Several clinical guidelines for the management of infants with severe neonatal hyperbilirubinemia recommend immediate exchange transfusion (ET) when the risk or presence of acute bilirubin encephalopathy is established in order to prevent chronic bilirubin encephalopathy or kernicterus. However, the literature is sparse concerning the interval between the time the decision for ET is made and the actual initiation of ET, especially in low- and middle-income countries (LMICs) with significant resource constraints but high rates of ET. This paper explores the various stages and potential delays during this interval in complying with the requirement for immediate ET for the affected infants, based on the available evidence from LMICs. The vital role of intensive phototherapy, efficient laboratory and logistical support, and clinical expertise for ET are highlighted. The challenges in securing informed parental consent, especially on religious grounds, and meeting the financial burden of this emergency procedure to facilitate timely ET are examined. Secondary delays arising from post-treatment bilirubin rebound with intensive phototherapy or ET are also discussed. These potential delays can compromise the effectiveness of ET and should provide additional impetus to curtail avoidable ET in LMICs.

Exchange transfusion (ET) is a definitive and effective therapy for preventing kernicterus, usually where intensive phototherapy is either lacking or proves to be ineffective in arresting rapidly rising bilirubin levels in infants with severe neonatal hyperbilirubinemia or symptoms of acute bilirubin encephalopathy (ABE)[1,2]. The procedure is not risk-free however, as it may be associated with such complications as sepsis, electrolyte imbalance, air embolism, portal vein thrombosis, cardiac overload, thrombophlebitis, thrombocytopenia, necrotizing enterocolitis, and the transmission of blood-borne diseases, even in settings with advanced clinical care[3-6]. Several guidelines for the management of neonatal hyperbilirubinemia in developed and developing countries recommend immediate ET for infants with, or at risk of, acute or chronic bilirubin encephalopathy[2,7,8]. This is primarily because the timing of ET vis-à-vis the complex interaction between the level and duration of exposure of the neuronal cells to unbound bilirubin crucially affects intervention outcomes[9]. However, this timely goal is rarely achieved in many low- and middle-income countries (LMICs), where excessive rates of ET persist as a result of weaknesses in the health-care delivery system in these locations[10-13]. For example, it is not uncommon for a severely jaundiced infant to first present in a hospital not adequately equipped to provide emergency care, including ET, and are thus subsequently referred to a better equipped hospital[11,14]. This experience often results in considerable delay in providing ET[15]. Several reports also suggest that delays of up to 24 h from the time the decision to carry out ET is made and when treatment is received by the affected infant in the same hospital are not uncommon[6,14,15], compared to the estimated 4-6 h in developed countries[16]. Such delays are likely to account for the high incidence of bilirubin-induced neurological dysfunctions (ABE and kernicterus) and the associated devastating consequences in many LMICs[15,17,18]. This paper, therefore, sets out to identify commonly reported facility-based challenges in providing timely and effective ET in hospitals designated for such an emergency procedure in LMICs.

We conducted an electronic search of PubMed, Scopus, Ovid EMBASE, and the Cumulative Index to Nursing and Allied Health Literature to retrieve articles published between January 1990 and June 2015 on exchange transfusion for hyperbilirubinemia in resource-limited countries. The search terms used were “neonatal hyperbilirubinemia”, “neonatal jaundice”, “exchange transfusion”, “bilirubin encephalopathy”, and/or “kernicterus”. The terms “resource-limited”, “resource-constrained”, and “resource-poor” countries are used interchangeably to refer to the 91 LMICs with a per capita gross national income (GNI) of ≤ $6000 using the Human Development Report 2013 published by the United Nations Development Program as previously reported (Table 1)[8,15]. These countries have an average life expectancy of 63.3 years and a median national frequency of 8.2% (inter-quartile range: 3.3%-14.6%) for glucose 6-phospho-dehydrogenase (G-6-PD) deficiency. Only articles or reports published from these 91 countries were reviewed. As this paper was designed as a narrative review, no systematic evaluation of the retrieved articles and reports was planned.

The metabolism of bilirubin has been well described in the literature[19-21]. Essentially, bilirubin production is a normal process of human physiology and begins from the degradation of heme from senescent red blood cells (Figure 1). Once produced, bilirubin is conjugated in the liver with glucuronic acid to form bilirubin glucuronide. Conjugated bilirubin is then conveyed across the canalicular membrane through the biliary tree to the intestinal lumen for excretion. Newborns, especially premature infants, have an immature bilirubin conjugation and excretion system. As a result, they have limited ability to conjugate bilirubin and excrete unconjugated bilirubin readily. These limitations account for an imbalance between bilirubin production and elimination. In effect, neonatal jaundice occurs when the rate at which bilirubin is produced exceeds the rate of elimination, reflecting the total bilirubin load in the body after birth, to become visible in the skin as yellow pigment. In full-term infants, serum bilirubin concentrations, known as physiologic jaundice, peak at 5 to 10 mg/dL in the first three days of life and decline thereafter to values commonly found in adults of approximately 1 mg/dL. However, in a few infants, serum bilirubin concentrations may become pathologic and exceed 17 mg/dL, which is indicative of a disorder that requires treatment. Total bilirubin levels beyond 17 mg/dL, especially in infants with predisposing hemolytic conditions, may lead to the movement of unconjugated bilirubin into brain cells to cause acute bilirubin encephalopathy. Continued exposure to free bilirubin may lead to irreversible damage or chronic bilirubin encephalopathy. Timely intensive phototherapy and ET can arrest this progression and prevent or minimize bilirubin-induced mortality and long-term neurologic morbidity.

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Figure 1 Metabolic pathway of bilirubin neurotoxicity. ABE: Acute bilirubin encephalopathy.

The facilities and techniques for undertaking ET in LMICs have been well described in the literature[4,8]. The clinical criteria for initiating ET have also been discussed in greater detail elsewhere[8,22]. Typically, regardless of the total plasma/serum bilirubin (TSB) level, a “crash-cart approach” (initiation of immediate intensive phototherapy and fluid supplementation, followed by ET) is recommended for infants with early signs and symptoms of intermediate/advanced ABE (lethargy, hypotonia, poor feeding, seizures, opisthotonos, and impaired level of consciousness) with or without evidence of neurotoxicity risk factors (prematurity, isoimmune hemolytic disease, G6PD deficiency, asphyxia, sepsis, acidosis, and hypoalbuminemia). It is also worth noting that the clinical diagnosis of hemolytic jaundice remains a challenge owing to the lack of advanced tests like end-tidal carbon monoxide (ETCO), eosin-5-maleimide flow cytometry to identify red blood cell membrane defects, and next-generation sequencing of relevant genes for mutations and polymorphisms[23].

Studies describing the process from when the decision to conduct ET has been made and the actual execution of ET systematically were surprisingly rare from our literature review[4,9,24,25]. We therefore also relied on our practice experience spanning over three decades in providing newborn care in a LMIC. For example, from 2012 to 2014, approximately 120 ETs were conducted annually in our hospital, Massey Street Children’s Hospital in Lagos, which is the oldest children’s hospital in Nigeria[26]. Typically, in most clinical settings, once the need for ET has been established by the resident physician and the consultant, the typical steps to ET can be summarized as shown in Figure 2. The delays that may be encountered at any of these stages are described as follows:

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Figure 2 Sequence of events and sources of potential delays following the decision to initiate exchange transfusion.

Post-ET monitoring is necessary because of the likelihood of repeat ET after a rebound of high TSB level due to unrecognized hemolytic disease, with potential secondary delays[28,30,44]. Not all attending clinicians in emergency situations are skillful in providing ET, even where facilities are available, and this may result in delays in getting a suitable individual when all preparations have been made. In settings where ET is infrequent, lack of expertise may be a source of delay, especially when referral to another hospital becomes imperative[14]. Lack of a clearly-defined protocol or failure to adhere to an existing protocol is likely to cause delay as a result of communication gaps among team members. Where ET protocol requires the express approval of a consultant before execution by attending junior physicians, this may result in more potential delays. When more than one infant requires urgent ET and resources are limited, identifying and prioritizing the infant(s) most at-risk of kernicterus may also inevitably result in delay for some infants. Additionally, inadequate support staff may be a source of delay in providing seamless communication with the laboratory and/or a skilled assistant for the procedure. In some settings, patients may be required to bear the costs of the laboratory investigations requested by the attending physicians, especially in private hospitals[47,48]. Inability to meet such expenses is also a potential source of delay in providing timely ET[49].

The nature and scope of these delays are likely to vary within and across LMICs. Perhaps the overarching implication of these challenges is the impetus to avoid ET as much as possible by facilitating early presentation and timely provision of effective/intensive phototherapy, as well as investment in functional, readily accessible, and appropriately staffed laboratories in all hospitals that offer emergency care for newborns. Side laboratory with facilities for real-time bilirubin measurements should be made available in all neonatal units. Education of mothers and caregivers on the value of timely presentation and intervention in preventing bilirubin-induced mortality and long-term neurodevelopmental disorders should be routinely offered during antenatal visits. There is also a need for better communication and understanding between clinicians and laboratory personnel, especially with regards to the challenge of minimizing wastage of blood due to over-ordering[43].

While the focus of this review is primarily to serve the needs of clinicians in LMICs, the emerging and rising profile of global child health makes the topic also relevant to clinicians in the developed world.

ET is widely embraced as an effective treatment for infants with, or at risk of, bilirubin-induced neurologic dysfunctions (ABE and kernicterus) in LMICs. However, several potential delays are associated with the various critical steps prior to the initiation of ET after the need for this emergency procedure has been established. Efforts to minimize these delays, including efficient laboratory and logistical support, are imperative in ensuring timely and efficacious ET. Timely, effective, and intensive phototherapy should also be routinely provided to curtail the prevailing high rates of avoidable ET in LMICs.