Therapeutic Plasma Exchange Application in Children Requires Individual Decision

Abstract

Therapeutic plasma exchange (TPE) is a treatment administered with the aim of removing a pathogenic material or compound causing morbidity in a variety of neurologic, hematologic, renal, and autoimmune diseases. In this study, we aimed to assess the indications, efficacy, reliability, complications, and treatment response of pediatric patients for TPE. This retrospective study analyzed data from 39 patients aged from 0 to 18 years who underwent a total of 172 TPE sessions from January 2015 to April 2018 in a tertiary pediatric intensive care unit. Indications for TPE were, in order of frequency, macrophage activation syndrome (28.2%, n  = 11), renal transplantation rejection (15.4%, n  = 6), liver failure (15.4%, n  = 6), Guillain–Barre's syndrome (15%, n  = 6), hemolytic uremic syndrome (7.7%, n  = 3), acute demyelinating disease (7.7%, n  = 3), septic shock (5.1%, n  = 2), and intoxication (5.1%, n  = 2). No patient had any adverse event related to the TPE during the procedure. The TPE session was ended prematurely in one patient due to insufficient vascular access and lack of blood flow (2.6%). In the long term, thrombosis due to the indwelling central catheter occurred (5.1%, n  = 2). TPE appears to be an effective first-stage or supplementary treatment in a variety of diseases, may be safely used in pediatric patients, and there are significant findings that its area of use will increase. In experienced hands and when assessed carefully, it appears that the rate of adverse reactions and vascular access problems may be low enough to be negligible.

Introduction

Therapeutic plasma exchange (TPE) is a treatment administered with the aim of removing a pathogenic material or compound causing morbidity in a variety of neurologic, hematologic, renal, and autoimmune diseases. It was first used in 1952 to control hyperviscosity in patients suffering from multiple myeloma and later began to be administered for treatment of a variety of neurologic diseases in the 1970s. ¹ Currently, TPE is used effectively and safely in adult patients, but its use remains limited in pediatric patients due to vascular access limitations, low blood volume, side effects, and complications during the procedure, in addition to technical difficulties, patient compliance, and lack of universally accepted indications. ^{2 3 4 5}

The efficacy of TPE varies according the patient's total and removed plasma volume, distribution of pathogenic material to be removed between intravascular and extravascular areas and the rate of synthesis, and the distribution of the material between compartments. ⁶ Standardized indications have been provided in the past 4 years in the guidelines published by the American Society for Apheresis (ASFA), though these recommendations are advice and not binding. ⁷

The present study aimed to assess the indications, efficacy, reliability, and complications of TPE in pediatric patients.

Materials and Methods

This retrospective study analyzed TPE data from 39 patients aged from 0 to 18 years who underwent treatment from January 2015 to April 2018 in a tertiary care pediatric intensive care unit (PICU).

Before TPE, a form including the patients' demographic characteristics, primary diseases, clinical parameters assessing cardiorespiratory status, and laboratory analyses was filled out using patient records. Thirty-nine patients were assessed with a total of 172 TPE sessions administered.

TPE was completed with a double-lumen central venous catheter and Plasauto∑ apheresis machine (Asahi Kasei Medical Co. Ltd, Japan). Femoral (82.1%, n  = 32), subclavian (12.8%, n  = 5), and jugular (5.1%, n  = 2) venous catheters were used. The total blood volume (TBV) of patients was calculated using the Nadler formula and total plasma volume (TPV) was (1 − patient hematocrit) × TBV. The most commonly administered anticoagulant was heparin for 30 patients (76.9%) (15 U/kg loading and 10 U/kg/h during the procedure). In seven patients (17.9%) with hemorrhagic diathesis, heparin was not used. In two patients (5.9%), citrate was chosen as anticoagulant. Ionized calcium measurement was performed in patients administered citrate, and calcium replacement and citrate dose were adjusted.

The adjusted speed of the blood pump was 4 to 12 mL/kg/min. Patients had pulse oximetry, heart rate and electrocardiographic monitoring performed during the procedure, and symptoms and signs such as blood pressure and minute heart rate changes, vision differences, dizziness, nausea, and paresthesia were monitored. Patients had 1 or 1.5 times their TPV administered, using fresh frozen plasma (FFP)/albumin according to the underlying disease. In 34 patients (87.2%), FFP was used as TPE solution, while 5 patients had albumin solution used. Eleven patients (28.2%) underwent the media filtration in addition to TPE.

All TPE procedures were completed under clinician observation by a blood bank technician trained in TPE. Complications and side effects were recorded during and after the procedure.

The Medical Research Council scale was used to assess the degree of muscle power in neurologic patients. ⁸ Accordingly, 0 = no movement or contraction in the tested muscle, 1 = tested muscle cannot complete movement against gravity, but contracts, 2 = movement with gravity eliminated over almost full range of motion, 3 = tested muscle completes movement against gravity but shows no resistance against opposite applied force, 4 = movement against moderate resistance over full range of motion, and 5 = tested muscle completes movement against gravity and has full resistance to opposite applied force.

Informed consent was obtained from the parents of each patient before the procedure, with the procedure and possible side effects explained in detail. This study was permitted by Istanbul Faculty of Medicine Ethics Committee (2017/489).

Results

The demographic and clinical characteristics of patients are shown in Table 1 . The median age of patients was 80 months (1–198) and 20 were female (51.3%). The median duration in the PICU was 13 days (3–45) and median pediatric risk of mortality score was 9 (2–41).

Table 1. Clinical characteristics of patients.

Total patient number	39
Age, mo, median (interval)	80 (1–198)
Gender ( n , %)
Female	20 (51.3)
Male	19 (48.7)
Therapeutic plasma exchange indications ( n , %) ASFA category and combined with specific pharmacologic treatment	n (%)		Other treatments
Macrophage activation syndrome	11 (28.2)	3 (2C)	Steroids
Acute liver failure	6 (15.4)	3 (2B)	a
Renal failure	6 (15.4)	1 (1B)	Steroids
Guillain–Barre's syndrome	6 (15.4)	1 (1A)	IVIG
Hemolytic uremic syndrome	3 (7.7)	3 (2C)	IVIG
Acute demyelinating disease	3 (7.7)	1 (1A)	IVIG
Septic shock	2 (5.1)	3 (2B)	CVVHD
Intoxication	2 (5.1)	b	a
PICU admission duration, d, median (interval)	15 (3–45)
PICU admission PRISM score, median (interval)	9 (2–41)

Abbreviations: ASFA, American Society for Apheresis; PICU, pediatric intensive care unit; PRISM, pediatric risk of mortality.

^aNo combined specific pharmacologic treatment.

^bIt is not included in the category of ASFA.

Patients had at least 1 and at the most 11 sessions, with mean 5 sessions of TPE performed. TPE indications were, in order of frequency, macrophage activation syndrome (MAS) (28.2%, n  = 11), renal graft rejection (15.4%, n  = 6), liver failure (15.4%, n  = 6), Guillain–Barre syndrome (GBS) (15%, n  = 6), hemolytic uremic syndrome (HUS) (7.7%, n  = 3), acute demyelinating disease (7.7%, n  = 3), septic shock (5.1%, n  = 2), and intoxication (5.1%, n  = 2). No patients had adverse events related to TPE during the procedure. TPE procedure had to be terminated prematurely in one patient due to insufficient vascular access and lack of blood flow. In two patients, thrombosis due to the indwelling central venous line occurred (5.1%, n  = 2). TPE data are shown in Table 2 .

Table 2. Therapeutic plasma exchange data.

Total number of sessions	172
Number of sessions, median (interval)	5 (1–11)
Catheter site number ( n , %)
Femoral	32 (82.1)
Subclavian	5 (12.8)
Jugular	2 (5.1)
Anticoagulant used ( n , %)
Heparin	30 (76.9)
Citrate	2 (5.9)
No anticoagulant	7 (17.9)
Solution used ( n , %)
Fresh frozen plasma	34 (87.2)
Albumin	5 (12.8)
Additional treatment used ( n , %)
Hemodiafiltration	12 (30.7)
Steroids	13 (33.3)
Intravenous immunoglobulin	3 (7.6)
Catheter complication ( n , %)
Thrombus development	2 (5.1)
Insufficient venous access	1 (2.5)

In nine of the patients with MAS (82%), treatment was successful (fall in ferritin values, increase in platelet count, regression of clinical findings), while two patients had partial regression in laboratory results but no resolution of clinical findings. When the diagnosis of the two nonresponsive patients was reinvestigated, they were considered to have primary hemophagocytic lymphohistiocytosis (HLH). Genetic confirmation of the diagnosis of primary HLH was obtained for one patient.

Six patients underwent TPE due to liver failure. The international normalized ratio levels of two patients decreased and they were transferred to the transplantation unit, while four patients expired. Six patients underwent TPE for GBS. When muscle power was assessed according to the Medical Research Council scale on discharge from intensive care, two patients had increased from 0 to 2, two patients had increased from 1 to 3, and two patients had increased from 1 to 5. In the two septic shock patients undergoing TPE for multiorgan failure, improvement on clinical and laboratory parameters was observed. Plasma lactate levels declined from 5 to 7 mmol/L to normal values. Increased oxygen saturation levels in central venous blood gas levels and decline in procalcitonin levels were noted.

Discussion

TPE is a treatment method used for a variety of neurologic, hematologic, renal, and autoimmune diseases. It is known to be effective and safe in adults, but its use in children is limited due to lack of universally accepted indications, technical problems such as difficulty in obtaining vascular access, incidence of side effects, and insufficient patient compliance. ^{2 3 4 9} In this study, the incidence of vascular access problems and adverse reactions were seen to be very low.

We think our research would be indicative in terms of clarifying the indications for TPE, albeit without high evidence level. A study by Demirkol et al ¹⁰ showed that in 23 cases with MAS, TPE was effective in lowering ferritin values, increasing platelet values, and lowering lactate dehydrogenase levels from the first session. They revealed that TPE was more successful than available treatments at the time and reported the indications. ¹⁰ Our data suggest that TPE is effective (81.8%, n  = 9) and can be considered as one of the primary treatment methods for MAS patients. Though it is included as a rescue treatment such as category 3 class (undetermined optimum role of apheresis treatment) and 2 class (weak recommendations, low evidence level) in ASFA guidelines, it was included as a first-line treatment in our study and treatment success was found to be high. TPE not only removes pathologic factors but may also deliver other factors, included in FFP, required in HUS (e.g., complement regulators).

In our study, GBS was one of the most common indications for TPE. GBS may be treated with TPE or intravenous immunoglobulin (IVIG). Especially in patients with axonal involvement, TPE is reported to be superior to IVIG, and there are studies showing that it is effective to control symptoms of neuroimmunologic disorder if begun within 7 days after onset of disease. ^{11 12} Small-group pediatric studies have been added to these adult-dominated studies; however, there are no studies showing it is superior to IVIG. ⁹ In our study, though TPE appears to be an effective and safe treatment choice for GBS, our patient number remains limited at six. Though it appears to be the first treatment in the ASFA guidelines in category 1 (first-stage treatment) class A (high evidence level), it is notable that it is in last place.

When TPE is administered to either children or adults because of liver failure, it may improve the clotting profiles, vasopressor requirements, and encephalopathy severity. However, there are studies showing it does not change survival and neurologic outcomes. ^{13 14} Contrary to this, a study in adults reported the view that high-volume plasma exchange improved survival and neurologic outcomes. ¹⁵ In the present study, it was observed that TPE was not effective on survival rates in cases without liver transplantation. The discussion as to which therapy is more efficient in acute liver failure is often focused on serum ammonia concentration, preceding the brain edema and several threshold different ammonia levels (or dynamics of increase) have been regarded as important values for initiation of the extracorporeal removal. Therefore, continuous venovenous hemodiafiltration (CVVHDF) (early initiated) is reported as effective by some adult centers; however, combination (hybrid) of TPE + CVVHDF was recommended by pediatric group in acute liver failure. ¹⁶

Single TPE may be enough in acute intoxication with protein-bound substances that cannot be removed by hemodialysis. There are reports of successful use of TPE in poisoning. In keeping with this report, our patients also had good clinical outcomes. ¹⁷ However, the timing of the procedure is crucial; toxic substance must be still in the blood, not already whole in the tissues, and therefore, clinical history of the poisoning is extremely important.

Complications are very frequently observed in studies about TPE in the pediatric age groups. The main complications are insufficient vascular access and adverse reactions. ⁹ A study by Michon et al ¹⁸ observed 55% adverse reactions with the procedure and the reported allergic reactions linked to TPE were frequent. The most common symptoms were hypotension, symptomatic hypocalcemia, and catheter-related side effects. In the present study, such adverse reactions were not observed. In patients with hemorrhagic diathesis, citrate was used for anticoagulation. Hypocalcemia is a frequent complication of citrate anticoagulation, but recent studies state that calcium infusion lowers the rate of hypocalcemia to 0.17%. ¹⁹ In the present study, only two patients were administered citrate as anticoagulant and complications were not encountered. Seven patients underwent TPE with no anticoagulation, and they did not have complications or tubing obstruction. This observation suggests that TPE can be administered with no anticoagulation, especially in patients with hemorrhagic diathesis.

Conclusion

TPE appears to be a safe and effective first-line or supplementary treatment in a variety of diseases in pediatric practice and its use is likely to increase. In experienced hands and when assessed carefully, it appears that adverse reactions and vascular access problems may be rare enough to be considered as negligible.

Funding Statement

Funding None.