Surgical evacuation of neonatal intracranial hemorrhage due to vitamin k deficiency bleeding

J Neurosurg: Pediatrics / Volume 7 / March 2011 J Neurosurg Pediatrics 7:000–000, 2011 295 I ntracranIal hemorrhage in the neonatal period is a well-recognized and frequent occurrence. Four types are generally described: SAH, intracerebral hemor- rhage, IVH, and SDH. 3,34,35 In 1894, Charles Townsend rst described the syndrome of hemorrhagic disease of the newborn that usually occurs 1–5 days after birth in infants with nonclassic hemophilia. 4,6,14 Vitamin K is an essential fat-soluble vitamin that was discovered in 1929 by Danish biochemist Henrick Dam— K stands for koagulation. 4 There are 2 types of vitamin K: vitamin K1 (phylloquinone), from plants and vegetable oils, whose absorption from the small intestine needs the presence of bile salts; 10 and vitamin K2 (menaquinone), which is synthesized by the intestinal ora. 5 Vitamin K is required for the posttransitional gamma carboxylation of the coagulation factors II, VII, IX, and X (prothrom- bin complex). 21,30 Vitamin K1 does not cross the placenta easily, 15 and its concentration in blood is less than 10% of the mean maternal serum level. 29 Thus, newborn babies J Neurosurg Pediatrics 7:295–299, 2011 Surgical evacuation of neonatal intracranial hemorrhage due to vitamin K deciency bleeding Clinical article AshrAf shAker ZidAn, M.d., 1 And heshAM Abdel-hAdy, M.d. 2 Departments of 1 Neurosurgery and 2 Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt Object. Although the incidence of vitamin K deciency bleeding (VKDB) in neonates has dramatically de- creased in the developed world since the adoption of routine vitamin K prophylaxis, in developing countries the incidence is still high. Intracranial hemorrhage (ICH) is the most dangerous complication. Early recognition and management are important to decrease the mortality rate and neurological sequelae. The authors conducted a prospec- tive study between January 2008 and June 2010. They included all full-term neonates referred to the Department of Neurosurgery at Mansoura University Children’s Hospital with ICH complicating VKDB and necessitating surgical evacuation. The objective was to evaluate the clinical presentation, diagnosis, hospital course, and outcome of ICH in full-term neonates with VKDB after surgical evacuation. Methods. Thirty-two neonates with ICH due to VKDB were included. Diagnosis and classication of ICH were based on detailed history, physical examination, and the interpretation of CT or MR imaging studies. The diagnosis of VKDB was based on pretreatment coagulation studies (prothrombin time [PT] and partial thromboplastin time [PTT]), which are grossly abnormal, together with a normal platelet count and correction of coagulation results to normal after vitamin K administration. Results. The mean age (± SD) at onset of symptoms was 20.4 ± 4.9 days. Two neonates (6.25%) had early VKDB, 7 (21.9%) had classic VKDB, and 23 (71.9%) had late VKDB. The most common neurological manifesta- tions included focal seizures, disturbed consciousness level, and tense anterior fontanel. The most common general manifestations included pallor, respiratory distress, and bleeding from other sites. Radiological ndings varied from acute subdural hemorrhage (SDH) in 18 cases (56.3%), intracerebral hemorrhage in 10 (31.3%), and acute SDH with underlying intracerebral hemorrhage, intraventricular hemorrhage, and/or subarachnoid hemorrhage in 4 (12.5%). Before administration of vitamin K, the PT was 72.1 ± 45.0 seconds and the PTT was 112.4 ± 57.6 seconds. Six to 12 hours after administration of vitamin K, the PT was 14.6 ± 1.6 seconds and the PTT was 34.4 ± 1.0 seconds. All patients underwent surgery for evacuation of the ICH after correction of PT, prothrombin activity, and international normalized ratio. Evacuation of the ICH was done by either free or osteoblastic bone ap. Six patients (18.8%) died, and the other 26 patients had variable degrees of morbidity during the follow-up period (3–24 months). Conclusions. Vitamin K deciency bleeding, especially the late-onset form, is an important cause of neonatal ICH. In the present study, the most frequent form of ICH in neonates was SDH. Focal seizures, disturbed conscious- ness level, tense anterior fontanel, unexplained anemia, and respiratory distress were the major presenting signs. Despite early surgical evacuation, these cases are associated with high mortality rate and neurological disabilities. Vitamin K prophylaxis at birth may reduce these severe complications. (DOI: 10.3171/2010.12.PEDS10473) key Words      •      vitamin K deciency bleeding      •      intracranial hemorrhage      •      newborn      •      surgical evacuation 295 Abbreviations used in this paper: ICH = intracranial hemorrhage; IVH = intraventricular hemorrhage; PT = prothrombin time; PTT = partial thromboplastin time; SAH = subarachnoid hemorrhage; SDH = subdural hemorrhage; VKDB = vitamin K deficiency bleeding. A. S. Zidan and H. Abdel-Hady 296 J Neurosurg: Pediatrics / Volume 7 / March 2011 receive vitamin K in small amounts from the mother at birth. Prothrombin complex levels will decrease at 1–2 weeks of age and become normal at 6 weeks–6 months of age. 20 Vitamin K deciency bleeding in infants was for- merly known as hemorrhagic disease of the newborn. 32 It is dened as hemorrhage in infants due to vitamin K deciency shown by low activity of vitamin K–dependent factors (II, VII, IX, and X), normal activity of vitamin K– independent coagulation factors (I, V, VIII, XI, XII, and XIII), and the presence of protein induced by vitamin K absence (PIVKA II); also, administration of vitamin K is followed by shortening of the PT and correction of coag- ulation abnormalities after 30–60 minutes. 31 There are 3 types of VKDB in infants dened according to the etiolo- gy and the age at hemorrhage onset: early VKDB (occurs within 24 hours of birth), classic VKDB (occurs between 2 and 7 days after birth), and late VKDB (occurs more than 1 week after birth). Although VKDB is rare in most developed countries, the prognosis of the few in whom it develops is potentially catastrophic, with more than 50% of infants with late-onet VKDB presenting with ICH. 22 Methods In this prospective study, all full-term neonates (ges- tational age ≥ 37 weeks at birth and < 1 month old) diag- nosed with ICH due to VKDB and referred to the Neu- rosurgery Department in Mansoura University Children’s Hospital between January 2008 and June 2010 were in- cluded. Mansoura University Children’s Hospital is one of the largest pediatric medical centers in Egypt; it is a refer- ral center for patients from 5 governorates from the Delta region of Egypt serving a population of approximately 7 million children with 101,000 outpatient visits, 110,000 emergency department visits, and 35,000 patient admis- sions annually. During the study period, 48 neonates with ICH due to VKDB were evaluated, and only 32 required surgical evacuation for clinical signs of increased intra- cranial pressure or radiological evidence of mass effect (midline shift). Of the 32 patients, 22 were boys and 10 were girls; their ages ranged from 1 day to 4 weeks (mean 20.4 ± 4.9 days); their delivery histories were uneventful; none were delivered via forceps or vacuum extraction; and none had a history of trauma, drug intake, or famil- ial bleeding tendency. The neonates presented with acute neurological manifestations, especially seizures and/or general manifestations, particularly lethargy. Urgent CT scans of the brain were obtained in patients except one in whom MR imaging was performed. Laboratory inves- tigations were performed in all cases including complete blood workup (to exclude anemia and thrombocytopenia), PT, prothrombin activity, INR (international normalized ratio), and PTT at the time of presentation and 6–12 hours after receiving vitamin K. The diagnosis of VKDB was based on the presence of grossly abnormal PT, PTT, and correction of coagula- tion results after vitamin K administration with normal platelet, brinogen, and liver function tests. 33 Patients with the other bleeding disorders and secondary, late- onset hemorrhagic disease of the newborn were not in- cluded in the study. Diagnosis and classication of ICH were based on the interpretation of cranial CT or MR imaging studies. Surgical intervention was based on the evaluation of clinical and radiographic ndings. Anticon- vulsant therapy (phenobarbital, diphenylhydantoin) was instituted in all patients. Dexamethasone and mannitol were administered in 21 patients, and acetazolamide was used in 7 patients during the acute phase. Twenty-three patients required mechanical ventilation, and 19 patients received dopamine to correct hypotension. Mean results are presented ± SD or as number (%). Results The age at onset of symptoms was 20.4 ± 4.9 days. The male/female sex ratio was 2.2:1.0 (22:10). Neuro- logical manifestations included focal seizures, disturbed consciousness level, tense anterior fontanel, progressive head enlargement, sunset appearance of both eyes, hyper- tonia, diminished or absent neonatal reexes, generalized seizures, and hypotonia. General manifestations includ- ed pallor, respiratory distress, lethargy or irritability, or bleeding from other sites (Table 1). Before administration of vitamin K, the PT was 72.1 ± 45.0 seconds and PTT was 112.4 ± 57.6 seconds. The PT and PTT were correct- ed within 6 to 12 hours after administration of vitamin K—PT was 14.6 ± 1.6 seconds and PTT was 34.4 ± 1.0 seconds. Neurological condition deteriorated during that period and necessitated neurosurgical intervention. At the time of admission, alanine aminotransferase, aspartate aminotransferase, and bilirubin levels were normal, and the hemoglobin level was 7.8 ± 2.5 g/dl (range 3.5–12.3 g/ dl). Two patients had early VKDB, 7 had classic VKDB, and 23 had late VKDB (Table 2). Brain CT scanning was conducted in all cases, and MR imaging was performed in 1 neonate. Radiological ndings included acute SDH in 18 patients, intracerebral hemorrhage in 10, and acute SDH with underlying intracerebral hemorrhage, IVH, and/or SAH in 4 (Table 3; Figs. 1–3). All infants received vitamin K (1 mg/kg intramus- TABLE 1: Summary of clinical manifestations in 32 patients Clinical Findings No. of Patients (%) focal seizures 26 (81.3) disturbed consciousness level 26 (81.3) tense anterior fontanel 26 (81.3) hypertonia 26 (81.3) progressive head enlargement 25 (78.1) sunset appearance of both eyes 25 (78.1) diminished/absent neonatal reexes 8 (25) generalized seizures 4 (12.5) hypotonia 4 (12.5) pallor 18 (56.3) respiratory distress 18 (56.3) lethargy or irritability 16 (50) bleeding in another site (gastrointestinal tract, skin) 6 (18.8) J Neurosurg: Pediatrics / Volume 7 / March 2011 Intracranial hemorrhage due to VKDB 297 cularly), 9 (28.1%) received fresh-frozen plasma, and 18 (56.3%) received fresh blood for correction of anemia. All neonates underwent surgery for evacuation of the ICH af- ter correction of PT and PTT. Evacuation of the ICH was done by either free or osteoblastic bone ap. In 5 patients with acute SDH, surgery was performed using free bone ap, but the bone ap was not replaced in the same sur- gery because the brain was tense. The ap was preserved in the anterior abdominal wall of these patients; it was re- positioned again after 2 weeks in 2 patients only; the oth- er 3 patients died. Six patients died, and the other 26 cases experienced marked improvement with varying degrees of morbidity during the follow-up period (3–24 months); hydrocephalus developed in 3 patients, persistent seizure disorder in 8 patients, major motor disturbance in 4, and vegetative state in 2 (Table 4). Discussion Intracranial hemorrhage in the neonatal period is a well-recognized and frequent occurrence. Spontaneous neonatal ICH may be due to VKDB, 22 germinal matrix hemorrhage extending to brain parenchyma, 17, 36 or rup- ture of vascular malformations. Three patterns of VKDB are recognized in infancy: 1) early, 2) classic, and 3) late. Early VKDB occurs with- in the rst 24 hours of birth, usually in a baby born to mother who has been taking certain drugs (anticonvul- sants [barbiturates, phenytoin], 11 antituberculous drugs [rifampin], and vitamin K antagonist). 26 The mortality rate is high in this type of VKDB. In our study, 2 infants (6.25%) had early VKDB, 1 whose mother took antitu- berculous drugs early in her pregnancy. These 2 patients underwent surgery for evacuation of the ICH, and 1 died due to the severity of bleeding (this patient also had a low preoperative Glasgow Coma Scale score). Classic VKDB occurs at 2–7 days of age and is usually due to vitamin K deciency from low vitamin intake and low storage at birth. Classic VKDB was found in infants who did not receive vitamin K after birth. It is associated with a low mortality rate 18 and bleeding usually occurs in the gas- trointestinal tract, skin, or intracranially. In our series, 7 patients (21.9%) had ICH due to classic VKDB, with none having received vitamin K at birth, and 1 (14.3%) of the 7 patients died due to associated extensive gastrointestinal bleeding. Late VKDB occurs more than 1 week after birth and is usually associated with a high rate of ICH as a pre- senting feature. 8 Another common feature is widespread deep ecchymosis or nodular purpura. 24 Known risk fac- tors include breast feeding alone and failure to give vita- min K prophylaxis at birth. An association between late VKDB and undiagnosed abnormalities of liver function has been reported in surveillance programs from several countries, 23 especially cholestatic liver diseases. 12,22 In our study, 23 patients (71.9%) had late VKDB; only 1 neonate had biliary atresia and died of rapid deterioration of liver function postoperatively. Clinical presentations of ICH in neonates are non- specic. Any presentation of the core neurological symp- toms (for example, seizure, fever, reduced consciousness, TABLE 2: Classication according to age at onset of bleeding after birth No. of Patients (%) Age at Onset of Hemorrhage 2 (6.25) early (w/in 24 hrs of birth) 7 (21.9) classic (w/in 2–7 days of birth) 23 (781.9) late (1 wk after birth) TABLE 3: Classication according to the radiological ndings No. of Patients (%) Type of Hemorrhage 18 (56.3) acute SDH 10 (31.3) intracerebral hemorrhage 4 (12.5) acute SDH w/ underlying intracerebral hemor- rhage, IVH, &/or SAH Fig. 1. Case 1. Acute SDH. Preoperative T1-weighted MR image (A), preoperative T2-weighted MR image (B), postoperative T1-weighted MR image (C), and postoperative T2-weighted MR image (D). Fig. 2. Case 2. Intracerebral hematoma. Preoperative (left) and postoperative (right) CT scans. A. S. Zidan and H. Abdel-Hady 298 J Neurosurg: Pediatrics / Volume 7 / March 2011 generalized hypotonia, and increased intracranial pres- sure) may be indicative of ICH. Hanigan et al. 16 reported that the most common presenting symptoms in infants with ICH were seizures, respiratory distress, and apnea within 2 days of birth (in 24 [72%] of 33 infants). In an- other study, it was found that the most frequent present- ing symptoms were pallor (77.4%), seizures (58%), altered consciousness (58%), vomiting (44%), and poor feeding (35%). Pulsatile fontanel was found in 61% and bulging in 26%. Seven patients (22.5%) had a history of antibiotic use. 27 In a more recent study, 25 the initial presentation of ICH included seizures in 11 neonates (46%), cyanosis in 7 (29%), tachypnea in 5 (21%), and fever, hypothermia, and poor feeding (1 child in each category [4%]). These ndings were consistent with those of the current study. More than half of the full-term infants with ICH in this study also exhibited anemia. Anemia or abnormal hematological ndings may suggest the presence of in- ternal hemorrhage, including ICHs (that is, large SDHs). A diagnosis of intracranial SDH should be considered in such cases, especially when anemia is left unexplained. The presence of one or more of the common presenting signs in full-term neonates should alert physicians to the possibility of ICH. In the present study, the most frequent form of ICH in neonates was acute SDH (56.3%); this was followed by in- tracerebral hemorrhage (31.3%) and multiple-compartment hemorrhage (12.5%). In our study, all patients received pre- operative vitamin K to correct the coagulation defect, as well as blood to correct anemia (if present). Fresh-frozen plasma was given to patients with severe ICH in whom blood transfusion was not required to achieve rapid hemo- stasis. Fresh-frozen plasma contains all blood-clotting fac- tors and is recommended for neonates with severe VKDB. A common dosing regimen is 10–20 ml/kg every 12–24 hours depending on the clinical situation, 3,13 together with dehydrating measures to reduce the elevated intracranial pressure. Open surgery is then performed using either os- teoblastic or free bone aps for evacuation of acute SDH and/or intracerebral hematoma as early as possible. The prognosis in infants with neonatal ICH due to VKDB depends on early diagnosis, rapid and adequate correction of the coagulation defect, and the general con- dition of the patient, including factors such as the presence of anemia and rapid surgical intervention. Symptomatic ICH in neonates is associated with a relatively low mor- tality rate (11% at 3-year follow-up), but it remains a cause of neurological morbidity in survivors. 19 Our ndings revealed a high rate of disability among survivors. This may vary with the type of ICH. Jhawar et al. 19 performed a follow-up study of term infants with ICH and found that the most favorable outcomes were seen in those with acute SDH (80% had no reported problems in cognitive or motor development), whereas the worst outcomes were seen in infants with SAH and those with multiple-com- partment involvement. We also found that ICH involving multiple compartments (with SAH, SDH, or IVH) tended to be associated with poorer developmental outcomes: the 4 infants with multiple-compartment involvement exhib- ited abnormal outcomes. Vitamin K deciency bleeding is a signicant neona- tal threat that is entirely preventable in newborns by uni- versal prophylaxis with a safe and inexpensive interven- tion that is akin to immunization. Public health policy in developing countries should underscore intramuscular in- jection of vitamin K for all newborns. A recent Cochrane Review supports use of vitamin K for all newborns at birth. 28 The weight of evidence indicates that injection of vitamin K has the advantage over oral administration be- cause 1 dose sufces for injection, whereas when admin- istered orally, more than 3 doses are required. 9 In their policy statements, the American Academy of Pediatrics has endorsed the universal supplementation of vitamin K delivered via intramuscular injection. 1,2 Although intra- muscular administration of vitamin K has been report- ed to be associated with an increased risk of childhood cancer, subsequent extensive studies have yielded no evi- dence of any such relationship. 7 Conclusions Vitamin K deciency bleeding, especially the late- onset form, is an important cause of neonatal ICH. The most frequent form of ICH in term neonates in the present study was SDH. Focal seizures, disturbed consciousness level, tense anterior fontanel, unexplained anemia, and respiratory distress were the major presenting signs. De- spite early surgical evacuation, these cases are associated with a high mortality rate and neurological disabilities. Vitamin K prophylaxis at birth may reduce these severe complications. Disclosure The authors report no conflict of interest concerning the mate- TABLE 4: Mortality and morbidity following surgical evacuation of neonatal ICH Patient Outcome No. of Patients (%) death 6 (18.8) hydrocephalus 3 (9.4) persistent seizure disorder 8 (25) major motor disturbance 4 (12.5) vegetative state 2 (6.3) Fig. 3. Case 3. Acute SDH. Preoperative (left) and postoperative (right) CT scans. J Neurosurg: Pediatrics / Volume 7 / March 2011 Intracranial hemorrhage due to VKDB 299 rials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Zidan. Acquisition of data: both authors. Analysis and interpretation of data: both authors. Drafting the article: Zidan. Reviewed final version of the manuscript and approved it for submission: both authors. Administrative/techni- cal/material support: Abdel-Hady. Study supervision: both authors. References 1. American Academy of Pediatrics Committee on Fetus and Newborn: Controversies concerning vitamin K and the new- born. Pediatrics 112:191–192, 2003 2. American Academy of Pediatrics Committee on Nutrition: Vitamin K compounds and the water soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics 28:501–507, 1961 3. Andrew M, Brooker LA: Blood component therapy in neona- tal hemostatic disorders. Transfus Med Rev 9:231–250, 1995 4. Bandyopadhay PK: Vitamin K-dependent gamma-glutamyl- carboxylation: an ancient posttranslational modication. Vi- tam Horm 78:157–184, 2008 5. 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Philadelphia: WB Saunders, 1995, pp 403–463 Manuscript submitted October 22, 2010. Accepted December 23, 2010. Address correspondence to: Ashraf Shaker Zidan, M.D., Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. email: ournour2004@yahoo.com.