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Exchange Transfusion Using Peripheral Vessels Is Safe and Effective in Newborn Infants

Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. The purpose of this study was to compare the efficiency and safety of exchange transfusion by using peripheral arteries and veins with that of conventional exchange transfusion via the umbilical vein in treating neonatal pathologic hyperbilirubinemia.

PATIENTS AND METHODS. We retrospectively reviewed the medical charts of all neonates who had undergone exchange transfusion at our institution from January 1995 to December 2006. Causes of jaundice, efficiency of exchange transfusion in lowering serum bilirubin concentrations, adverse events, and outcomes were recorded. Data were compared between neonates who had undergone exchange transfusion via the peripheral arteries and veins method and those who had undergone exchange transfusion via the umbilical vein method. Data were also compared between stable neonates (body weight > 1500 g without medical problems other than jaundice) and unstable neonates.

RESULTS. A total of 123 exchange-transfusion procedures were performed in 102 neonates in the 12-year study period: 24 were performed via the umbilical vein method and 99 via the peripheral vessels method. A total of 87 procedures were performed in 75 stable neonates and 36 in 27 unstable neonates. There was no significant difference in reduction of serum bilirubin level from circulation or the duration of procedures between the 2 methods. Eight neonates died before discharge, but none of the deaths seem to have been attributable to the exchange-transfusion procedure. Severe adverse events occurred more commonly in the umbilical vein group than the peripheral arteries and veins group in the stable neonates. All of the severe and minor events resolved completely without noticeable sequelae before discharge.

CONCLUSIONS. Exchange transfusion using peripheral arteries and veins is efficient and effective in reducing serum bilirubin from circulation and is associated with few adverse events. This method should be considered for all neonates requiring exchange transfusion for treatment of neonatal hyperbilirubinemia.

Key Words: hyperbilirubinemia • exchange transfusion • peripheral vessels • adverse events • neonates

Abbreviations: ET—exchange transfusion • UV—umbilical vein • PA—peripheral artery • PV—peripheral vein • DIC—disseminate intravascular coagulopathy • NEC—necrotizing enterocolitis

Although the frequency of neonatal exchange transfusions (ETs) has declined markedly in the past 20 years in the United States,¹ newly diagnosed kernicterus cases are continuing to be reported in different areas of the world.^2–5 ET is still performed in many countries to prevent the development of kernicterus, especially in countries with a high incidence of neonatal hyperbilirubinemia.^6,7

Umbilical vessels, especially the umbilical vein (UV), are used in conventional double-volume blood ETs in neonates with hyperbilirubinemia; however, the incidence of adverse events, including death, associated with this method is high.^6–10 Several studies have reported that ET via the peripheral arteries (PAs) for withdrawal and peripheral vein (PV) for infusion of blood is associated with few complications.^11–15 To our knowledge, there have been no reports comparing the efficiency and adverse-event rate between the UV and PA/PV methods. This study was undertaken to compare the efficiency of the PA/PV method with that of the UV method and the incidence of adverse events attributable to ET. We also compared the incidence of adverse events between stable and unstable neonates who had undergone the procedures.

	PATIENTS AND METHODS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The study population included all neonates who had undergone ET for neonatal hyperbilirubinemia in our NICU from January 1995 to December 2006 (12 years) at the Changhua Christian Hospital. The following data were collected from case records: patient demographics, indications for ET, duration of ET, percentage decrease in bilirubin level after ET, and adverse events caused by ET. Neonates with conditions other than hyperbilirubinemia, such as polycythemia and anemia, were excluded from this study.

The causes of hyperbilirubinemia were categorized into 1 or more of the following: glucose-6-phosphate dehydrogenase deficiency, ABO incompatibility, infection (proven by culture or suggested by clinical signs), Coombs’ test–positive hemolytic jaundice, and idiopathic hyperbilirubinemia.

The indications for ET were determined by the attending clinicians on the basis of established criteria.

Stable neonates were defined as neonates with birth weights of >1500 g and no medical problems other than jaundice. Unstable neonates were those with birth weights of <1500 g and/or neonates with medical problems.

NICU pediatric residents and/or interns performed all of the ET procedures. The PA/PV method was performed via PAs (radial artery in most instances). The arteries were cannulated percutaneously with a 24-gauge catheter under aseptic conditions to withdraw blood. A 24-gauge catheter was inserted aseptically into a superficial vein of the other limb for the infusion of donor blood. The 2 catheters were both connected to a syringe and a 3-way stopcock to withdraw and infuse blood, respectively. All of the infants in this study received isovolemic double-volume ET, simultaneously pulling blood out of the PA and pushing new blood in the PV. The blood was removed in aliquots of 5 mL for infants <1500 g, 10 mL for infants 1500 to 2500 g, 15 mL for infants 2500 to 3000 g, and 20 mL for infants >3000 g. The rate of ET was 5 mL/kg per minute according to standard published guidelines.

The UV method was performed by inserting an umbilical venous catheter under aseptic conditions. Withdrawal and infusion of blood were done at the same speed as that for the PA/PV method.

Heart rate, respiratory rate, skin temperature, and oxygen saturation were monitored during and at least 24 hours after the procedure. Arterial blood pressure was measured every 10 minutes through the arterial line via a pressure transducer connected to 3-way stopcock. Serum bilirubin, sodium, chloride, potassium, total or ionized calcium, arterial blood gas, and complete blood cell counts were checked 3 times: immediately before the ET procedure was initiated (preexchange), halfway through the procedure, and immediately after discontinuing the procedure (postexchange). The serum bilirubin level was then measured every 8 hours to monitor potential rebound of bilirubin. The catheters were left in place when the neonate was expected to receive another ET for severe hyperbilirubinemia. The arterial catheter was kept patent by continuous infusion of heparinized saline (1 unit/mL) at a rate of 1 mL/hour.

An adverse event was defined as any complication that was not present before the ET that occurred within 7 days after the exchange. The following definitions were used: thrombocytopenia (platelet count < 100 000/mL), hypocalcemia (total serum calcium level < 8.0 mg/dL or ionized calcium < 1 mol/dL), hypotension (systolic arterial pressure < 40 mm Hg), catheter malfunction (including blood clots in the catheter resulting in the need for removal and/or replacement of the catheter), desaturation (percutaneous oxygen < 90 mm Hg), necrotizing enterocolitis (NEC) (according to Bell's criteria),¹¹ sepsis (clinical signs of infection in the presence of a positive blood culture), and omphalitis (inflammation of the umbilicus). ET-related mortality was defined as any death that was directly related to the ET procedures. The incidence of adverse events related to ET was calculated on the basis of the number of procedures performed rather than the number of neonates treated.

The Pearson ² test and the Fisher's exact test were used to compare categorical variables. The Mann-Whitney U test (Wilcoxon rank-sum test) was used to compare continuous variables. A P value of <.05 was considered to be statistically significant. All data were analyzed by using the Statistical Package for Social Sciences 15.0 software for Windows (SPSS Inc, Chicago, IL).

	RESULTS

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From January 1995 to December 2006, a total of 105 neonates received ET. Hospital records were available for 102 patients; therefore, the study population comprised 102 neonates who had undergone a total of 123 ET procedures. Sixteen neonates received >1 ET: 1 neonate received 4 ETs, 3 received 3 ETs, and 12 received 2 ETs. The UV group comprised 24 procedures performed in 19 neonates, and the PA/PV group comprised 99 procedures performed in 83 neonates (Table 1). Most of the 24 UV ETs were performed when the PA/PV method was first introduced into our NICU in 1995. Some of the attending physicians and residents were not confident with the method in the beginning years; however, the PA/PV method became the treatment of choice shortly thereafter. Four of the 24 procedures in the UV group were originally scheduled for the PA/PV method; however, the method was changed to the UV method because the arteries could not be catheterized successfully.

The ET procedure could not be completed in 3 neonates in the PA/PV group. This failure was because of malfunction of the radial artery catheter near the end of the procedure in 2 of the 3 patients; the third neonate developed hypotension and desaturation near the end of the procedure. Infection was suspected, because the infant's mother was pyrexic during delivery. The 3 neonates did not need to receive additional ET for hyperbilirubinemia.

Causes of hyperbilirubinemia requiring ET were idiopathic for 52 (42.2%) neonates, infection with positive culture results (n = 7) or clinical signs suspected for infection (n = 18) in 25 (20.3%), ABO incompatibility in 18 (14.6%), glucose-6-phosphate dehydrogenase deficiency in 21 (17.1%), and Coombs’ test–positive hemolytic jaundice in 7 (5.7%).

The mean duration of ET via the UV method was 80.9 ± 41.0 minutes, and that via the PA/PV method was 79.8 ± 28.6 minutes. There was no statistical difference in the duration of the procedures between the 2 methods (P = .46) (Table 1).

A total of 8 neonates died (UV group: n = 4; PA/PV group: n = 4); however, none of the deaths were attributable to ET. The causes of death in the UV group were extreme low birth weight with sepsis (n = 2), severe asphyxia (n = 1), and severe respiratory distress syndrome with disseminated intravascular coagulopathy (DIC) (n = 1). The causes of death in the PA/PV group were sepsis and pulmonary hemorrhage (n = 1), severe hemolysis with severe acidosis (n = 1), echo viral sepsis (n = 1), and sepsis with DIC (n = 1).

Two of the 102 neonates in the PA/PV group developed clinical signs of kernicterus. One of them was a term neonate with underlying sepsis and DIC who had spastic posture suggestive of kernicterus before ET; he died as a result of underlying sepsis after 3 ET procedures. The other neonate was a 5-day-old term male infant who presented with a spastic posture and a serum bilirubin level of 44.6 mg/dL before the ET. Profound mental retardation and hearing impairment were diagnosed in this patient at the age of 6 years 10 months.

ET procedure-associated severe complications such as sepsis and cardiac arrest did not occur in our neonates. There were no differences in the incidences of adverse events between the UV and the PA/PV groups (Table 2). There were 9 adverse events during or after the 24 UV procedures and 34 adverse events associated with the 99 PA/PV procedures.

Among the stable neonates in the PA/PV group, there were 24 minor adverse events: asymptomatic hypocalcemia treated with calcium gluconate transfusion (n = 7); transient ischemic change of the arterial catheterized hand after the ET (n = 5), although all of these patients recovered within hours after warm parking of the hands; catheter malfunction (n = 5); thrombocytopenia without platelet transfusion (n = 3); an episode of desaturation with oxygen saturation of <90 mm Hg during ET (n = 2), which did not require treatment; transient hypotension (n = 1); and a posttransfusion serum potassium level of 6.1 mEq/L (n = 1).

Among the unstable neonates in the UV group, 3 developed thrombocytopenia, which did not require platelet transfusion (platelet count between 50 000 and 100 000/mL).

Among the unstable neonates in the PA/PV group there were a total of 10 adverse events. Two of them were serious events: 1 neonate who had underlying sepsis required endotracheal ventilation for desaturation during the ET, and the other had ischemic change of the catheterized hand during the third-time ET procedure and required urokinase treatment for suspected embolization of the radial artery. The ischemic hand improved completely 1 day later. Eight of the 10 adverse events were minor: transient oxygen desaturation in 3 neonates with underlying sepsis and DIC; asymptomatic hypocalcemia in 2 neonates treated by calcium gluconate transfusion; thrombocytopenia without platelet transfusion in 2 neonates; and catheter malfunction in 1 neonate.

All of the adverse events noted in the UV and PA/PV groups occurred within 24 hours after the ET, and all events resolved completely without noticeable sequelae before the affected neonates were discharged.

	DISCUSSION

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Several studies have reported that ET via peripheral vessels is an effective and safe alternative to ET via the UV in neonates.^11–14 Despite its practical advantages, ET through the peripheral vessels does not seem to have gained much acceptance by pediatricians since it was first described. To our knowledge, our study is the first to report a comparison of the efficiency and safety of ET using PA/PV with that of conventional UV ET.

We found that there was no statistical difference in the efficiency of eliminating bilirubin from circulation between the 2 methods. Furthermore, most of the ET procedures performed via the PA/PV could be completed within a reasonable time (80 minutes) by using a 24-gauge catheter. The average duration for both procedures in our series was compatible with the duration of the UV method reported by Patra et al.⁸

In general, access via the UV is the recommended ET method for treatment of severe hyperbilirubinemia in neonates.¹⁶ However, some reports have shown that ET via the umbilical vessels is a relative high-risk procedure. For example, Steiner et al¹ reported that the overall ET-related adverse-event rate including hypocalcemia and thrombocytopenia was up to 73% (33 of 45 patients). Guaran et al¹⁷ reported that 7 (4.3%) of 248 neonates who underwent ET died as a result of complications associated with the procedure. In our 24 UV-method cases, there were no mortalities attributable to ET. Two serious but reversible adverse events occurred after 24 (8.3%) of the procedures in our study. The overall incidence of adverse events (36.7%) in the UV group in our series is lower than that reported by Jackson⁹ (63%) but higher than that reported by Sanpavat (15%)⁶; however, there were fewer patients who underwent the UV method in our series and, therefore, no conclusion on the safety of the UV method in neonates can be drawn from our study.

Studies have found that adverse events related to ET occur less frequently when ET is performed via the PA/PV method.^11,12,15 Our findings are compatible with those reports. In our series, we found that in stable neonates, there were significantly (P = .024) fewer severe adverse events when using the PA/PV method (0%) compared with 14.3% when using the UV method (Table 3).

Hypocalcemia is a common complication of ET.^1,8,9 Steiner et al¹ reported that 38% of neonates who received ET via the UV method developed hypocalcemia and that 45% of these hypocalcemic neonates required calcium-replacement therapy. The calcium levels may be complexed by the citrate in the exchange-transfused blood. That means that the number of true hypocalcemia cases may have been fewer than the number indicated by the laboratory results. In our series, only 9% of the neonates in the PA/PV group and 12.5% in the UV group developed asymptomatic hypocalcemia and received calcium-replacement therapy.

Jackson⁹ reported that 16% of 106 neonates experienced thrombocytopenia after ET via the UV method and that 60% of them required platelet transfusion; Patra et al⁸ reported that the incidence of thrombocytopenia was 44% in 66 neonates. Steiner et al¹ reported that 38% of 141 patients developed thrombocytopenia and that 49% of them needed platelet transfusion. In our series, although not statistically significant (P = .072), only 5.1% of the neonates who underwent ET via the PA/PV method developed thrombocytopenia, compared with 16.7% in the UV group. None of the neonates in either group required platelet transfusion.

Previous reports have indicated that NEC is a severe complication of conventional UV ET. Guaran et al¹⁷ reported that 2 neonates died as a result of NEC in 248 UV-ET procedures. Jackson⁹ reported that 1 previously stable neonate developed severe NEC requiring surgery in 106 UV-ET procedures. In our series, 1 previously stable neonate developed NEC after undergoing ET via the UV method. However, none of the neonates in the PA/PV group developed NEC after ET; this finding is compatible with that reported in previous studies of the PA/PV method.^11,12 Compared with the UV method, gastrointestinal complications are minimized when using the PA/PV method and there is no need to restrict feeding during and after the procedure.

Jackson⁹ reported a mortality rate of 8% in 25 previously ill neonates who underwent UV ET. Because of the much higher rates of complications in unstable neonates who undergo ET, some authors do not support recommendations to use lower exchange levels in these neonates.^6,9 Instead, they have suggested that ET be reserved for neonates with hemolysis in whom intensive phototherapy has failed and for whom the risk of encephalopathy exceeds the risk of complications and death resulting from the procedure.^6,9 However, this suggestion is based on the relatively high incidence of serious adverse events caused by the conventional UV-ET method and in areas with a lower incidence of hyperbilirubinemia. Therefore, this suggestion may not be suitable for populations with a higher incidence of hyperbilirubinemia, such as east Asian, Greek, or American Indian neonates.^2,18,19 In our series, there were 10 adverse events in 26 unstable neonates in the PA/PV method group, and only 2 of the 10 were severe but reversible events. We suggest that the PA/PV method might be safer in high-risk infants who require ET.

The peripheral arterial catheterization procedure is needed for every neonate requiring PA/PV ET. The reported adverse events associated directly with arterial catheterization were few. Fok et al¹² reported that using a 24-gauge catheter causes no more catheter-induced hemolysis than standard umbilical catheters. Randel et al²⁰ reported 2 (1.27%) complications in 158 arterial lines in preterm and term neonates; both were related to sepsis. In comparison, Jackson⁹ reported 21 cases (of a total of 81 UV procedures) of clotting of the umbilical catheter that required replacement or discontinuation of ET. In our PA/PV neonates, these adverse events included catheter malfunction, transient ischemic changes of the radial arteries, and suspected occlusion of the radial artery. These reversible events were more common in our series than in previously reported studies regarding the PA/PV method, although these adverse events are also encountered during routine monitoring with arterial catheterization of neonates in the NICU. We suggest, with appropriate caution in ischemic changes and occlusion of the radial artery, that peripheral arterial cannulation is a relative safe and reliable alternative to umbilical vessel catheterization.

In addition to leading to fewer adverse events, the PA/PV method may have more advantages than the conventional UV method for several reasons. First of all, the procedure is easier and less expensive (50% less in expendable material in our NICU) to perform than the UV method. Second, in some unstable neonates, peripheral arterial lines rather than umbilical arterial lines are used for drawing blood and monitoring blood pressure, which makes it unnecessary to canalize the UV if an ET is later deemed necessary for these patients. Third, the simultaneous isovolemic removal and replacement of blood via the PA and PV may minimize fluctuation in cardiovascular changes caused by changes in circulation volume, which is especially important in very low birth weight and unstable neonates. Fourth, unlike the UV, the peripheral vessels can be used in neonates of older age with a healed umbilicus. The umbilicus usually heals within 7 to 10 days. Performing ET by using the conventional method in patients with a healed umbilicus requires invasive procedures such as venous cut-down or placement of a central venous pressure line. These procedures may cause more complications by less experienced staff. In our series, neonates in the PA/PV group were significantly older than those in the UV group when the ET was performed. Twenty of the neonates who underwent ET via the PA/PV method ranged in age from 7 to 30 days and had a healed umbilicus.

The limitations of our study include its retrospective nature and the relatively small sample size. Additional large-scale prospective studies are needed to clarify the safety and efficiency of ET via the PA/PV method, especially in unstable or premature neonates.

	CONCLUSIONS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
ET via peripheral vessels is an efficient and safe alternative to umbilical vessel ET. The technique can be used in most neonates who require ET to minimize iatrogenic risks, especially in premature and ill neonates.

	FOOTNOTES

 
Accepted Jun 4, 2008.

Address correspondence to Hsiao-Neng Chen, MD, Changhua Christian Hospital, Department of Pediatrics, 135 Nansiau St, Changhua, Taiwan. E-mail: 19184{at}cch.org.tw

The authors have indicated they have no financial relationships relevant to this article to disclose.

This work was presented, in part, as a poster at the Pediatric Academic Societies annual meeting; May 5, 2008; Honolulu, Hawaii.

What's Known on This Subject Several studies have reported that ET via peripheral vessels is an effective and safe alternative to ET via the UV in the treatment of neonatal hyperbilirubinemia.

 

What This Study Adds There was no difference in the reduction of serum bilirubin level from circulation and the time of procedures between the 2 methods. The peripheral vessels can be used in neonates of older age with a healed umbilicus. This ET method may minimize iatrogenic risks.

 

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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16. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344 (8):581 –590[Free Full Text]
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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Chen, H.-N. Articles by Tsao, L.-Y. PubMed PubMed Citation Articles by Chen, H.-N. Articles by Tsao, L.-Y. Related Collections Premature & Newborn

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