ExtracorporeaI Membrane Oxygenation Therapy in Neonates With Septic Shock By Susan McCune,

Billie Lou Short,

Marilea

Washington,

K. Miller, Andrea

DC and Bethesda,

9 Neonatal septic shock has significant morbidity and mortality with current therapeutic measures. At Children’s National Medical Center, from June 1964 to October 1996, 10 of 100 patients treated with venoarterial extracorporeal membrane oxygenation (EC&JO) had a documented diagnosis of septic shock. All of these infants fulfilled criteria consistent with 80% mortality using conventional intensive medical management. However, the survival rate for the septic neonates in this study was 169%. Compared with other groups of infants treated with ECMO. these septic neonates required significantly more ventilatory support after ECMO and had a higher incidence of chronic lung disease (30% v 12%). The septic neonates were also at higher risk for intracranial hemorrhage than the other infants treated with ECMO (46% ~26%). The necessity for prolonged intubation after ECMO for patients with septic shock suggests that this condition may be associated with additional structural damage not seen with meconium aspiration syndrome or respiratory distress syndrome. Nevertheless, for neonatal patients with septic shock unresponsive to conventional medical management, ECMO must be considered a viable alternative treatment. @ 1990 by W.B. Saunders Company. INDEX WORDS:

Extracorporeal

membrane oxygenation

(ECMO): septic shock.

E

membrane oxygenation XTRACORPOREAL (ECMO) has been successfully used to treat full-term neonates having cardiorespiratory collapse, unresponsive to conventional medical management. The first animal studies using prolonged cardiopulmonary bypass for neonatal respiratory distress syndrome were undertaken in 1961 by Callaghan et al.‘v2Although technical and mechanical development of the procedure occurred during the mid-l 960s and 1970s it was not until 1975 that Bartlett et al3 reported the first neonatal ECMO survivor. Since that time, over 60 centers have developed successful ECMO programs to treat neonates with meconium aspiration syndrome (MAS), congenital diaphragmatic hernia (CDH), congenital heart disease (CHD), persistent pulmonary hypertension of the newborn (PPHN), and sepsis. The term “shock” was first used by LeDran in 1773 when he described the clinical sequelae of patients suffering trauma from gunshot wounds.4 In the broadest sense, shock refers to circulatory failure that can be secondary to multiple causes, including sepsis. Neonatal sepsis, which may be difficult to distinguish clinically from respiratory distress syndrome requiring ventilatory support, may quickly progress to septic Journal

of Pediatric

Sur@wy,

Vol 25, No 5 (May), 1990:

pp 479-402

Love,

and Kathryn

D. Anderson

Maryland

shock with hypotension, leukopenia, and bleeding diatheses. Septic shock can result in increased pulmonary vascular resistance, right-to-left shunting, and full development of the PPHN syndrome.5*6The majority of these patients can be successfully managed with aggressive ventilation, fluids, vasopressor support, antibiotics, and Priscoline hydrochloride (CIBA-Geigy, Edison, NJ) therapy where indicated. When conventional management for persistent pulmonary hypertension has a risk of failure greater than 80% these infants have been treated with ECM0,7-9 Because of the risks of hemorrhage and the history of poor survival, there are a number of institutions that now do not consider septic neonates for ECMO therapy.‘* A retrospective study of the clinical features of septic infants treated with ECMO at Children’s National Medical Center (CNMC) was undertaken to compare that group of patients with other neonates supported with ECMO. MATERIALS

AND

METHODS

In the period from June 1984 to October 1986, 100 patients at CNMC qualified for ECMO support, as defined by a greater than 80% mortality rate using conventional medical management (Table 1). Entry criteria for ECMO at CNMC have been previously described.”

ECiUO Procedures Venoarterial (VA) ECMO is used for the nonseptic infants.12 Systemic heparinization is instituted and activated clotting times are maintained at approximately twice baseline (240 to 280 seconds). Without evidence of bleeding disorders, ECMO bypass is weaned as tolerated. For septic infants, because of the increased risk of hemorrhage, the heparin management and weaning techniques are altered. ECMO Bows are maintained at full (60%,to 70%) bypass for the first few days without weaning. This allows the activated clotting times (ACT) to be kept as low as 190 to 210 seconds without the danger of developing clots in the systems. When patient oxygenation is satisfactory, the percent of oxygen to the membrane is reduced. In

From the Departments of Child Health and Development and Surgery, George Washington University and Children’s National Medical Center, Washington, DC; and the Institute of Child, Health, and Development, Laboratory of Developmental Neurosciences, National Institutes of Health, Bethesda, MD. Dr McCune is a National Research Service Award Fellow. Date accepted: February 13. 1989. Address reprint requests to Dr Billie Lou Short, MD, Department of Neonatology.ChildrenS National Medical Center, 11I Michigan Ave. NW, Washington, DC 20010. 0 1990 by W.B. Saunders Company. 0022-3468/90/2S05-0003$03.00/0 479

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McCUNE ET AL

Table 1. ECMO Patients

by No.

Diagnosis Meconium aspiration syndrome Persistent pulmonary hypertension Hyaline membrane disease Congenital diaphragmatic hernia Presumed

sepsis

Proven septic shock

Diagnosis

of Patients

Survival(%I

49

92

7

88

15

80

7

57

5

80

10

100

Congenital heart disease

5

40

Other

2

50

Total

100

84

other words, weaning is accomplished by decreasing F,O, via the blender, rather than the more conventional weaning by decreasing ECMO blood flow rates. Clinical status, determined by improved pulmonary compliance,” determines the timing of attempted weaning. Serial head ultrasounds are obtained daily to look for evidence of intracranial hemorrhage. Of the 100 ECMO patients, 15 presented with a presumptive diagnosis of sepsis. Two of these 15 cases were complicated by other underlying conditions (CHD and MAS). Of this initial subset of 15, 10 exhibited signs of shock with hypotension requiring vasopressor support, and had a positive diagnosis of sepsis as defined by (1) positive blood cultures in seven (group B streptococcus [6], and group D enterococcus [I]); (2) two with negative blood cultures, but positive serum and urine Wellcogens; and (3) one with negative cultures and Wellcogens but a clinical course consistent with septic shock, moreover, the infant had been pretreated with antibiotics in utero secondary to maternal amnionitis. The severity of the disease process in seven of the 10 patients resulted in a white blood cell count of less than 6,600 prior to the institution of ECMO. Clinical deterioration necessitated exchange transfusion prior to ECMO for three patients. Two infants received white cell transfusions at outside institutions prior to their transfer to CNMC. The clinical features of these infants before the institution of ECMO were examined, as well as the age at onset of ECMO, predisposing factors to instituting ECMO, the length of time on ECMO, and the morbidity and mortality following ECMO therapy. The survival and subsequent clinical course of these patients were documented and compared with the other 90 patients treated at this institution and with patients in the Central Registry.

Statistical

ment of chronic lung disease. The average length of time on ECMO was 167 hours (k60). This is slightly, but not significantly, longer than other groups (Table 2). The three patients who developed chronic lung disease required ECMO therapy for a greater period of time than the other seven infants. Following discontinuance of ECMO support, there was a significant difference in the average number of hours of intubation required for patients with septic shock [169 hours (+165)] and CDH [192 hours (*68)] versus the other groups (P < .OOl) (Table 2). The incidence of chronic lung disease, as defined by oxygen requirement longer than 1 month was greater in the septic infants than in the other ECMO candidates (30% v 12%). Four patients in the septic group had intracranial hemorrhage. This was an incidence of 40%, compared with 20% in other neonates supported with ECMO. One of these patients had sustained a grade II intraventricular hemorrhage before the institution of ECMO. This did not extend while on bypass. Two infants suffered grade I intracranial hemorrhages and one neonate developed a grade III hemorrhage requiring a ventriculoperitoneal shunt after ECMO. Minor surgical site bleeding occurred in two patients, and one patient had upper gastrointestinal hemorrhage without sequelae that stopped spontaneously. DISCUSSION

ECMO therapy has been successfully applied to infants with cardiorespiratory decompensation who have not responded to conventional intensive medical management. Cardiorespiratory collapse can be secondary to MAS, respiratory distress syndrome, CDH, CHD, PPHN of the newborn, or sepsis. Many centers are reluctant to accept patients with sepsis as ECMO candidates because of the history of poor survival and bleeding complications.” Fifteen of 100 patients treated

Analysis

Group means were analyzed via the Student’s t test and x2 analysis with statistical significance considered for P 5 .05.

Table 2. Infants With Septic Shock Versus Other Infants Treated

RESULTS

The National ECMO Registry (courtesy of Dr Robert Bartlett) reports a 68% survival rate in septic infants. Of the 15 neonates with presumed sepsis at CNMC, there was a 93% survival rate. All 10 of the patients with proven septic shock survived (Table 1). The average age at onset of ECMO for patients with septic shock was 80 hours (*37), which was slightly shorter than patients in the other diagnostic categories (Table 2). However, this difference is not significant. The age at commencement of ECMO support did not correlate with bleeding complications or the develop-

Diagnosis (n)

With ECMO

Average Age on ECMO (hours)

Average Time on ECMO (hours)

Average Hoursto Extubation

Maconium aspiration syndrome (42)

67 (SD 43)

154 (SD 176)

Septic shock (10)

80 (SD 37)

167 (SD 60)

169 (SD 165)

36 (SD 48)

78 (SD 44)

111 (SD 49)

38 (SD 29)

24 (SD 7)

152 (SD 64)

192 (SD 68)

61 (SD 32)

126 (SD 35)

20 (SD 9)

Hyaline membrane disease ( 12) Congenital diaphragmatic hernia (4) Persistent pulmonary hypertension of the newborn (6)

Abbreviation: SD, standard deviation.

481

ECMO: SEPTIC SHOCK

with ECMO at CNMC were identified as having presumed sepsis. Ten of these 15 fulfilled the criteria for septic shock, and all 10 survived. We believe that the strict heparin management in this group of patients may account for the marked increase in survival. By maintaining high flows in the ECMO system to avoid clot formation, the infant can be heparinized at much lower levels. The ACTS are kept at only 190 to 210 seconds, instead of the conventional 240 to 280 seconds. This probably decreases the risk of intracranial and other bleeding in a group already at a high risk for hemorrhagic diatheses. ECMO blood flows are maintained high until sepsis is controlled and the risk of bleeding diminishes. At this time weaning and heparin management are returned to the more conventional method. Lung function can be measured by compliance, and patients can be weaned quickly off of ECMO when compliance is adequate.13 Although survival rates improved in these septic patients, an increase in nonfatal intracranial hemorrhagecompared with other infants treated with ECMO was noted. Patients with septic shock pose unique problems while being supported by ECMO therapy. The hematogenous toxins released during septic shock produce manifestations of multisystem failure on a metabolic and hemodynamic level. Clinically, in the newborn, these can present as heart failure, renal failure, respiratory distress syndrome and disseminated intravascular coagulation (DIC). DIC, with depletion of clotting factors, predisposes the septic neonate to hemorrhage. Therefore, it is not surprising that these patients are at increased risk for bleeding disorders while heparinized on the ECMO circuit, and that bleeding has been the primary cause of death in these patients nationally, according to the ECMO Central Registry. In the septic infants at this institution, there was a 40% incidence of intracranial hemorrhage compared with 26% in the other ECMO survivors. However, there were no fatal hemorrhages and only one neonate had a major intraventricular hemor-

requiring a ventriculoperitoneal shunt. An infant who was placed on ECMO in spite of a grade II intracranial hemorrhage had no extension of his hemorrhage. Therefore, it seems that bleeding dyscrasias can be controlled by keeping the ACTS in the 190- to 2 1O-second range. The other interesting observation made was a much higher incidence of chronic lung disease in the septic group of infants (30% v 12%). The prolonged need for ventilatory support after ECMO and the higher incidence of chronic lung disease in neonates with septic shock may reflect some degree of parenchymal or vascular damage unique to these patients, damage that is mediated possibly through white cell factors such as leukotrienes.14 It is known that endotoxin release stimulates complement activation, mast cell binding, and polymorphonucleocyte (PMN) aggregation as potentiators of the inflammatory response. This inflammatory response may generate pulmonary epithelial damage. PMNs have been shown to release active oxygen metabolites,” hydrolases,‘63’7and leukotrienes.” It has also been demonstrated in animal studies that pulmonary capillary damage can be prevented by granulocyte depletion before the administration of endotoxin.ig*” It is of interest that two of the three infants treated with white cell transfusions prior to ECMO went on to develop chronic lung disease. ECMO is a viable alternative for neonates with septic shock who have not been successfully treated by conventional medical management. Improved survival of 100% is documented in this institution when ECMO therapy is tailored to these individuals. The increased risk of bleeding diatheses can be controlled with decreased heparinization and maintenance of high ECMO flows until pulmonary improvement can be documented. Although these patients have increased morbidity, we believe that infants with documented neonatal sepsis should be considered for ECMO therapy if they are dying with conventional treatment. &age

REFERENCES 1. Callaghan JC, Cardoza D, Boracchia B: Study of prepulmonary bypass in the development of an artificial placenta for prematurity and respiratory distress syndrome of the newborn. J Thorac Cardiovasc Surg 44:600-604,1962 2. Callaghan JC, de Los Angeles J: Longterm extracorporeal circulation in the development of an artificial placenta for respiratory distress syndrome of the newborn. Surg Forum 12:215-217, 1962 3. Bartlett RH, Gazzaniga AB, Jefferies MR, et al: Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Tram Am Sot Artif Intern Organs 22:80-93,1976 4. Altura BM, Lefer AM, Schumer W: Historical perspective of shock, in Handbook of Shock and Trauma, vol 1: Basic Science. New York, NY, Raven, 1983

5. Hess ML, Hastillo A, Greenfield LF: Spectrum of cardiovascular function during gram-negative sepsis. Prog Cardiovasc Dis 23:279-281. 1981 6. Shankavan S, Farooki ZQ, Desai R: Hemolytic streptococcal infection appearing as persistent fetal circulation. Am J Dis Child 136:725-730, 1982 7. Kirkpatrick BV, Krummel TM, Mueller DC, et al: Use of extracorporeal membrane oxygenation for respiratory failure in term infants. Pediatrics 72:872-876, 1983 8. Bartlett RH, Andrews A, Toomasian JM, et al: Extracorporeal membrane oxygenation for newborn respiratory failure: Forty-five cases. Surgery 92:425-433, 1982 9. Bartlett RH, Roloff DW, Cornell RG. et al: Extracorporeal

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circulation in respiratory failure; A prospective randomized study. Pediatrics 76:479-487, 1985 10. Kornhausen MS, Gilbert PL, Desai HJ, et al: The efficacy of extracorporeal membrane oxygenation (ECMO) in meconium aspiration syndrome and group B streptococcal pneumonia. Pediatr Res 23:414A, 1988 (abstr) 11. Beck RB, Anderson K, Miller M, et al: Criteria for extracorporeal membrane oxygenation (ECMO) in a population of infants with persistent pulmonary hypertension of the newborn (PPHN). J Pediatr Surg 21:297-302, 1986 12. Short BL, Pearson CD: Neonatal extracorporeal membrane oxygenation: A review. J Int Care Med 1:47-54.1986 13. Lotze A, Short BL, Taylor GA: Lung compliance as a measure of function in newborns with respiratory failure requiring extracorporeal membrane oxygenation. Crit Care Med 15:226-229, 1987 14. Christensen RD, Rothstein G, Anstall HB, et al: Granulocyte

McCUNE ET AL

transfusions in neonates with bacterial infection, neutropenia and depletion of mature marrow neutrophils. Pediatrics 70:1-l 1, 1982 15. Wong C, Glynn J, Demling RH: Role of oxygen radicals in endotoxin-induced lung injury. Arch Surg 119:77-82, 1984 16. Balis JH, Berber LK, Rappaport ES, et al: Mechanism of blood vascular reactions of the primate lung to acute endotoxemia. Exp Molec Pathol2 1:123- 129, 1974 17. Demling RH, Proctor R, Grossman J, et al: Lung injury and lung lysosomal enzyme release during endotoxemia. J Surg Res 20:135-141, 1981 18. Lexis RA, Austern KF: The biologically active leukotrienes. J Clin Invest 73:889-896, 1984 19. HeRin AC, Brigham RL: Prevention by granulocytedepletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest 68:1253-1260,198l 20. Zimmerman JJ, Deitrich KA: Current perspectives on septic shock. Pediatr Clin North Am 34:131-138, 1987

Extracorporeal membrane oxygenation therapy in neonates with septic shock.

Neonatal septic shock has significant morbidity and mortality with current therapeutic measures. At Children's National Medical Center, from June 1984...
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