The Use of Recombinant Activated Factor VII to Control Bleeding in a Preterm Infant Undergoing Exploratory Laparotomy

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EXPERIENCE AND REASON—Briefly Recorded

‘‘In Medicine one must pay attention not to plausible theorizing but to experience and reason together. . . . I agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions from what is observed. . . . But conclusions drawn from unaided reason can hardly be serviceable; only those drawn from observed fact.’’ Hippocrates: Precepts. (Short communications of factual material are published here. Comments and criticisms appear as letters to the Editor.)

The Use of Recombinant Activated

Factor VII to Control Bleeding in a

Preterm Infant Undergoing

Exploratory Laparotomy

ABSTRACT. The case of a preterm infant weighing 1120 g who successfully received recombinant activated factor VII (rFVIIa) without complication for control of a life-threatening bleeding event resulting from a ruptured umbilical artery is reported. After performing an explor-atory laparotomy at 27 hours of age, hemorrhage from the surgical wound and various sites persisted. By 63 hours of age, the infant had received a total of 192 mL (171 mL/kg) of packed red blood cells, 115 mL (103 mL/kg) of fresh frozen plasma, 8 mL of cryoprecipitate, and 75 mL (67 mL/kg) of platelet concentrate without stabilization. Hemorrhage ceased after 2 doses of 40␮g/kg/dose recom-binant activated factor VII given at 63 and 70 hours of age, with subsequent stabilization of the hematocrit and without need for additional transfusion therapy.

Pediatrics2002;107:169 –171;rFVIIa, preterm, bleeding.

ABBREVIATIONS. rFVIIa, recombinant activated factor VIIa; LP-PRBC, leukocyte-poor packed red blood cells; FFP, fresh frozen plasma.

R

ecent studies have demonstrated the efficacy of recombinant activated factor VIIa (rFVIIa) in patients with hemophilia and inhibitors. The use of rFVIIa as a hemostatic agent has been extended to a wide variety of other hemorrhagic situations.1 _{The mechanism of action of rFVIIa in}

inducing hemostasis is most likely twofold. At a site of injury or bleeding, rFVIIa forms a complex with expressed tissue factor, subsequently activating fac-tor X to facfac-tor Xa. Facfac-tor Xa, in complex with facfac-tor Va, converts prothrombin to thrombin, which results in the formation of a hemostatic plug through the cleavage of fibrinogen to form fibrin. High levels of rFVIIa in plasma have the ability to overcome the inhibition of zymogen factor VII and ensure satura-tion of tissue factor molecules with rFVIIa.2 _This

mechanism of action provides maximum activation of the coagulation system localized to a site of injury, which is helpful for treating surgery-related

bleed-ing. Independent of tissue factor, rFVIIa also binds directly to the surface of an activated platelet with low affinity and induces the sufficient thrombin burst required for the cleavage of fibrinogen and hemostasis.3 _{These effects of rFVIIa lead to}

genera-tion of hemostasis localized to sites of injury, without development of generalized activation of the coagu-lation system. Initial use of rFVIIa has focused on the control of bleeding episodes in both congenital mophilic patients with inhibitors and acquired he-mophilia.4 _{However, it has also become apparent}

that rFVIIa, because of its unique effects on hemo-stasis, is useful for other bleeding diatheses includ-ing congenital factor VII deficiency,5_{liver disease,}6

thrombocytopenia,7 _{thrombocytopathia,}8 _and

mas-sive hemorrhage.9_{In addition, rFVIIa has been}

effec-tively used in the management of severe uncon-trolled bleeding in patients undergoing heart valve replacement.10

We report the efficacious and safe use of rFVIIa to control a life-threatening hemorrhage in a low birth weight preterm infant who previously did not re-spond to exploratory laparotomy and aggressive transfusion support. To our knowledge, this is the youngest patient to receive rFVIIa.

CASE REPORT

The patient was a male preterm infant weighing 1120 g, whose mother had a history of 2 previous spontaneous abortions. At 29 weeks’ gestation, the mother developed premature labor unre-sponsive to tocolytic agents. The infant was delivered vaginally and immediately intubated because of poor respiratory effort. His Apgar scores at 1 and 5 minutes were 8 and 9, respectively. After several failed attempts to catheterize the umbilical artery, an ar-terial line was successfully placed in a radial artery. One milligram of vitamin K was administered intramuscularly after birth. The initial complete blood count revealed a hematocrit of 44%, a white cell count of 5400/␮L (43% neutrophils, 57% lymphocytes), and a platelet count of 154 000/␮L.

At 9 hours of age, the infant began to bleed from the umbilical stump. The umbilical stump was ligated, and 10 mL of leukocyte-poor packed red blood cells (LP-PRBC) was administered. Sys-temic ampicillin and gentamicin were initiated and were subse-quently changed to vancomycin and cefotaxime at 9 hours of age. At 12 hours, a baseline cranial ultrasonography was performed and revealed a grade II intraventricular hemorrhage.

At 22 hours of age, the infant developed hypotension rapidly progressing to shock and cardiac arrest. The hematocrit was ob-tained and found to have strikingly decreased to 25%. Cardiopul-monary resuscitation was immediately performed, and intrave-nous fluid and blood components were administered rapidly. The abdomen became distended, and an intraabdominal hemorrhage was suspected. Abdominal paracentesis revealed 0.5 mL of un-clotted blood. Therefore, an emergency exploratory laparotomy was performed at 27 hours of age. The operative findings revealed a large (80-mL) extraperitoneal hematoma around the abdominal wall and pelvis attributable to a ruptured left umbilical artery. In addition, an isolated perforation at the terminal ileum was found. Received for publication Jun 25, 2001; accepted Jan 14, 2002.

Reprint requests to (A.C.) Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Rd, Bangkok 10400, Thailand. E-mail: [email protected]

PEDIATRICS Vol. 107 No. 1 July 2002 169 at Viet Nam:AAP Sponsored on August 30, 2020

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The umbilical artery was ligated and ileo-ileostomy were unevent-fully performed. However, there was persistent oozing at the surgical sites despite aggressive support with blood components. At 36 hours of age, the infant developed abnormal motor activity that responded to the administration of phenobarbital. It was suspected that the previously documented intraventricular hemorrhage had progressed; this was confirmed by cranial ultra-sonography 28 hours later, indicating a grade III bilateral intra-ventricular hemorrhage.

During the postoperative period, the infant developed hema-turia, melena, and oozing from the abdominal surgical wound and venipuncture sites. Fresh blood and coffee ground contents were found at the endotracheal and nasogastric tubes, respectively. Massive blood components were continuously transfused to ob-tain hemostasis and mainob-tain vital signs. Coagulogram studies performed at 40 hours of life revealed an activated partial throm-boplastin time of 55 seconds (normal range: 27.5–79.4 seconds), a prothrombin time of 34.7 seconds, (normal range: 10.6 –16.2 sec-onds), and a thrombin time of 13.6 seconds (normal range: 19.2– 30.4 seconds). Two additional doses of vitamin K were adminis-tered at 40 and 50 hours. Although the infant received continuous infusion of blood components, hematocrits were maintained at 21% to 23% and platelet counts at 70 000 to 150 000/uL (except for the first-hour postplatelet concentrate transfusion, at which time platelet counts increased to 449 000/uL). At 60 hours, dissemi-nated intravascular coagulation was suspected because of the infant’s moribund condition with sepsis and massive hemorrhage, and laboratory findings of thrombocytopenia and fragmented red blood cells on the peripheral blood smear. However, the fibrin-degradation products were not evaluated because of the infant’s size and condition. By 63 hours of age, the infant had received a total of 192 mL (171 mL/kg) of LP-PRBC, 115 mL (103 mL/kg) of fresh frozen plasma (FFP), 8 mL of cryoprecipitate, and 75 mL (67 mL/kg) of platelet concentrate.

Because of the life-threatening bleeding uncontrolled by blood product support, informed consent was obtained from the par-ents, and a 40␮g/kg/dose of rFVIIa (NovoSeven, Novo Nordisk A/S Bagsvaerd, Denmark) was intravenously administered at 63 hours. Within 10 minutes, the oozing from the surgical wound and the bleeding at the endotracheal tube completely stopped. The hematuria resolved at 6 hours, and melena and coffee ground contents in the nasogastric tube gradually subsided over a period of 18 hours. Because the hematocrit at 67 hours of age remained at 23%, 2 doses of LP-PRBC, 15 mL each, were transfused. A second dose of rFVIIa (40␮g/kg/dose) was administered at 70 hours to ensure hemostasis. The hematocrit increased to 32% and 41.6% at 72 and 86 hours, respectively, with subsequent stabilization.

Follow-up cranial ultrasonography revealed posthemorrhagic hydrocephalus and periventricular leukomalacia. Serial lumbar punctures were performed, resulting in spontaneous regression of the hydrocephalus. The infant was discharged on day 65 of life with a weight of 2000 g. Follow-up examination at 6 months’ postnatal age (3 months’ corrected age) revealed appropriate body weight and length with a normal neurologic examination.

DISCUSSION

This report presents what is most likely the young-est child treated with rFVIIa. This clinical observa-tion may serve to demonstrate that rFVIIa may be an important additional therapeutic option for infants experiencing life-threatening hemorrhage but who fail to respond to conventional therapies. The use of rFVIIa in this situation was without complete data documenting its safety in this setting; therefore, the decision to utilize this agent must be balanced against an individual risk/benefit assessment. In this infant’s circumstances, it was apparent that all con-ventional therapies had failed to provide adequate hemostasis and the infant was deemed to be at high risk for continued deterioration and death. The cau-tious administration of rFVIIa was considered a life-saving necessity in this infant’s condition.

Dose levels of rFVIIa at 90␮g/kg with 2- to 3-hour

intervals are commonly used among hemophilia A and B patients with inhibitors. This same dosing strategy also has been adopted for other patient groups with bleeding disorders, except in patients with a congenital factor VII deficiency in which lower doses are required to obtain hemostasis.

However, the most appropriate therapeutic dose level and interval of rFVIIa to treat nonhemophiliac patients, especially in pediatric patients, have not been well established. Kenet et al8 _{from Israel first}

reported using 2 doses of 60␮g/kg of rFVIIa with an interval of 1 hour to treat a soldier with massive hemorrhage from a high velocity rifle wound to the inferior vena cava. Recently, we reported using 40 ␮g/kg of rFVIIa combined with FFP as a single or repeated dose at intervals of 6 hours for controlling bleeding episodes and providing hemostasis for in-vasive procedures in 5 children with liver disease.11

Therefore, a dose of 40␮g/kg of rFVIIa was selected for this small and critically ill preterm. Once a dra-matic response to the initial dose was observed, a second dose was given to maintain hemostasis with an interval of 7 hours. Despite technical difficulties obtaining repeated laboratory evaluations, it was ap-parent that the bleeding had ceased and the hemat-ocrit levels had stabilized without additional replace-ment therapy. The infant did not experience any adverse events related to the use of this agent. Also, no evidence of thrombosis was observed. The previ-ously documented intraventricular hemorrhage could be explained by hypoxia, shock, and cardiac arrest before the administration of rFVIIa. The periventricular leukomalacia and hydrocephalus were attributed to be sequelae of the intraventricular hemorrhage.

The coagulation system, especially in the preterm, is physiologically premature with low levels of all the vitamin K-dependent factors. In addition, in this infant the profound persistent hemorrhage markedly decreases the coagulation factors that are insuffi-ciently replaced by infusing FFP. The prolonged pro-thrombin time in this reported case could be caused by either decreased synthesis attributable to im-paired liver function and/or increased consumption secondary to sepsis and massive bleeding.

This case report adds an important clinical obser-vation for treating patients with life-threatening bleeding, who have failed to respond to conventional replacement therapies. Recombinant factor VIIa may be an alternative life-saving treatment. However, ad-ditional studies with the use of rFVIIa are needed on newborns and infants.

Ampaiwan Chuansumrit, MD* Pracha Nuntnarumit, MD* Chusak Okascharoen, MD* Sumete Teeraratkul, MD‡ Saranya Suwansingh, MD* Sarayut Supapannachart, MD* Department of *Pediatrics and ‡Surgery Ramathibodi Hospital

Mahidol University Bangkok, Thailand

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REFERENCES

1. Hedner U. NovoSeven as a universal haemostatic agent.Blood Coagul Fibrinolysis.2000;11(suppl 1):S107–S111

2. van’t Veer C, Mann KG. The regulation of the factor VII-dependent coagulation pathway: rationale for the effectiveness of recombinant factor VIIa in refractory bleeding disorders.Semin Thromb Haemost.

2000;264:367–372

3. Monroe DM, Hoffman M, Allen GA, Roberts HR. The factor VIIa-platelet interplay: effectiveness of recombinant factor VIIa in the treat-ment of bleeding in severe thrombocytopathia.Semin Thromb Haemost.

2000;264:373–377

4. Hedner U. Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000.Semin Thromb Haemost.2000;264:363–366

5. Wong WY, Huang WC, Miller R, McGinty K, Whisnant JK. Clinical efficacy and recovery levels of recombinant factor VIIa (NovoSeven) in the treatment of intracranial hemorrhage in severe neonatal FVII defi-ciency.Haemophilia.2000;61:50 –54

6. Chuansumrit A, Chantarojanasiri T, Isarangkura P, Teeraratkul S, Hon-geng S, Hathirat P. Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravas-cular coagulation.Blood Coagul Fibrinolysis.2000;11(suppl 1):S101–S105 7. Kristensen J, Killander A, Hippe E, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemosta-sis.1996;26(suppl 1):159 –164

8. Tengborn L, Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa.Thromb Haemost.1996;756:981–982

9. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa.Lancet.1999:354:1879 10. Al Douri M, Shafi T, Al Khudairi D, et al. Effect of the administration of

recombinant activation factor VII (rFVIIa; NovoSeven) in the manage-ment of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery.Blood. Coagul Fibrinolysis.2000;11(suppl 1): S121–S127

11. Chuansumrit A, Treepongkaruna S, Phuapradit P. Combined fresh frozen plasma with recombinant factor VIIa in restoring hemostasis for invasive procedures in children with liver diseases.Thromb Haemost.

2001;854:748 –749

Recurrent Nursemaid’s Elbow

(Annular Ligament Displacement)

Treatment Via Telephone

ABSTRACT. Annular ligament displacement (ALD)— also termed radial head subluxation, nursemaid’s elbow, or pulled elbow— can be successfully diagnosed and treated over the telephone by properly trained medical professionals instructing nonmedical caretakers. Two case reports of successful ALD reduction via telephone are described. The pathology of ALD and techniques for its treatment are reviewed, and guidelines are given. The rationale for the introduction of the new term annular ligament displacement as well as areas for additional investigation are discussed. To our knowledge, this is the first published account of ALD reduction via telephone.

Pediatrics 2002;110:171–174; annular ligament displace-ment, nursemaid’s elbow, pulled elbow, radial head sub-luxation.

ABBREVIATIONS. ALD, annular ligament displacement; ED, emergency department.

N

ursemaid’s elbow or annular ligament dis-placement (ALD), formerly termed radial head subluxation, is a common pediatric or-thopedic problem. It is most often seen in children between 1 and 4 years of age.1 _{This displacement}

usually occurs as the result of a sudden forceful longitudinal traction on the hand while the forearm is pronated and the elbow is extended, as when one lifts a child by the forearm or pulls the forearm of a resisting child.2

Nursemaid’s elbow is actually a displacement of the annular ligament between the capitulum of the distal humerus and the radial head.2_{The radial head}

does not move out of its position relative to the capitulum. The annular ligament is displaced, from its normal position covering the radial head, into the radiohumeral joint. Radiographs of an untreated nursemaid’s elbow are normal without any evidence of abnormal positioning of the radial head. Ultsound demonstrates that the space between the ra-dial head and the capitulum of the humerus is in-creased in nursemaid’s elbow.3 _{This is presumably}

attributable to the interposition of the annular liga-ment into the radiohumeral joint.

Tachdjian2_{describes how the specific anatomy of}

the radial head determines the pathophysiology of ALD: “The anterior part of the radial head elevates acutely from the radial neck, whereas the posterior and lateral parts of the radial head rise rather grad-ually (Fig 1). When longitudinal traction is applied on the wrist with the forearm in supination, the annular ligament is firmly held in place by the acute elevation of the radial head. When the forearm is in pronation, longitudinal traction on the wrist results in the annular ligament slipping over the radial head.”

The pathology of ALD occurs in 3 consecutive steps (Figs 2 and 3): 1) a transverse tear of the thin, relatively weak distal attachment of the annular lig-ament to the radial neck occurs, 2) the radial head then slides through the anterior portion of the annu-lar ligament, and 3) the detached portion of the an-nular ligament slips over the radial head into the radiohumeral joint.4 _{Although there is a transient}

subluxation of the radial head, prolonged subluxa-tion does not occur. It is the displacement of the

Received for publication Sep 6, 2001; accepted Feb 15, 2002.

Reprint requests to (K.A.L.) Division of Emergency Medicine, Children’s Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222. E-mail: klillis@upa. chob.edu

Acad-emy of Pediatrics. Fig 1. Anatomy of the radial head.

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DOI: 10.1542/peds.110.1.169

2002;110;169

Pediatrics

Teeraratkul, Saranya Suwansingh and Sarayut Supapannachart

Ampaiwan Chuansumrit, Pracha Nuntnarumit, Chusak Okascharoen, Sumete

Infant Undergoing Exploratory Laparotomy

The Use of Recombinant Activated Factor VII to Control Bleeding in a Preterm

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