns during our study period.

Conclusion: Prematurity, RDS, and neonatal sepsis were the significant clinical indicators leading to neonatal morbidity and mortality.The most common isolated organisms leading to neonatal sepsis were Staphylococcus aureus and Klebsiella.The majority of admitted neonates were term and latepreterm infants delivered by cesarean section.

Keywords: NICU admissions, Neonatal mortality, Neonatal outcomes, Early and Late onset sepsis.

Introduction

The neonatal period is the most critical phase of life and is associated to risk for various diseases due to vulnerability during the period of physiological adjustment to adapt for life outside the uterus[1]. Survival rates of new borns highlight the development and quality of the healthcare system.

Overthe last two decades, developed countries have achieved a significant improvement in neonatal management, leading to increases survival rates of newborns as compared to those in developing countries, where both morbidity and mortality are higher[2].

Globally, UNICEF and the World Health Organization (WHO) estimated that about5.4 million deaths occurred in 2017 of children under 5 years. Significantly, the highest risk reportedly came in the first month of life, with2.5 million newborns dyingin the first month after birth, representing 47% of deaths at age below 5 years, compared to 29% and 25% of deaths occurring between 1 and 11 months and 1 and 4 years, respectively. The majority of newborn deaths occurred in developing and low-income countries with a mortality rate of 69 deaths per 1000 live births, in comparison witha lower mortality rate of 5.4 deaths per 1000 live births in developed countries[3].

Research points to various factors leading to neonatal mortality and morbidity. The most common causes of neonatal death include preterm birth, low birthweight, and congenital anomalies[4]. Infants withpreterm birth before 37 weeks and low birthweight are susceptible to serious medical complications associated withthe immune system, birth asphyxia, cardiovascular disorders, the gastrointestinal system, respiratory distress syndrome, and chronic lung disease[5, 6]. Furthermore, gestational age (GA) has been identified as a significant predictor of mortality and as extremely associated with chronic heart disease and respiratory problems[5]. Also, congenital anomalies lead to functional or structural disorders influencing mortality and morbidity rates of neonates. Commonly, heart defects, neural tube defects, and Down syndrome are the most severecongenital anomalies [7]. In addition, infections are among the major causes leading to neonatal death and are associated with 27% of neonatal deaths in developing and low-income countries, as compared with 4% of mortality in developed countries [6, 8]. However, most of the factors influencing neonatal mortality are potentially preventable and could be avoided by adequate neonatal care. Accordingly, the WHO has establishedsustainable development goals (SDGs) to beachieved by the year 2030[9]. These goals aim to reduce the neonatal mortality rate to less than 12 per 100 live newborns. Based on Jordan statistics data issued by UNICEF for2019, the infant mortality rate was 13 per 1000 live births, while neonatal mortality rate was 9 per 1000 live births [10].

Early diagnosis and proper management of neonatal intensive care units (NICUs) leads to improved survival rates and therapeutic outcomes with fewersevere morbidities[11]. Therefore, it is essential to study the admission rate and variability of preventable and treatable neonatal cases. This study aims to determine the indications, clinical profile and prevalence of the NICU admission rate at Prince Rashid bin Al-Hassan Hospital.

Methodology

A retrospective study was conducted at the NICU of Prince Rashid bin AL-Hassan Hospital from January 1, 2016, to September 30, 2017. Inborn and outborn admissions during the study period were included. Collected data included gender, birth weight, maternal age, gestational age, mode of delivery, respiratory support, sepsis, culture results, initial diagnosis, days of admission, discharged weight, and cause of deaths. All data was entered into Microsoft Excel and analyzed by IBM (SPSS) Statistics version 26.Analyzed data was presented as frequency distributions and percentages for categorical variables.Student’s t-test and ANOVA were applied to examine the significance level for continuous normally distributed variables. The normality of the distribution of data was tested using the Kolmogorov–Smirnov test.

Collected data was documented based on pretested variables; newborns were categorized based on gestation age into preterm neonates delivered before completed 37 weeks,whileterm neonates delivered at gestational age of 37 to 42 completed weeks[12]. Birth weight of neonates was categorized according to the WHO classification into low birth weight (LBW) less than 2500 grams, very low birth weight (VLBW) less than 1500 grams, and extreme low birth weight (ELBW) less than 1000 grams[13].

Respiratory Distress Syndrome (RDS) occurred when neonate’s lung not completely developed and cannot provide enough oxygen. Diagnosis is based on oxygen level and chest X-ray findings of hyaline membrane or surfactant deficiency disease[14].

Transient Tachypnea of newborn (TTN) is a breathing disorder seen shortly after delivery, occurred by a delay in the clearance of fetal lung fluid after birth. Leading to tachypnea represented by faster breathing more than normal, ineffective gas exchange and associated with early RDS [15].Also, Birth asphyxia is defined based on WHO as the failure to initiate and sustain breathing at birth [16].  Meconium aspiration syndrome (MAS) is a clinical condition which characterized by respiratory complications occurred by meconium-stained amniotic fluid[17].Neonatal hyperbilirubinemia is a clinical condition when bilirubin increased above the normal level. Hyperbilirubinemia was diagnosed and managed according to AAP guidelines[18].

Cause of death was identified and recorded based on neonatal death report issued by pediatric specialist. Total number of deaths was used to calculate mortality rate.

Results

    A total of 2120 neonates were admitted to the NICU during the study period. The demographic profile in Table I shows that 52.6% of admitted neonates were males and 47.3% were females. Inborn and outborn admitted neonates accounted for 73.2% and 26.8%, respectively. A total of 1930 (91%) neonates were admitted within the first 7days of birth. Preterm neonates accounted for 44.7%, while term neonates accounted for 55.3%. Delivery mode showed cesarean delivery associated with 1285 (60.6%) of total admitted cases.

Table I: Characteristic of Admitted Neonates (n=2120)

 Abbreviations

  ELBW: Extreme Low Birth Weight, VLBW: Very Low Birth Weight, LBW: Low Birth Weight

VD: Vaginal Delivery, CS: Caesarean section

Common morbidity-based admissions patterns in the NICU are summarized in Table II below. Preterm and respiratory distress syndrome (RDS) were the significant indicators leading to NICU admissions, accounting for 43% of total admissions cases. In addition to that, transient tachypnea of newborn (TTN) and suspected neonatal sepsis were associated to 16% and 15% of admissions, respectively. Birth asphyxia was reported among 193 neonates and accounted for 9.1%, while hyperbilirubinemia was observed among 153 neonates (7.2%).

Furthermore, the incident of neonatal sepsis was defined based on bacterial isolation from blood or cerebrospinal fluid (CSF) samples. Bacterial isolates causing neonatal sepsis are shown in Table III.

Proved positive cultures were reported in 266 cases among our study. The most common microorganisms isolated were Staphylococcus aureus and Klebsiella pneumoniae, which significantly caused 35.5% and 29.2% of neonatal sepsis. Also, Escherichia coli associated with 15.7% of neonatal sepsis compared to Staphylococcus epidermidis 6%. In addition, Acinetobacter, Enterobacter, Pseudomonas,and Streptococcus were reported. Three samples were positive formethicillin-resistant Staphylococcus aureus (MRSA).

Furthermore, the distribution of culture positivity according to gender shows that 64% of positive cultures were associated to male neonates as compared to 36% for female neonates.

Table IV: Blood Culture Positivity-based Gender and Age(n=266)

Neonatal sepsis was classified based on onset symptoms. Early onset sepsis (EOS) within the first 7 days of life accounted for 56.4%, while late onset sepsis (LOS) after 7 days of birth was associated with (43.6%). Table V represents the isolated microorganisms in EOS and LOS.

The length of stay for NICU admissions is shown in Table VI. The majority of admissions (80%) stayed at the NICU for approximately1 week, while 36% of total admission cases were hospitalized for 3 days only. Only 5.5% of neonates were admitted for 24 hours.

In addition, discharge statistics showed that 1935 of total admitted neonates were discharged alive from the NICU, compared to 160 neonatal deaths and 25 cases that were transferred to a tertiary hospital. The obtained overall neonatal mortality rate (NMR) was 7.5%, as shown in Table VII.

The distribution of risk factors causing death are presented in Table VIII. Prematurity and RDS were the significant risk factors leading to death and associated with 30% and 51%, respectively. Neonatal sepsis and congenital anomalies were reported to cause 14% and 3.2% of total deaths among our study.

Discussion

      Among all neonatal admissionsduring the period of our study, the leading indicators for morbidity and mortality were prematurity and RDS. Along with TTN, neonatal sepsis, birth asphyxia, and hyperbilirubinemia were common causes of admissions. In addition, 60% of admitted neonates were delivered by cesarean section, significantly increasing the risk of respiratory problems.Approximately 50% of infants delivered by cesarean section required respiratory support compared to 12% of those withnormal deliveries[19, 20],highlighting the guidelines of the American College of Obstetrics and Gynecology (ACOG) that do not recommended elective delivery before gestation age of 39 weeks [21].

Furthermore, our findings are comparable to those of Sivasubramaniam et al.,who described the outcomesof Jordanian newborns admitted to a NICU at Al-Bashir Government Hospital, concluding that RDS and prematurity were the most common indicators for neonatal admissions (67%) and mortality (52%). Also, neonatal sepsis was reported in10%, jaundicein5%, and birth asphyxia in 4%[22].

In the current study, the obtained incident rate of proved neonatal sepsis was 12.5% within all neonatal admissions. Gram-negative bacteria were the main microbial isolates causing infection in both EOS and LOS, contributing 62% and 60% of all positive cultures, respectively. Staphylococcus aureus,Klebsiella pneumoniae,and Escherichia coli were the most common isolated pathogens. Furthermore, EOS was associated with 56.4% of neonatal sepsis, while LOS represented 43.6%. Median hospital stays for EOS and LOSwere reported as6.4 and 7.6 days. Moreover, the obtained incident and epidemiologic trend of neonatal sepsis is comparable with a 2015 study by Shehab El-Din et al., who reportedthe incident rates for LOS and EOS were45% and 55%, respectively.Staphylococcus aureus and Klebsiella pneumoniae were the predominant isolated pathogens causing EOS and LOS sepsis[23]. Also, Khasawneh et al. demonstrated in a 2020 study that streptococcus (GBS) and Klebsiella pneumoniae were the most common isolated microorganisms leading to EOS and LOS[24]. In addition, Al-Matary et al., in a 2019 study in King Fahad Medical City (KFMC), found that the risk of neonatal sepsis at EOS was 12% and at LOS was 88% among all positive cases. Streptococcus (33%) and E. coli (27%) were the most causative organisms for EOS,while Staphylococcus aureus (60%) and Klebsiella pneumoniae (17.5%) were the most frequent detectable pathogens at LOS [25]. However, inverse relationship was found between incidence rate of sepsis and gestational age and birth weight,putting premature neonates at higher risk of sepsis-associated mortality. Globally, sepsis-related mortality represented about30% in cases of EOS and ranged from 18% to 35% for LOS [26-28].

The status upon discharge represented the obtained mortality rate(7.5%) among all admitted neonatesduring the study period.Prematurity and RDS were the main causes leading to deaths (132/160); likewise, sepsis and congenital anomalies were associated with 23/160, 5/160 correspondingly.

On the other hand, Sivasubramaniam et al. in 2015 reported a higher mortality rate (8.7%) among admitted neonates at Al-Bashir Hospital. Similarly, the most frequent causesassociated with noenatal deaths were RDS (50%), prematurity (40%), and sepsis (9%)[22]. Also, Khasawneh et al.in 2020 demonstrated a lower neonatal mortality rate (3.5%) and reported the major cause for neonatal deaths was extreme prematurity (30/55) [11].

In parallel, Batieha et al. in 2016 found that neonatal mortality was 12% of all births in Jordan. Also, RDS was reported as the main cause of mortality and related to 53% of neonatal deaths, neonatal sepsis accounted for 16.2%, and birth asphyxia represented 10% of total neonates deaths [29]. Compatible results were obtained by Baghel et al. who reported in 2016 that 55% of neonatal mortality occurred due to prematurity, RDS (38%), sepsis (11%), and congenital anomalies (2%) [30].

Furthermore, a retrospective cohort study at The University of Texas Southwestern Medical Center was performed by McIntire et al. who declared that respiratory distress syndrome (RDS), transient tachypnea of newborn (TTN), sepsis and hyperbilirubinemia were the most common causes leading neonatal morbidity. Also, neonatal death rate was found to be 4 deaths per 1000 lives, and associated with prematurity as leading cause of mortality [31].In addition, Reuter et al. declared that prematurity, respiratory complications including respiratory distress syndrome (RDS) and meconium aspiration syndrome (MAS) were the most common causes leading to neonatal admissions and associated with 29% and 15% respectively [32]. As well as, Edwards et al. studied the neonatal admissions rate in England and Wales at Cardiff University School of Medicine. Their findings demonstrated that the most common reason for admissions were associated with prematurity and respiratory distress. Also, they reported an inverse relationship between gestational age and incidence of respiratory distress[33].

During our study, the median length of hospitalization was 4 to 7 days, which is shorter than other reported hospitalization periodsof 2 to 8 days and 5.5 to 12.5 days[22, 24]. Significantly, the longer median length of stay at a NICU influences the economic burden for healthcare providers.The estimated cost of term neonate admissionto aNICU is approximately $2500,including respiratory support, medication, and nutrition[34]. However, a dramatic increase inNICU cost has beenreported for preterm, low birth weight, and congenital anomalies neonates[35, 36]. Inour study, the median gestational age (GA) was 37 weeks, median birth weight was 2.45 kg, and the median discharge weight was 2.63 kg. The mortality rate per live births was 160/15,024,leading to 9 deaths per 1000 live births, which is in line with the recommendation of the United Nation’s Sustainable Development Goals (UN SDG3) to reduce perinatal and neonatal mortality rate to fewerthan 12 deaths per live births bythe end of 2030[37]. However, NICU admissions costs have not been fully described in government hospitals in Jordan, leading to difficulties related to adequate funding in developing countries fortreating severe prematurity complications for neonates (GA < 24 weeks).

In addition to that, Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS) and National Institute for Health and Care Excellence (NICE) have recommended preventable measures to reduce infection and to ensure better management of invasive procedures within NICU. Essentially, hand hygiene-based alcohol sanitizer before and after patient contact is effective and efficient against many microorganisms[38]. Also, many studies in developing countries have confirmed that maternal breast feeding contains secretory antibodies, phagocytes, lactoferrin and prebiotics which improve host defense and gastrointestinal function and associated with lower rate of neonatal sepsis and out breaks of infection [39, 40]. As well as proper management and safe procedure of Total Parenteral Nutrition (TPN) according to the guidelines of (IDSA), (PIDS) and (NICE) should be strictly followed by healthcare providers in NICU [41]. TPN with good medical practices including medications preparation and antibiotic stewardship have significantly improve the prevention and treatment of neonatal infections [42, 43]. Furthermore, continuous education and training for healthcare personnel regarding intravascular catheter use, proper procedures for the insertion, sterilization, and update infection control guidelines have been widely recommended [44].

Conclusion

      Prematurity, RDS, TTN, and neonatal sepsis were the leading clinical indicators for NICU admissions and were responsible for 74% of the morbidity profile. On the other hand, prematurity, RDS, and sepsis were the most frequent causes of neonatal deaths, leading to a 7.5% neonatal mortality rate of all admitted neonates, and 9 deaths per 1000 live births meeting the target ofUN SDG3.

Ethics Approval

An Institutional Review Board (IRB) approval was obtained from the ethical committee at Royal Medical Services.

Patient data privacy and confidentiality are maintained as this study was conducted in compliance with the ethical standards per Helsinki declaration.

Limitation of study

References

1.Hillman, N.H., S.G. Kallapur, and A.H. Jobe, Physiology of transition from intrauterine to extrauterine life. Clinics in perinatology, 2012. 39(4): p. 769-783.

2.Moller, A.B., et al., Monitoring maternal and newborn health outcomes globally: a brief history of key events and initiatives. Tropical Medicine & International Health, 2019. 24(12): p. 1342-1368.

3.Ray, J.G., A.L. Park, and D.B. Fell, Mortality in infants affected by preterm birth and severe small-for-gestational age birth weight. Pediatrics, 2017. 140(6).

4.Reyes, J., et al., Neonatal mortality and associated factors in newborn infants admitted to a Neonatal Care Unit. Arch Argent Pediatr, 2018. 116(1): p. 42-8.

5.Steurer, M.A., et al., Gestational age and outcomes in critical congenital heart disease. Pediatrics, 2017. 140(4).

6.Seale, A.C., et al., Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. The Lancet infectious diseases, 2014. 14(8): p. 731-741.

7.Kirby, R.S., The prevalence of selected major birth defects in the United States. Seminars in Perinatology, 2017. 41(6): p. 338-344.

8.Lawn, J.E., et al., Every Newborn: progress, priorities, and potential beyond survival. The Lancet, 2014. 384(9938): p. 189-205.

9.Hug, L., et al., National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis. The Lancet Global Health, 2019. 7(6): p. e710-e720.

10.(JOR)., J., Demographics, health & infant mortality. UNICEF DATA. . Available from: https://data.unicef.org/country/jor/.

11.Doubova, S.V., et al., Evaluating the quality of the processes of care and clinical outcomes of premature newborns admitted to neonatal intensive care units in Mexico. International Journal for Quality in Health Care, 2018. 30(8): p. 608-617.

12.Quinn, J.-A., et al., Preterm birth: Case definition & guidelines for data collection, analysis, and presentation of immunisation safety data. Vaccine, 2016. 34(49): p. 6047-6056.

13.Cutland, C.L., et al., Low birth weight: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine, 2017. 35(48Part A): p. 6492.

14.Suzanne, R., M. Chuanpit, and B. Michelle, Respiratory distress in the Newborn. Pediatr Rev, 2014. 35(10): p. 417-429.

15.Jha, K. and K. Makker, Transient tachypnea of the newborn. 2019.

16.Organization, W.H., Basic newborn resuscitation: a practical guide. 1998, World Health Organization.

17.Monfredini, C., et al., Meconium Aspiration Syndrome: A Narrative Review. Children, 2021. 8(3): p. 230.

18.Hyperbilirubinemia, A.A.o.P.S.o., Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics, 2004. 114(1): p. 297-316.

19.Benterud, T., L. Sandvik, and R. Lindemann, Cesarean section is associated with more frequent pneumothorax and respiratory problems in the neonate. Acta obstetricia et gynecologica Scandinavica, 2009. 88(3): p. 359-361.

20.Offermann, H., et al., Cesarean section increases the risk of respiratory adaptive disorders in healthy late preterm and two groups of mature newborns. Z Geburtshilfe Neonatol, 2015. 219(6): p. 259-65.

21.ACOG Committee Opinion No. 765 Summary: Avoidance of Nonmedically Indicated Early-Term Deliveries and Associated Neonatal Morbidities. Obstetrics & Gynecology, 2019. 133(2): p. 404-405.

22.Sivasubramaniam, P.G., et al., Neonatal outcomes of infants admitted to a large government hospital in Amman, Jordan. Global journal of health science, 2015. 7(4): p. 217.

23.Shehab El-Din, E.M.R., et al., Epidemiology of Neonatal Sepsis and Implicated Pathogens: A Study from Egypt. BioMed Research International, 2015. 2015: p. 509484.

24.Khasawneh, W., et al., Indications and Clinical Profile of Neonatal Admissions: A Cross-Sectional Descriptive Analysis from a Single Academic Center in Jordan. Journal of Multidisciplinary Healthcare, 2020. 13: p. 997.

25.Al-Matary, A., et al., Characteristics of neonatal Sepsis at a tertiary care hospital in Saudi Arabia. Journal of infection and public health, 2019. 12(5): p. 666-672.

26.Stoll, B.J., et al., Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002–2003. The Pediatric infectious disease journal, 2005. 24(7): p. 635-639.

27.Pammi, M. and L.E. Weisman, Late-onset sepsis in preterm infants: update on strategies for therapy and prevention. Expert review of anti-infective therapy, 2015. 13(4): p. 487-504.

28.Ganatra, H.A., B.J. Stoll, and A.K. Zaidi, International perspective on early-onset neonatal sepsis. Clinics in perinatology, 2010. 37(2): p. 501-523.

29.Batieha, A.M., et al., Level, causes and risk factors of neonatal mortality, in Jordan: results of a national prospective study. Maternal and child health journal, 2016. 20(5): p. 1061-1071.

30.Baghel, B., A. Sahu, and K. Vishwanadham, Pattern of admission and outcome of neonates in a NICU of Tribal Region Bastar, India. Congen Anomal, 2016. 2(6): p. 147-50.

31.McIntire, D.D. and K.J. Leveno, Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstetrics & Gynecology, 2008. 111(1): p. 35-41.

32.Reuter, S., C. Moser, and M. Baack, Respiratory distress in the newborn. Pediatrics in review, 2014. 35(10): p. 417.

33.Edwards, M.O., S.J. Kotecha, and S. Kotecha, Respiratory distress of the term newborn infant. Paediatric respiratory reviews, 2013. 14(1): p. 29-37.

34.Petrou, S. and K. Khan, Economic costs associated with moderate and late preterm birth: primary and secondary evidence. Semin Fetal Neonatal Med, 2012. 17(3): p. 170-8.

35.Helle, E., et al., Morbidity and Health Care Costs After Early Term Birth. Paediatr Perinat Epidemiol, 2016. 30(6): p. 533-540.

36.Cheah, I.G.S., Economic assessment of neonatal intensive care. Translational pediatrics, 2019. 8(3): p. 246.

37.Howden-Chapman, P., et al., SDG 3: Ensure healthy lives and promote wellbeing for all at all ages. A guide to SDG interactions: from science to implementation. Paris, France: International Council for Science, 2017: p. 81-126.

38.Bolon, M., Hand hygiene. Infectious Disease Clinics, 2011. 25(1): p. 21-43.

39.Rønnestad, A., et al., Late-onset septicemia in a Norwegian national cohort of extremely premature infants receiving very early full human milk feeding. Pediatrics, 2005. 115(3): p. e269-e276.

40.Meier, P., A. Patel, and A. Esquerra-Zwiers, Donor human milk update: evidence, mechanisms, and priorities for research and practice. The Journal of pediatrics, 2017. 180: p. 15-21.

41.Fishman, N., S.f.H.E.o. America, and I.D.S.o. America, Policy statement on antimicrobial stewardship by the society for healthcare epidemiology of America (SHEA), the infectious diseases society of America (IDSA), and the pediatric infectious diseases society (PIDS). Infection Control & Hospital Epidemiology, 2012. 33(4): p. 322-327.

42.Jaeschke, R., et al., Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. Bmj, 2008. 337.

43.Dellit, T.H., et al., Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clinical infectious diseases, 2007. 44(2): p. 159-177.

44.Marschall, J., et al., Strategies to prevent central line–associated bloodstream infections in acute care hospitals: 2014 update. Infection Control & Hospital Epidemiology, 2014. 35(7): p. 753-771.