|Year : 2018 | Volume
| Issue : 2 | Page : 89-93
Clinical pearls in pediatric anesthetic considerations for peripheral blood stem cell transplant and lacunae in our current knowledge
Shagun B Shah1, Ajay K Bhargava1, Sangeeta Bhagat1, Dinesh Bhurani2, Narendra Agrawal2
1 Department of Anaesthesiology Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
2 Department of Hemato-Oncology and Bone Marrow Transplant, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
|Date of Web Publication||31-Dec-2018|
Shagun B Shah
H. No: 174–175, Ground Floor, Pocket 17, Sector 24, Rohini, New Delhi 110085
Source of Support: None, Conflict of Interest: None
Clinical introduction of peripheral blood stem cell transplant (PBSCT) has replaced bone marrow as a stem cell source in 99% autologous and 75% allogeneic transplantation cases. Incompliant pediatric donors require general anesthesia for PBSCT. Whether the CD34-positive (CD34+) stem cell yield from PBSC donor is affected by age, weight, and sex of donor and type/duration of anesthesia is not very clear from the current literature. These factors may have significant clinical implications as is evident from the poor yield (0.11 million/kg CD34+ cells) on the second day of stem cell harvest from our 2-year-old donor.
Keywords: Allogeneic transplantation, general anesthesia, pediatric, stem cells
|How to cite this article:|
Shah SB, Bhargava AK, Bhagat S, Bhurani D, Agrawal N. Clinical pearls in pediatric anesthetic considerations for peripheral blood stem cell transplant and lacunae in our current knowledge. J Curr Oncol 2018;1:89-93
|How to cite this URL:|
Shah SB, Bhargava AK, Bhagat S, Bhurani D, Agrawal N. Clinical pearls in pediatric anesthetic considerations for peripheral blood stem cell transplant and lacunae in our current knowledge. J Curr Oncol [serial online] 2018 [cited 2019 Jul 20];1:89-93. Available from: http://www.journalofcurrentoncology.org/text.asp?2018/1/2/89/249058
| Introduction|| |
Peripheral blood stem cell (PBSC) harvesting is a nonsurgical method of gathering hematopoietic cells for bone marrow transplants. Bone marrow and umbilical cord blood are other sources of stem cells. Circulating hematopoietic stem cells can completely and permanently regenerate a lymphohematopoietic system after myeloablative treatment. The T and B cell content of allogeneic PBSC grafts is 10 times greater than that of bone marrow grafts. The rate of infections after engraftment is 1.7 times higher in marrow recipients (fungal infections > bacterial infections > viral infections),,, possibly because of delayed engraftment and immune reconstitution. Average amount of harvest is 15–20mL/kg donor body weight in each procedure. Although adults tolerate the procedure under local/no anesthesia, pediatric donors are incompliant and require general anesthesia. Whether the CD34-positive (CD34+) stem cell yield from PBSC donor is affected by age, weight, and sex of donor and type/duration of anesthesia is not very clear from the current literature. These factors may have significant clinical implications as is evident from the poor yield (0.11 million/kg CD34+ cells) on day two of stem cell harvest from our healthy minor donor.
| Case Reports|| |
First PBSC Transplant (First Patient)
A 2-year-old girl of B-positive blood group weighing 10kg was posted for allogeneic PBSC harvest. She was a stem cell donor for her 9-year-old brother who was of 27kg body weight, 132cm height, and O-positive blood group with thalassemia major. She was primed with 100 µg subcutaneous injections of filgrastim following which she developed bone pain that was treated with paracetamol syrup. Her chest radiograph, urinalysis, complete blood count, metabolic panel, and coagulation profile were within normal limits. She was tested negative for human immunodeficiency virus (HIV), hepatitis B and C viruses, and positive for cytomegalovirus immunoglobulin G (IgG) [Figure 1]. In the operation theatre, inhalational induction with sevoflurane, endotracheal intubation with a 4-mm internal diameter uncuffed tube, auscultatory and capnographic confirmation of endo tracheal tube placement, and packing of oropharynx with ribbon gauze were followed by securing an intravenous (IV) 20G cannula on the dorsum of left hand. A 5F femoral sheath was placed in her left femoral vein under ultrasound guidance for the exit of peripheral blood from the body into the apheresis machine. The blood returned to the venous circulation via another cannula (18G) placed on the dorsum of her right hand. The urinary bladder was catheterized. Anesthesia was maintained with sevoflurane and 40% oxygen in medical air and three 5-µg boluses of fentanyl intravenously. Peripheral nerve stimulator–guided atracurium boluses of 2.5mg each were given. The duration of anesthesia was 6.5h, and the femoral sheath was removed at the end of the procedure. A total of 283mL of anticoagulant citrate was used. The maximum rate of blood circulation, which the apheresis machine could attain in this patient was just 11mL/min. One blood volume of the patient was 800mL, and 3600mL of blood was passed through the apheresis machine in six cycles spanning 45min each [Figure 2].
|Figure 1: CARE timeline for the case report.TIVA = total intravenous anesthesia, CBC = complete blood count, CXR = chest X-ray; VIMA = volatile induction and maintenance of anaesthesia. No relevant past medical history|
Click here to view
|Figure 2: Image of the pediatric patient while under general endotracheal anesthesia during peripheral blood stem cell harvest. Images of the monitor screen displaying the number and duration of apheresis cycles have been included|
Click here to view
Second PBSC Transplant (First Patient)
After processing, a total of 108mL of stem cell rich buffy coat (18mL/cycle) could be collected. This was considered inadequate as the CD34+ cell count was just 1.68 million/kg of the recipient body weight. Hence, the child donor was again posted for stem cell harvest next day. Endotracheal anesthesia was induced using fentanyl (20 µg), propofol (15mg), and atracurium (10mg) and maintained with 40% oxygen in medical air, propofol, and two boluses of fentanyl amounting to 5 µg each. A fresh 5F femoral sheath was sonographically placed in the right femoral vein as the previous one had been removed immediately after the procedure. Blood was returned to the body via the same 18G cannula placed during the previous procedure. A total of 70mL of stem cell concentrate was collected after five cycles each lasting 45min. The duration of anesthesia was 4.5h. After procedure, when the 18G cannula was removed, bleeding from the puncture site persisted for the next 10min despite constant application of pressure on the site. Serum calcium, 0.87 mmol/L; hemoglobin, 9.6 gm%; and platelet count, 98000/mm3 were the postprocedural values obtained. Anesthesia was reversed with neostigmine (0.5mg) and glycopyrrolate (0.08mg). Calcium gluconate (5mL) was administered 10min before removing the femoral sheath the next day after confirmation from the medical oncologist. Apheresis collection had a very poor CD34+ stem cell count of 0.11 million/kg of recipient weight. A total of 1.79 million/kg stem cells were infused into the recipient after myeloablative conditioning, followed by methotrexate and cyclosporine for graft versus host disease (GVHD) prophylaxis. He was engrafted on the 14th day and after 30 days of transplant, the patient had complete donor chimerism tested by FISH (fluorescent in situ hybridization) for XY on blood lymphocytes.
Third PBSC Transplant (Second Patient)
Our PBSC transplant (PBSCT) donor was a 3-year-old boy weighing 13kg. Left basilic vein was cannulated (20G cannula). Anesthesia was induced with IV fentanyl (30 µg), propofol (15mg), and atracurium (10mg) and maintained with 40% oxygen in medical air, propofol infusion, and IV fentanyl (three 5-µg boluses). A 5F femoral sheath was sonographically placed in the left femoral vein for the exit of blood for apheresis, which was returned to the body via another 18G cannula. The whole body was wrapped in cotton wool to prevent hypothermia. On removing cotton and drapes at the end of the procedure that lasted 4h, we noticed that the donor’s left foot was dusky with cyanosed nails. The dorsalis pedis pulsation was absent. The femoral sheath was immediately removed, hematoma drained and the pulsation returned.
| Discussion|| |
In allogeneic donors, stem cell mobilization entails donor preparation with subcutaneous injections (10 µg/kg body weight) of granulocyte colony-stimulating factor (G-CSF) also called filgrastim (Neupogen: Amgen; Thousand Oaks, California, USA) once daily for 4–6 days before harvest. G-CSF mobilizes CD34+38− hematopoietic progenitor cells from extravascular bone marrow sites to peripheral circulation. Bone pain (caused by the hyperactivity of bone marrow), fever, chills, and headache are common, whereas splenic rupture, acute lung injury, acute iritis, severe pyogenic infections, anaphylactoid reactions, and sickle cell crisis are rare, but severe side effects are reported. Theoretical concerns exist regarding the increased long-term risk of leukemia after G-CSF priming in healthy donors.,, Plerixafor approved by the Food and Drug Administration for improving PBSC mobilization in autologous donors has not been approved for allogeneic donors, and hence was not an option for our donors. In autologous transplant, chemotherapy is given to produce bone marrow suppression, and the body responds by producing more stem cells. Stem cells need to be harvested 7 days after chemotherapy/Neupogen, whereas they are still uncommitted and present in maximum number in peripheral circulation.,,The apheresis-induced stem cell efflux from peripheral blood is compensated for by continuous stem cell influx from bone marrow sites into circulating blood; thus, the exhaustion of circulating stem cell pool during apheresis is prevented.
Minimum number of stem cells required for transplant is 2 million/kg of the recipient’s body weight, whereas optimal is 5 million/kg (faster recovery and reduced risk of grade 3 and 4 neutropenia). In 89% of cases, the CD34+ cell target is achieved in a single harvest. A donor/recipient weight ratio <0.75 is associated with greater number of harvests required. The rate at which the fluid was being drawn from the patient could not be increased above 11mL/min in our patient owing to the young age and low body weight as a safety mechanism in the machine, unlike in adult patients, where rates up to 70–80mL/min can be attained.
Allogeneic PBSCT has a risk of inducing severe GVHD because of the tenfold greater amount of donor T cells contained in a PB allograft. Greater incidence of chronic GVHD after PBSCT and similar rates of acute GVHD, leukemia-free, and overall survival after bone marrow transplant (BMT) and PBSCT have been reported.
Clinical pearls in pediatric anesthetic considerations for PBSCT have been shared in [Table 1].
|Table 1: Clinical pearls in pediatric anesthetic considerations for peripheral blood stem cell transplant|
Click here to view
| Several Lacunaein KnowledgeStill Exist|| |
•How soon a sufficient number of stem cells reappear in the peripheral circulation of the donor after first harvest? Poor yield of the second harvest in our patient suggests that 18h is too short a time break for attempting a second harvest.
•What is the upper limit of the number of apheresis cycles in one sitting? Number of sittings directly translates into donor psychological and physical trauma, and the second fruitless sitting should have been avoided in our donor.
•Are anesthetic agents such as sevoflurane, fentanyl, midazolam, or atracurium responsible for low yield and to what extent? Which anesthetic agent is most suitable? No reference is available in current literature.
•Data from the National Marrow Donor Program show 0.6% serious adverse events attributable to stem cell mobilization, treatment, and collection. Minimum age for blood donation is 18 years. Likewise, we suggest that uniform international guidelines be issued to regulate allogeneic sibling stem cell donation, specifying the minimum donor age, besides addressing the ethical issues.
•Long-term effects of G-CSF treatment in healthy donors require further research.
| Conclusion|| |
G-CSF-based stem cell mobilization strategies have made PBSCT an effective replacement for BMT. Ethical issues and long-term safety of G-CSF have to be addressed. Incompliant pediatric donors require general anesthesia, which has unknown effects on stem cell yield.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Körbling M, Freireich EJ. Twenty-five years of peripheral blood stem cell transplantation. Blood 2011;117:6411-6.
Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA, et al
. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001;97:3380-9.
Ravagnani F, Coluccia P, Notti P, Arienti F, Bompadre A, Avella M, et al
. Peripheral blood stem cell collection in pediatric patients: Feasibility of leukapheresis under anesthesia in uncompliant small children with solid tumors. J Clin Apher 2006;21:85-91.
Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G. Filgrastim (r-methug-CSF): The first 10 years. Blood 1996;88:1907-29.
Bojanić I, Cepulić BG, Mazić S. Collection of hematopoietic progenitor cells from healthy donors. Acta Med Croatica 2009;63:237-44.
Schmitz N, Dreger P, Suttorp M, Rohwedder EB, Haferlach T, Löffler H, et al
. Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 1995;85:1666-72.
Pulsipher MA, Chitphakdithai P, Miller JP, Logan BR, King RJ, Rizzo JD, et al
. Adverse events among 2408 unrelated donors of peripheral blood stem cells: Results of a prospective trial from the national marrow donor program. Blood 2009;113:3604-11.
DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, et al
.; 3102 Investigators. Plerixafor and g-csf versus placebo and g-csf to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113:5720-6.
Anderlini P, Körbling M, Dale D, Gratwohl A, Schmitz N, Stroncek D, et al
. Allogeneic blood stem cell transplantation: Considerations for donors. Blood 1997;90:903-8.
Ringdén O, Labopin M, Bacigalupo A, Arcese W, Schaefer UW, Willemze R, et al
. Transplantation of peripheral blood stem cells as compared with bone marrow from hla-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia. j Clin Oncol 2002;20:4655-64.
Johnson MC, Swartz HM, Donati RM. Hematologic alterations produced by nitrous oxide. Anesthesiology 1971;34:42-9.
[Figure 1], [Figure 2]