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A long-acting vasopressin analog for septic shock: Brilliant idea or dangerous folly?*
his issue of Pediatric Critical Care Medicine includes two case reports regarding the successful use of terlipressin for catecholamine-dependent and catecholamine-resistant septic shock in children (1, 2). As a pediatric intensivist, my ﬁrst question is, What is terlipressin? My next questions are, What are the advantages and disadvantages of this agent, and similar agents, in catecholamine-dependent and catecholamine-resistant septic shock? Finally, do I have enough information to decide whether I should use the medication for my patients? Terlipressin (triglycyl lysine vasopressin) is a long-acting vasopressin analog (3– 8). In part, it is a prodrug that is slowly cleaved in vivo to lysine vasopressin by endo- and exopeptidases in the liver and kidney over 4 – 6 hrs, thereby allowing prolonged effects by intermittent intravenous injections rather than continuous intravenous infusion. However, it has some other characteristics suggesting independent pharmacological effects. Vasopressin and terlipressin stimulate vascular V1a receptors and renal tubular V2 receptors resulting in vasoconstriction and renal free water reabsorption, respectively. Terlipressin has relatively higher afﬁnity for the vascular V1a receptor and lower afﬁnity to the V2 receptor than vasopressin (7). In addition, terlipressin does not appear to increase ﬁbrinolytic activity, whereas vasopressin does (8). Because of the interplay between the coagulation/ﬁbrinolytic systems and the inﬂammatory system, these differential effects on ﬁbrinolytic activity may be pertinent for treatment of septic shock. Both vasopressin and terlipressin increase left ventricular afterload and decrease splanchnic blood ﬂow. In an endotoxemic sheep model, terlipressin resulted in increased
*See also pages 112 and 116. Keywords: terlipressin; vasopressin; septic shock; vasodilatory shock; catecholamines; pediatric; child; infant Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/01.PCC.0000121301.62216.0D
pulmonary vascular resistance, whereas vasopressin does not cause pulmonary vasoconstriction (6). Terlipressin has been extensively used and studied in adults with acute esophageal variceal bleeding and the hepatorenal syndrome (9, 10). Although numerous pharmacological agents have been used for acute esophageal variceal bleeding, terlipressin is the only one shown to reduce mortality rate compared with placebo, with an impressive 34% relative risk reduction in mortality rate (3, 4). Terlipressin is well studied and commonly used in adults throughout the world for this indication but is not presently available in the United States. Vasopressin and/or vasopressin analogs may have a role in the treatment of vasodilatory shock states, including septic shock (5, 11–14). Plasma vasopressin concentrations initially increase substantially with acute hemorrhage or sepsis (11, 12). However, adults with vasodilatory hypotensive septic shock receiving catecholamine infusions have low plasma vasopressin concentrations (i.e., relative vasopressin deﬁciency), although the concentrations are not low enough to precipitate diabetes insipidus (11). The low plasma vasopressin concentrations in vasodilatory septic shock are generally attributed to a hormonal deﬁciency syndrome due to neurohypophysial vasopressin depletion or depressed release. Interestingly, these patients have hypersensitive vasopressor responses to vasopressin infusions. Although vasopressin infusions of 0.2–2 units/min rarely affect the blood pressure in adults with gastrointestinal hemorrhage (or in normal subjects), low-dose infusions of 0.01– 0.07 units/min substantially increase the mean arterial pressure and decrease catecholamine requirements in patients with vasodilatory septic shock (11-13). This hypersensitivity to the pressor action of vasopressin has also been observed in other vasodilatory shock states (e.g., late-phase hemorrhagic shock, severe heart failure treated with a ventricular assist device, and postcardiopulmonary bypass) (11–14).
These two case reports on the use of terlipressin for pediatric septic shock in this issue of Pediatric Critical Care Medicine are consistent with a small series in adult patients with septic shock: Terlipressin can also increase the mean arterial pressure and decrease catecholamine requirements; however, the vasoconstriction can result in lower cardiac output (1, 2, 5). An 11-year-old child was demonstrated to be in hyperdynamic norepinephrine-dependent vasodilatory septic shock (1). Intravenous administration of 0.5 mg terlipressin (~0.14 mg/kg) promptly increased his systemic vascular resistance, thereby allowing rapid weaning of his norepinephrine infusion. However, his cardiac index promptly decreased. The duration of the vasoconstrictor effect with each terlipressin bolus was ~6 hrs. The use of terlipressin in an anuric 8-day-old neonate was especially bold (2). The baby improved while receiving 7 g/kg of intravenous terlipressin every 12 hrs. To my knowledge, terlipressin pharmacology had not been previously studied in neonates. It is conceivable that differences in neonatal hepatic function could result in substantial pharmacokinetic differences. It is somewhat reassuring that terlipressin had been used extensively in adults with hepatorenal syndrome and acute gastrointestinal hemorrhage associated with portal hypertension and severe hepatic dysfunction and that adverse effects seemed to be rare (3, 4, 9, 10). The use of terlipressin for hyperdynamic vasodilatory septic shock is intriguing. However, most children in septic shock have hypodynamic cardiac function with high systemic vascular resistance (15, 16). In this setting, a vasoconstrictor may further impede myocardial function and decrease tissue perfusion. Moreover, the wellknown decrease in splanchnic perfusion with both vasopressin and terlipressin is worrisome; splanchnic ischemia is associated with continued systemic inﬂammatory response syndrome and multiple-organ system failure. In addition, children in septic shock often change hemodynamic proﬁles (15, 16). For example, a child with vasodilatory shock at one moment may transform to a hypodynamic shock with
Pediatr Crit Care Med 2004 Vol. 5, No. 2
et al: Beneﬁcial effects of terlipressin in hepatorenal syndrome: A prospective. Bernadich C. Doust J. A long-acting agent like terlipressin may be inherently more dangerous during septic shock. Finally. Circulation 1997. and medical error* A dverse events involving patients. Petros AJ. including physicians (35%) and members of the public (42%). 15. 102:e19 Pediatric patient safety: Identiﬁcation and characterization of adverse events. Prowse CV. Peters MJ. Singer M: Terlipressin for norepinephrine-resistant septic shock. AZ 8. I believe there is sufﬁcient information to use terlipressin for adolescents with this disease process. Ioannou GN. the potential decreases in splanchnic ﬂow and myocardial function are concerning. 9. Boyle WA. Levin HR. Crit Care Med 2002. as well as the public’s increasing scrutiny of the health care system. compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension. the concept of low-dose vasopressin “hormonal replacement” therapy for catecholamine-resistant vasodilatory shock or for decreasing high-dose catecholamine usage in catecholamine-dependent vasodilatory shock is alluring. Westphal M. At this time. tide. Rockey DC: Terlipressin for acute esophageal variceal hemorrhage. Paschall JA. Vardi A. 18:152–156 Colle I. pediatric intensive care unit. REFERENCES 1. J Gastroenterol Hepatol 2003. Aliment Pharmacol Ther 2003. Sielenkämper AW. 359:1209 –1210 6. Fields AI: Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Terlipressin bolus induces systemic vasoconstriction in septic shock. reported errors in their own or a family member’s medical care. In contrast. Almost a third (32%) of the respondents indicated that the error had a permanent negative effect on the patient’s health (4). Rockey DC: Systematic review: Terlipressin in acute oesophageal variceal haemorrhage. Forrest JA. Chawla A. Key Words: medical error. 54:S149 –S154 Tsuneyoshi I. The increasing complexity in patient care. 5:116 –118 3. et al: Terlipressin dose response in healthy and endotoxemic sheep: Impact on cardiopulmonary performance and global oxygen transport. predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: A retrospective analysis. et al: Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock. Ann Thorac Surg 2003. 2). Doust J. especially for children with their unpredictable and rapidly changing hemodynamic proﬁles. This inﬂexibility is potentially quite problematic. pediatrics. 20:565–567 Solanki P. et al: Hemodynamic support in ﬂuid-refractory pediatric septic shock. However. According to a national poll conducted by the National Patient Safety Foundation. O’Brien A. et al: Effects of F-180. 17:882– 888 Landry DW. particularly the critically ill and medically fragile.high systemic vascular resistance as the disease progresses. Garg R. 1:1–11 Morales DL. Landry DW: Vasopressin deﬁciency in the syndrome of irreversible shock. Pediatr Crit Care Med 2004. Finally. Bandi JC. et al: Vasopressin deﬁciency contributes to the vasodilation of septic shock. An adverse event is deﬁned as an *See also pages 119 nd 124. Pediatrics 1998. MD The University of Arizona Steele Memorial Children’s Research Center Tucson. 5. 5:112–115 2. Durand F. et al: A double-blind randomized trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary bypass. randomized placebocontrolled clinical trial. Berg. 27:351–356 Douglas JG. Do I have enough information to decide if and when I should use terlipressin in my patients (if it were available in the United States)? Because there are abundant adult data indicating that terlipressin is a safe and effective agent for the treatment of acute esophageal variceal bleeding.1097/01. Gallant EM. Melin P.0000113928. et al: Effects of lysine vasopressin and glypressin on the ﬁbrinolytic system in cirrhosis. patient safety. 29:301–308 7. Oliver JA.24594. Pediatr Crit Care Med 2004. adverse events are a substantial safety concern in health care. 10. Intensive Care Med 2003. Cochrane Database Syst Rev 2003. infants. a new selective vasoconstrictor pep- 11. I would prefer more pharmacokinetic and pharmacodynamic information in neonates and young children before adding terlipressin to my therapeutic armamentarium in these age groups. Lancet 2002. 75:926 –930 Carcillo JA. Stubbe H. medication errors. for catecholamine-dependent and/or catecholamine-resistant vasodilatory septic shock.CCM. Hepatology 1998. occur at an alarming frequency (1. the data are less convincing for septic shock. Advances are being made to improve sur189 Pediatr Crit Care Med 2004 Vol. Moreover.1(CD002147) 5. 13. J Gastroenterol Hepatol 2002. Ioannou G. nearly half of respondents. Robert A. 2 . 2). These two case reports highlight the potential beneﬁts of terlipressin. The goal of all thoughtful and conscientious caregivers is to provide the best care possible without exposing patients to additional harm and suffering by experiencing an adverse event. Maffei F. neonatal intensive care unit Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. Garrido MJ. and other young children. Matok I. 30:1365–1378 Ceneviva G. A long-acting drug like terlipressin cannot be easily titrated as the disease process changes. They also highlight the need for delineation of terlipressin pharmacology in neonates. Contemp Crit Care 2003. Pessione F. there is no evidence that the hemodynamic beneﬁts translate into better outcomes. Clapp L. Madigan JD.94 injury resulting from a medical intervention or the “the failure to complete a planned action as intended or the use of a wrong plan to achieve an aim” (1. a longacting vasopressin analog. 17:53– 64 4. underscores the need to make patient safety and the reduction of adverse events an issue of highest priority (3). Gut 1979. 12. No. 95:1122–1125 Robin JK. the time has come for further studies of low-dose vasopressin and/or terlipressin hormonal replacement therapy for catecholamine-resistant vasodilatory septic shock and other vasodilatory shock states in children. Leibovitch L. Vasopressin: New uses for an old drug. Booth RA. Unfortunately. J Trauma 2003. et al: Clinical course. 16. adverse drug event. 14. adverse drug events.
little insight into timing of events.6 adverse events per 100 admissions (12. In a previous study. The next step in creating a safe environment is the development of targeted patient safety interventions. Washington. Gitte Larsen. Birth trauma has been reported to be at a frequency of 1.6% of orders) in prescribing errors. The ﬁrst step in designing a health care system to prevent medical injury is to identify errors and their pattern of occurrence within delivery systems to reduce the likelihood of adverse events (3). Cimino and colleagues (11) successfully developed a method to assess the rate of prescribing errors in nine freestanding PICUs. HCUP is a family of health care databases and related software tools developed through a federal-state-industry partnership and sponsored by the Agency for Healthcare Research and Quality (13). PhD Pediatric Intensive Care Unit Primary Children’s Medical Center University of Utah Salt Lake City.026 PICU medication orders at baseline and 9. Crossing the Quality Chasm: A New Health System for the 21st Century. However. Dr. PNP. The published literature focusing on the occurrence of medical errors in pediatrics is limited and concludes that hospitalized children experience signiﬁcant numbers of adverse medical events (17. Using a pretest. there was the puzzling ﬁnding of two institutions reporting an increase in identiﬁed prescribing errors. or monitoring. and coverage of large populations (15). National Academy Press. Cimino and colleagues identiﬁed medication errors prospectively for categorization and evaluation. The main goal of the study was to assess the overall rate of prescribing errors in nine PICUs participating in Child Health Accountability Initiative (CHAI) network (19) and to test the effectiveness of a variety of hospitalspeciﬁc interventions to reduce medication-associated adverse events (11). Strengths in using HCUP include ready availability. Identifying and characterizing adverse events and medical errors comprise a necessary ﬁrst step to effectively target efforts to decrease the risk of adverse events to our patients (8. The second patient safety-related article in this issue focuses on adverse drug events occurring in the PICU. consisting of the International Classiﬁcation of Diseases-9 discharge diagnosis of 996 –999 for medical error (10). 11). National Academy Press. Medication errors were deﬁned as errors in drug ordering. Preventable adverse drug events were uncommon (0. One of the most important aspects of this study was the establishment of a baseline rate for medication prescribing errors.1–7. 2 . there was considerable variation in the methods used to reduce error rates. document. Kanter and colleagues (10) contributes to the developing ﬁeld of patient safety by providing a descriptive epidemiology of medical errors in the population of premature newborns sampled from a diverse range of hospital settings. Grant. dispensing. UT REFERENCES 1.81–2. Adverse drug events are injuries that result from the use of a drug. There are many strengths and limitations to administrative databases. In 1984. 190 The HCUP database also is limited to hospitalized patients who survive to discharge and does not include medication errors (18). Slonim et al. posttest design. Their study determined the rate and characteristics of hospital-reported medical errors involving premature neonates (n ϭ 824). Despite the limitations of administrative databases. low cost. used the same database and methods and identiﬁed 1. The technique is labor intensive but yielded consistent results across the PICUs and correlated with other published studies (17). 5. the ﬁndings of Dr. two groups of researchers have tackled this challenging task (10.96 medical errors per 100 discharges of pediatric hospitalized patients (14). Nearly 20 yrs later. 2000 2. Dr. the rate of adverse events among newborns in New York State was 1. Kanter and colleagues (10) have found very little progress.4 in 100 hospitalizations with an associated 20. The study by Dr. Miller et al. a limitation of the HCUP database is its inability to discriminate between adverse events due to medical care and events due to birth trauma (10). the data provide limited clinical information. This national administrative database represents discharges from nearly 900 hospitals. administering. transcribing. No. They reported a national medical error rate of 1.7 to 16. Previous studies have found comparably low rates of preventable adverse drug events (17). thus providing a benchmark for other PICUs.8% rate of negligence (12). 18).187 orders postintervention were evaluated for prescribing errors. the occurrence of harm. Washington. 12. The authors found a 31% reduction (11. Cimino and colleagues (11) address the lack of measurement standards or a consistent benchmark for adverse drug events by demonstrating the usefulness of a generalizable method employed to identify. 0. The authors of these two articles have taken an important step to advance the understanding of the incidence and character of medical errors and adverse events occurring in hospitalized children.03% during the postintervention period) and of low severity at baseline. Kanter and colleagues (10). Although existing administrative databases can reasonably be used to deﬁne the epidemiology of adverse events and medical errors as done by Dr. 18). 16). 9). and they assessed the impact of initiatives to reduce medication error severity and rates. Dr. This method of analyzing prescribing errors captures error and harm associated with medication use. Kanter and colleagues are likely to be generalizable to the national population of premature infants given the large data set and representative sampling of hospitals in the HCUP database. Current efforts to enhance patient safety must include progress in the capture and characterization of adverse events. In this month’s issue of Pediatric Critical Care Medicine. In the Kanter study of premature neonates. Reducing the rate of medical errors and adverse events experienced by our patients should be one of the main goals of providing optimal health care for children.2 per 100 discharges using the Healthcare Cost and Utilization Project (HCUP) 1997 discharge database. Nowhere is this more important than in the pediatric intensive care unit (PICU). excluding resuscitation orders. DC. DC. 18). and analyze prescribing errors across a broad range of PICUs. In addition. cited signiﬁcant underreporting of patient safety events as a limitation in their study using the 1997 HCUP database (18).13% of all medication errors at baseline. and no ability to assess causality. and the study design did not allow for testing of any speciﬁc intervention. Institute of Medicine: To Err Is Human: Building a Safer Health System. Adult studies of medical errors have ranged from 3. 17. One concern is the underrecognition and underreporting of adverse events (1. Dr. Committee on Quality of Health Care in America. 15. and they probably result in underreporting (14.5 cases per 100 births (18).veillance of medical errors and occurrence of patient harm (5–7). 2001 Pediatr Crit Care Med 2004 Vol. and the degree of preventability of harm. MD Mary Jo C.
320:759 –763 6. Key Words: pressure-controlled ventilation. Barach P. Aron DC: Patient safety efforts should focus on medical errors. blood gas determination. Available at: http://www. 16: 809 – 814 8. Maas LA. Sangster W. No. 287:1997–2001 10. Ahmed W. had a low incidence of barotrauma and no mortality. one would need to know the prevalent approach to status asthmaticus in pediatric intensive care units across the nation or throughout the world. 2 . Pediatr Crit Care Med 2004. Layde PM. We know that the frequency of intubation in these patients is very different in different centers. 5:124 –132 12. Cimino MA. In Roberts et al. 16. Brennan TA. 3) and adults (4 – 6). Sarnaik and colleagues (1) received mechanical ventilation. Turenne W. 10). Blendon RJ.com/servpediat. McNutt RA. despite the investigators’ efforts at achieving and maintaining normal Pa CO 2 levels in the patients. Iezzoni LI: Looking for medical injuries where the light is bright. Laird NM. Weingart S: A physician-based voluntary reporting system for adverse events and medical errors.and low-use centers described by Roberts et al. This phenomenon probably indicates a lack of contentment with the traditional approach to mechanically ventilating these critically ill patients and the continual search for a better way. Leape LL. than patients at “low-use” institutions (where Ͻ20% of their patients with status asthmaticus were intubated). 5:119 –123 11. Case reports of the use of pressure support (8). The authors indicate that pressurecontrolled ventilation may represent a safe alternative to the “traditional” mode used in these patients. 287:1993–1997 9. Sarnaik and colleagues (1) are the ﬁrst to demonstrate its safety and effectiveness in a relatively large group of patients. Nelson K. Some centers were classiﬁed as “high-use” (Ͼ20% of admitted patients with status asthmaticus went on to intubation) and patients at these centers had a more than two-fold higher risk of intubation.0000113929.14813. et al: The quality in Australian health care study. 133. Brodsky L.htm. 17. JAMA 2002. et al: Developing a comprehensive electronic adverse event reporting system in an academic health center. and highfrequency oscillatory ventilation (11) suggest that physicians are using many of the numerous modes available on today’s sophisticated ventilators. et al: Assessing medication prescribing errors in pediatric intensive care units. 5. the overall rate of intubation and mechanical ventilation for status asthmaticus was 17%. Brodie M. Pediatrics 2003. et al: Hospital-reported medical errors in children.3. 111:617– 621 Weingart SN. 290:1917–199 Wilson RM. Agency for Healthcare Research and Quality: Healthcare Cost and Utilization Project. DesRoches CM. JAMA 2001. Available at http://www. respiratory failure Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. Slonim AD: Hospitalreported medical errors in premature neonates. JAMA 2003. Kanter DE.chca. Pediatr Crit Care Med 2004. N Engl J Med 2002. The 40 patients. Kirschbaum MS. N Engl J Med 1991. 111:1358 –1366 Child Health Corporation of America. Pediatrics 2001. but the incidence ranged from a low of 3% to a high of 46%.CCM. Although this is a retrospective review. Abrams R. some series do not I *See also p. 28: 583–594 7. How likely is it that the data presented in Dr. 286:915–916 Miller MR. Gibberd RW. which the authors believe to be volume-controlled ventilation. What does this tell 191 Pediatr Crit Care Med 2004 Vol. BMJ 2000. but Dr. Elixhauser A. 19.1097/01. Teret SP. Sarnaik and colleagues (1) review their 5-yr experience using pressure-controlled ventilation in pediatric patients with status asthmaticus and respiratory failure. (14) previously showed that the approach of the pediatric critical care community varies widely with respect to frequency of the use of invasive monitoring. 163:458 – 471 Kaushal R: Medication errors and adverse drug events in pediatric inpatients. Med J Aust 1995. the patients undergoing mechanical ventilation were treated by a predetermined protocol. 347: 1933–1940 5. Small SD: Reporting and preventing medical mishaps: Lessons from nonmedical near miss reporting systems. There have been previous suggestions in the literature that pressure control may be a rational alternative to volume control (12. Accessed October 24. it is impossible to state what the standard is for initiating mechanical ventilation in critically ill pediatric patients with status asthmaticus. Pediatrics 2003. et al: Patient safety efforts should focus on medical injuries. Twenty percent of the patients cared for by Dr. Accessed on October 24. 18. J Qual Improv 2002. let alone to know what the standard approach is once the patients are intubated. and use of mechanical ventilation. At this point. who underwent 51 episodes of mechanical ventilation. Patients at high-use centers had a longer pediatric intensive care unit and hospital length of stay than patients at the low-use centers. putting their center at the breakpoint between the high. but mortality rates were not different between the two types of centers. after adjustment for severity of illness. noninvasive ventilation (9.ahrq. status asthmaticus.’s (14) database interrogation study.51 mention the speciﬁc modes of ventilation used in the patients reported (7). 2003 Mechanical ventilation of the intubated asthmatic: How much do we really know?* n this issue of Pediatric Critical Care Medicine. 15. et al: Views of practicing physicians and the public on medical errors. LaFleu BJ. Runciman WB. Child Health Accountability Initiative. (14).html. Dr. 13). 107:1473–1475 4. Kivlahan C. Principles of patient safety in pediatrics. et al: Incidence of adverse events and negligence in hospitalized patients: Results of the Harvard Medical Practice Study I. Although volume-controlled ventilation may be the most commonly used mode in reported series in children (2. Roberts et al.gov/ 14. American Academy of Pediatrics. data/hcup/hcupnet. Sarnaik and colleagues’ article will be applicable to the practice of the readers of this journal? To answer that question. JAMA 2002. 324:370 –376 13. Zhan C: Patient safety events during pediatric hospitalizations. 2003 Slonim AD. J Gen Intern Med 2001.
Newer therapeutic options have been embraced by many. with this particular population. 30: 350 –353 12. Terry M. Monaldi Arch Chest Dis 2000. the peak inspiratory pressure was adjusted in a tightly controlled manner. Pediatr Pulmonol 1991. pressure-controlled ventilation has been successful. MD REFERENCES 1. et al: Noninvasive positive pressure ventilation in status asthmaticus. Lopez-Herce J. Pediatr Pulmonol 1996. et al: To the editor: On pressure-controlled ventilation in severe asthma. and terbutaline. a varying percentage of patients were treated with heliox. Georgopoulos D. they should compare the results to their own practice and consider letting the rest of the world know how they care for such patients in their own institutions. Daphtary KM. Despite these problems. magnesium.us about the practice of this group of investigators? Most of their patients were intubated for respiratory arrest or respiratory acidosis. to achieve normal PCO2 values as quickly as possible. National Institutes of Health. Alice D. Morales I. theophylline. including the use of noninvasive ventilation to avoid some of the perils of intubation (9. Turner RE. Meert KL. Crit Care Med 1996. Werner HA: Status asthmaticus in children. It suggests that in the hands of this particular group of physicians. 27:486 – 492 10. et al: Helium-oxygen therapy for pediatric acute severe asthma requiring mechanical ventilation. Sarnaik and colleagues (1). patients were handled in a variety of ways. 30:477– 480 5. et al: Mechanical ventilation in children with severe asthma. Any of these adjunctive measures may have affected the course of the patients presented. There are no randomized controlled trials comparing different modes of mechanical ventilation in asthma. but 22% were intubated for the “clinical impression of fatigue. No. 10). Intensive Care Med 2001. Bethesda. 15). the strength of the current research lies in the nature of the initial approach to these patients’ respiratory failure. 1991 17. FCCM University of Maryland Medical System Baltimore. In the population presented by Dr. Kaila M.” This latter group of patients proves problematic in its evaluation and emphasizes the subjective nature of our approach to this disease. and the incidence of barotrauma was low. Cury JD: Clinical course and outcome of patients admitted to an ICU for status asthmaticus. although recommended by both National Institutes of Health panels (16. and why to initiate mechanical ventilation in this disease. et al: Non-invasive mechanical ventilation in status asthmaticus. Pediatr Pulmonol 2000. Schwartz DE. Once intubated. 5:133–138 2. Sarnaik AP. 30:581–585 15. It does not address the issues of how long one can safely wait for medical therapies to work. 24:1603–1605 9. Prinianakis G: How to set the ventilator in asthma. Kaemmerlen JT: Intensive care of status asthmaticus: A 10-year experience. Kondili E. Villagra A. MD. JAMA 1990. Korhonen K. 5. There is no single gold standard of how. Chest 1996. Despite the availability of National Institutes of Health guidelines on the treatment of asthma. Mutlu GM. Gari M. Blanch L. Abd-Allah SA. Malmstrom K. 1997 192 Pediatr Crit Care Med 2004 Vol. isoproterenol. Meduri GU. 110: 767–774 11. There was no mortality. when. Does this article prove the safety of pressure-controlled ventilation in caring for children with status asthmaticus? No. Additional reports of well-described approaches to this care would be most helpful. Bratton SL. When ready for weaning. MD. Barker GA. Brogan TV: Acute severe asthma: Differences in therapies and outcomes among pediatric intensive care units. van Vught AJ: Status asthmaticus treated by high-frequency oscillatory ventilation. The reasons for this variation are not clear. As pediatric critical care practitioners read this article. Bethesda. 11:120 –126 3. Braman SS. Duval EL. The median length of mechanical ventilation was 29 hrs. comparing favorably with previous reports in children (2) and adults (5. Pediatr Pulmonol 2001. Pediatr Crit Care Med 2004. Rogers MS. Bustinza A. many patients receive nonstandard care. 55:74 – 83 7. National Institutes of Health. National Heart Lung and Blood Institute: The Expert Panel Report: Guidelines for the Diagnosis and Treatment of Asthma. 120: 1616 –1621 6. It therefore makes it even more difﬁcult to compare the reported population to that in other intensive care units or to compare the results in this article to other reported series of patients ventilated for status asthmaticus. 264:366 –368 16. Factor P. Afessa B. nor are they addressed in the article. Cox RG. Ackerman. Cook TR. 4:353–357 4. without resorting to mechanical ventilation. Crit Care Med 2002. results and complications of mechanical ventilation in children with status asthmaticus. et al: Pressure-controlled ventilation in children with severe status asthmaticus. Crit Care Med 2002. Fernandez MM. in most cases predating the initiation of mechanical ventilation. 21:401– 403 14. These are all agents that have been reported but not proven to be of beneﬁt in the intensive care unit. Pediatr Crit Care Med 2003. Wetzel RC: Pressure-support ventilation in children with severe asthma. The use of inhaled ipatropium. Roberts JS. ketamine. 31: 405– 411 8. Chest 2001. 2 . A review. National Heart Lung and Blood Institute: The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. 119:1913–1929 13. Chest 2001. clearly at the discretion of the treating physician. MD. et al: Severe status asthmaticus: Management with permissive hypercapnia and inhalation anesthesia. 17). It does not preclude the safe use of other modes of ventilation in other people’s hands. Nor are there likely to ever be any. was only used in 47% of the patients. Bohn DJ: Efﬁcacy.
12). Ericka L. Importantly.000 emergency department visits annually associated with TBI (6). Furthermore. Morrison and colleagues (5) attempt to determine whether there is an association between a much more common “polymorphism” after TBI. Cohen A. et al: Genetic associations in large versus small studies: An empirical assessment. there was no gender difference in neurologic outcome in the current study by Dr. These patients often present for medical care after a signiﬁcant time delay after injury and perhaps after repeated insults. MD Robert S. a clinical trial in adult patients using progesterone as a neuroprotective agent after TBI is underway. head injury.16). et al: Genetic Pediatr Crit Care Med 2004 Vol. pediatric. prematurity (14). traumatic brain injury Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. MD University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh Pittsburgh. and neurologic outcome after TBI in a pediatric population. sex hormones. a recent ﬂurry of clinical study has been directed toward genetic associations and disease (1). et al: A map of human genome sequence variation containing 1. perhaps present-day approaches to intensive care unit medicine should begin to identify pathologic processes requiring gender-. Fallin D. Nature 2001. The simplest polymorphism is referred to as a single nucleotide polymorphism. In this issue of Pediatric Critical Care Medicine. Clark. 361:567–571 2. Dr. and endogenous and injected progesterone reduced cerebral edema in female rats after TBI (7.theapolipoprotein E allele. Morrison and colleagues (5) disproved their original hypothesis that boys would fare worse than girls after TBI.PCC. 5. or even likely. and as such A *See also p. Indeed. there are 3. 409: 928 –933 3. that innate. The impact of gender in pediatric intensive care unit patient populations extends beyond TBI.0000115621. the presence of inﬂicted TBI in the younger age group may have contributed to the higher mortality rate. In contrast to the previously mentioned studies (11. it remains possible. Just as futuristic approaches to intensive care unit medicine will likely include genotypeand phenotype-speciﬁc management and therapy. a shorter intensive care unit length of stay for boys vs.000 deaths. Indeed.1097/01. these age-group subpopulations are known to have unfavorable outcomes after TBI (9. 2 193 . Morrison and colleagues (5) found that younger age was a signiﬁcant risk factor for death after TBI (9). 10). as gender differences are seen in either outcomes or responses to therapy in children with stroke (13). children and the elderly). There was. boys are believed to have poorer memory function (11) and a higher incidence of neuropsychiatric sequelae (12) than girls after TBI. Lancet 2003. No. Fink. 29. PA REFERENCES 1.. and outcome assessment in pediatric intensive care unit patients. 145. Thus. Weissman D. survival. With Ͼ1 million genetic polymorphisms (2). sex hormoneindependent gender effects also contribute. As with previous studies.42 million single nucleotide polymorphisms. Studies have shown that the highest pediatric age incidence of TBI is among persons aged 15 – 24 yrs followed by ages 5 and younger. Ioannidis JP. Morrison and colleagues (5) is important because it attempts to correlate gender and age with intensive care unit length of stay. age-. Not discounting an important role for sex hormones in the pathophysiology and outcome after TBI. Dr. Biochemical differences also exist in these two patient populations (18 –20).000 hospitalizations. this and other pediatric studies support the notion that the inﬂuence of gender should be considered in the study design. this becomes of clear signiﬁcance given that many future therapies are likely to be genotype-directed and many studies genotype-stratiﬁed. Morrison and colleagues (5). This experimental evidence is based entirely on carefully controlled studies in reproductive-aged animals using hormone replacement therapy. Trikalinos TA. namely the Y-chromosome. clinical management. gender.Don’t forget the “single chromosome polymorphism”: A need for gender-stratiﬁcation in pediatric patients?* ppropriately. Current understanding suggests that being of female gender (XX) imparts a degree of protection from the sequelae of TBI compared with male gender (XY). B. Estrogen has been shown to preserve cerebral blood ﬂow after TBI in rats. Among children aged 0 –14 yrs in the United States. This issue’s report by Dr. and cancer (15. hospital length of stay.73210. and they have notoriously poor outcomes compared with TBI due to noninﬂicted (accidental) trauma (17). illustrated by the fact that TBI is the leading cause of death and disability in infants and children. Schmidt SC. This may be of particular importance in terms of TBI patients outside of the reproductive years (i. and males are more than twice as likely as females to become victims of TBI. 8). Ntzani EE. TBI is unarguably a major public health problem in the United States. however. and 400.B9 many of the beneﬁcial effects seen in females are attributed to the inﬂuence of sex hormones. and mechanismspeciﬁc treatment.e. Essioux L. This may be related to the predominance of inﬂicted trauma (child abuse) in infants and toddlers. These genetic polymorphisms can signiﬁcantly inﬂuence susceptibility and/or outcome in manydiseasestates. girls. which is important in Alzheimer’s disease (3) and traumatic brain injury (TBI) (4). Key Words: child abuse. Sachidanandam R. it begins to direct our attention to the possible need for “gender-stratiﬁcation” in terms of treatment and study design in pediatric patients with acute brain injury cared for in our pediatric intensive care units. when the inﬂuence of circulating sex hormones is less dominant.forinstance. Although the study by Dr.
11. Neuropsychology 2002. Mol Chem Neuropathol 1997.7D The wide range in reported incidence is likely due to differences in the methods used to detect aspiration and in the populations studied. JAMA 1998. et al: Biochemical. 15. 152. Research on the epidemiology of aspiration has been complicated by the lack of sensitive and speciﬁc bedside markers to detect aspiration.4. presence of a nasogastric or endotracheal tube. 53:219 –223 Donders J. whereas aspiration pneumonia is an infectious process caused by the inhalation of oropharyngeal secretions or gastric contents colonized with pathogenic bacteria (1). 31:1–11 Levin HS. 16:491– 499 Poggi G. 279:1474 –1476 Ishii E. 16. 17:1155–1169 Roof RL. aspiration of oropharyngeal secretions is assessed by the application of blue dye to the base of the tongue and subsequent testing of tracheal secretions for the dye’s presence. Aldrich EF. J Pediatr 2001.1097/01. Vanderploeg RD. Other studies in which blue dye was used to color enteral formulas delivered through nasogastric feeding tubes also have shown that blue dye lacks sensitivity in detecting aspiration (9. Adelson PD. Mohay HA. Christian CW. Early Hum Dev 2000. Pediatr Rehabil 1999. Dr. Rorke LB. For example. 19. Pediatr Crit Care Med 2004. No. Freeman MJ. 138: 18 –25 Incidence and risk factors for oropharyngeal aspiration in mechanically ventilated infants and children* echanically ventilated infants and children are at risk for aspiration of oropharyngeal and gastric contents into their tracheobronchial tree. Key Words: aspiration. 20. Aspiration pneumonitis is a chemical injury caused by the inhalation of sterile gastric acid. Hoffman NM: Gender differences in learning and memory after pediatric traumatic brain injury. et al: Functional outcome of paediatric stroke survivors. Liscio M. come of acute lymphoblastic leukemia in children with AL90 regimen: Impact of response to treatment and sex difference on prognostic factors. Med Pediatr Oncol 2001. Amantea and colleagues (7). 18. 58:1115–1118 Morrison WE. et al: Out- 17. 5:145–151 Traumatic Brain Injury in the United States: Assessing Outcomes in Children. aspiration of large volumes or recurrent aspiration of small volumes can lead to lower respiratory tract disease. intermittent feeding delivery methods. Pediatr Crit Care Med 2000. Hall ED: Estrogen-related gender difference in survival rate and cortical blood ﬂow after impact-acceleration head injury in rats.PCC. mechanical ventilation. infant. 5. Stein DG: Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Adelson PD. Saydjari C. 7. the traumatic coma data bank. Neurology 2002. 338:1822–1829 Kochanek PM. Arbelaez JJ. Hoffman SW. Beale L. M *See also p. 12. Among the risk factors identiﬁed were frequent swallowing movements detected by surface electromyography. J Neurotrauma 2000. Although aspiration can be clinically silent. DiRusso SM. et al: Excitatory amino acid concentrations in ventricular cerebrospinal ﬂuid after severe traumatic brain injury in infants and children: The role of child abuse. Risk factors for aspiration in critically ill patients are numerous. 8. 60: 115–122 Weil MD. Kochanek PM. intubation. Atlanta. Kochanek PM. No data are available to show that results from the dye method correlate with those from established diagnostic methods to detect aspiration. Adduci A. cellular. To the contrary. 9. 13. Neurosurgery 1992. however. there are data to show that the dye method lacks sensitivity. with reported values ranging from 0. Clark RS. 3:43–51 Hindmarsh GJ. The overall incidence of oropharyngeal aspiration was 28%. In this issue of Pediatric Critical Care Medicine. 137: 197–204 Ruppel RA. et al: Severe head injury in children: Experience of 10. Genome Res 2001. 37:10 –19 Duhaime AC. child Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. and Pediatr Crit Care Med 2004 Vol. 2 194 . and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside. 5. et al: Traumatic brain injury in the elderly: Increased mortality and worse functional outcome at discharge despite lower injury severity. 31:435– 444 Susman M. 1:4 –19 Clark RS.04557. supine positioning. their ﬁndings suggest that the incidence of aspiration in their population is Ն28%.” N Engl J Med 1998. et al: Gender and age effects on outcome after pediatric traumatic brain injury. (8) demonstrated that dye added to small volumes of oral liquid and semisolid feedings failed to detect aspiration in tracheotomized adults in whom aspiration was conﬁrmed by modiﬁed barium swallow or ﬁberoptic endoscopic evaluation. analysis of case/control data using estimated haplotype frequencies: Application to APOE locus variation and Alzheimer’s disease. Ruppel RA. Edwards MS. Fackler JC. Thompson-Henry et al. The incidence of aspiration in critically ill patients is difﬁcult to ascertain from the literature. Amantea and colleagues (7). Ried S. 14. Considering the methods used by Dr. 2000 Roof RL. and lack of adequate sedation (increased wakefulness). Eguchi H.0000113267. Matsuzaki A. Centers for Disease Control and Prevention. Amantea and colleagues (7) take on the challenge of estimating the incidence and describing the risk factors for oropharyngeal aspiration in a group of 50 mechanically ventilated infants and children. In the study by Dr.8 to 95% (2– 6). Sullivan T. J Trauma 2002. Lamborn K. 11:143–151 Crawford FC. et al: Neuropsychiatric sequelae in TBI: A comparison across different age groups. et al: Gender differences in cognitive abilities at 2 years in ELBW infants. most commonly cited are decreased level of consciousness. Brain Injury 2003. et al: APOE genotype inﬂuences acquisition and recall following traumatic brain injury. et al: Inﬂuence of a child’s sex on medulloblastoma outcome. 17:835– 846 Hurvitz EA. et al: Nonaccidental head injury in infants—the “shaken-baby syndrome. Extremely low birth weight. J Pediatr 2000. the presence of an oral endotracheal tube. O’Callaghan MJ. 6. 10). et al: Increases in bcl-2 protein in cerebrospinal ﬂuid and evidence for programmed cell death in infants and children after severe traumatic brain injury.
Amantea and colleagues (7) evaluated the contribution of various risk factors for aspiration using both univariate and multivariate analyses. whether pharmacologically induced in the critical care setting or due to preexisting neurologic compromise before endotracheal intubation. Metheny. 15–16). The relationship between route of intubation and clinically signiﬁcant pulmonary aspiration needs to be further addressed in a randomized controlled trial. These features make their ﬁndings difﬁcult to apply to those intensive care units where patients are routinely cared for in the semirecumbent position and cuffed endotracheal tubes are frequently used. inadequate sedation (i. anticipated outcomes. suppression of cough and predilection for atelectasis. planned interventions. MI St. thereby keeping the oropharynx clear of foreign materials. The incidence of postextubation stridor was low and similar between groups. allowed the use of lower rates of fresh gas ﬂow. Practitioners would be amiss to conclude that sedation is inadequate in mechanically ventilated children unless swallowing reﬂexes are inhibited. trauma. All of the patients studied by Dr. Short-term complications include postextubation stridor. These studies suggest that cuffed endotracheal tubes can be safely used in young children as long as cuff pressures are carefully followed. increased wakefulness). The latter speculation is not supPediatr Crit Care Med 2004 Vol. furthermore. Awake swallowing occurs during the expiratory phase of respiration. uncuffed endotracheal tubes in 488 children mechanically ventilated during anesthesia. which is surrounded by a rigid cartilaginous complete cricoid ring. whereas in the long term tracheal stenosis can develop.high-risk conditions such as neurologic disorders (11). 13). Amantea and colleagues (7) were mechanically ventilated with uncuffed endotracheal tubes and were evaluated for aspiration in the supine body position. Due to the anatomy of the infant’s airway. Mechanical ventilation for Ն7 days and decreased level of consciousness (Glasgow Coma Scale Ͻ9) were additional risk factors. rendering the patient susceptible to aspiration.e. No patient experienced any long-term airway complications. In a prospective observational study. semirecumbent body positioning conducted by Drakulovic et al. the presence of an endotracheal tube not withstanding. According to Nishino. Dr. and that children who swallow frequently expose their airways to oropharyngeal secretions more often than sedated children who swallow less. The overall incidence of postextubation stridor was 15% with no signiﬁcant difference between the two endotracheal tube groups even after controlling for age. Dr. The incidence of nosocomial pneumonia was highest for patients receiving enteral nutrition in the supine position. Deakers et al. Lack of swallowing thus could be expected to result in accumulation of colonized secretions in the oropharynx. Meert. It is also possible that the questionable efﬁcacy of the detection method used in the study partially explains why risk factors identiﬁed by the investigators are incongruent with what is typically reported in the literature. inadequate sedation was not an independent risk factor. increased frequency of swallowing movements. and reduced the concentration of anesthetics in the operating room atmosphere. PhD Department of Pediatrics Children’s Hospital of Michigan Wayne State University School of Medicine Detroit. and Pediatric Risk of Mortality Score. An important ﬁnding of this study is the beneﬁt of nasal intubation compared with oral intubation in reducing aspiration risk. MD Norma A. however. presumably due to the high correlation between level of sedation and frequency of swallowing movements. on the other hand. predisposing the patient to aspiration pneumonia. The integrity of the barrier preventing oropharyngeal secretions from gaining access to the tracheobronchial tree is markedly inﬂuenced by the interaction between the swallowing reﬂex and the respiratory cycle. are the ﬁndings from this study concerning the inﬂuence of sedation and swallowing ability on aspiration in critically ill children. thus serving as a protective mechanism that prevents low-grade aspiration from occurring. 5. Compression of the respiratory mucosa by a tight-ﬁtting endotracheal tube can cause subglottic edema. 2 ported by a comprehensive review of the physiology and pathophysiology of upper airway reﬂexes by Nishino (14). (16) compared the use of cuffed vs. Kathleen L. decisions must be based on the underlying disease process. Khine et al. practitioners are cautious about using cuffed endotracheal tubes in these patients (17). and hemodynamic instability. Amantea and colleagues (7) speculate that the presence of an oral endotracheal tube impairs tongue movement and laryngeal closure. Louis University School of Nursing St. Adnet and Baud (13) demonstrated an increased frequency of suspected aspiration pneumonia on intensive care unit admission in adults with impaired consciousness at the time of initial contact with prehospital personnel. the main function of the swallowing reﬂex is to propel food and secretions from the oral cavity to the stomach. Assessing the adequacy of sedation requires clinical judgment. It is clear that pulmonary aspiration in infants and children is a multifactorial process. The infant’s airway is narrowest at the laryngeal subglottis. occurs equally during inspiration and expiration. Most investigators agree that supine positioning and impaired consciousness are major risk factors for aspiration. leak around the endotracheal tube before extubation. Swallowing in the unconscious state.. (15) studied 282 consecutive tracheal intubations in a pediatric intensive care unit to compare the outcomes of patients with cuffed and uncuffed endotracheal tubes. duration of intubation. On multivariate testing. MO 195 . A randomized trial of supine vs. and patient preferences. Louis. Cuffed tubes prevented the need for repeat intubations due to airleak. Several studies have found the use of cuffed endotracheal tubes to be protective against aspiration (4. and oral intubation were associated with increased aspiration risk. These ﬁndings are in contrast with previous studies of both intubated and nonintubated patients in which decreased levels of consciousness were found to contribute to aspiration risk (12. On univariate testing. The contrasting ﬁndings may be explained by the nature of the impaired consciousness. The degree of sedation required to suppress swallowing may be associated with other unwanted outcomes such as prolonged mechanical ventilation. (12) demonstrated that the frequency of clinically suspected and microbiologically conﬁrmed nosocomial pneumonia was signiﬁcantly greater in supine positioned patients. Less clear. Recent studies in both the pediatric intensive care unit and operating room settings have demonstrated the safety and efﬁcacy of cuffed endotracheal tubes in infants and young children. No.
increases in pulmonary artery pressure and pulmonary vascular resistance may lead to deterioration in the postoperative period. 157. Dysphagia 1995. Kingston GW. Frei FJ: The use of cuffed endotracheal tubes in infants and small children. et al: Aspirated nasogastric feeding solution detected by glucose strips. After CPB. Adnet F. Corddry DH. Drakulovic MB. It is possible that the study (90 mins) may not be of sufﬁcient duration to determine the full extent of the effect of INO on the cardiopulmonary variables in piglets. In an attempt to settle the score. However. J Parenter Enteral Nutr 1983. 9. Inhaled nitric oxide (INO) has been proposed as a likely candidate to ameliorate these untoward effects. Baud F: Relation between Glasgow Coma Scale and aspiration pneumonia. inhaled nitric oxide. 102:582–584 5. 86:627– 631 17. 5:152–156 Thompson-Henry S. 95:67– 68 3. Erb T. Deakers TW. and during both ischemia and reperfusion (8). et al: Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: A randomized trial. Kettrick RG. 26:S26 –S33 12. there should be. J Parenter Enteral Nutr 1992. Strong RM. However. et al: Complications occurring during enteral nutrition support: A prospective study. et al: Cuffed endotracheal tubes in pediatric intensive care. which do not mimic the clinical scenario after CPB (6 –7). 5. however. J Parenter Enteral Nutr 2002. reported in this *See also p. 50:395– 400 Nitric oxide: To inhale or not to inhale* C ardiopulmonary bypass (CPB) is an iatrogenic hierarchical kill of vital organ perfusion. Braddock B: The modiﬁed Evan’s blue dye procedure fails to detect aspiration in the tracheotomized patient: Five case reports. the effect of INO in decreasing the deranged physiology of ischemic reperfusion injury has met with contrasting results. no adverse effects on hemodynamic status if given during CPB. et al: Oropharyngeal aspiration in pediatric patients with endotracheal intubation.C0 issue of Critical Care Medicine. It is also possible that the authors found no difference in lung damage using dry lung-weight ratio. 8. as seen in septic shock. 10. basal NO pro- duction is needed to maintain normal vascular tone whereas large amounts. in which basal concentrations of NO are important for normal lung physiology (bronchodilation and maintenance of normal arterial tone) but the large amounts produced during asthma exacerbations may increase lung edema and mucus secretion (9). and alveolar destruction on a score of 0 for best to 3 for worst for each of category). Lancet 1996. whereas administration of INO after CPB only may be beneﬁcial. These ﬁndings are puzzling in that intuitively we would expect that if INO administered after CPB is beneﬁcial. Their elegant experiments in a piglet model of CPB compared the effects of INO on cardiopulmonary status when INO was administered during ischemia only.64484.1097/01. Torres A. 2 196 . 344: 665– 671 2. 122:276 –281 11. Ann Intern Med 1981. 50:3–14 15. 354:1851–1858 13. Hubble and colleagues (8) conducted experiments in an in vivo ischemic reperfusion lung injury model. 7:546 –552 4. Seltzer MH. Guerrero PA. 103:117–121 Metheny NA. It is associated with a deﬁned period of altered perfusion of lung and myocardium. ischemic reperfusion injury.REFERENCES 1. 125:57– 62 16. Jpn J Physiol 2000. pulmonary hypertension Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. No. Nishino T: Physiological and pathophysiological implications of upper airway reﬂexes in humans. Sanches P. Chest 1993. Solinger MR. cardiopulmonary bypass. et al: Efﬁcacy of dye-stained enteral formula in detecting pulmonary aspiration. Stretton M. Condon SC. 348:123–124 14. Browning DH. J Pediatr 1983. at a minimum. Am J Surg 1991. It is possible that accumulation of NO in the lung tissue of the piglets that received INO during the ischemic phase of CPB may set up the milieu for the generation of potentially toxic substances under hyperoxic study conditions. Key Words: nitric oxide. Marik PE: Aspiration pneumonitis and aspiration pneumonia. Anaesthesist 2001. what are likely explanations if these ﬁndings of worsening hemodynamics are real? The authors offered several plausible explanations. N Engl J Med 2001. Zaroukian MH. Slocum BA. Barron E. Dahms TE. Cataldi-Betcher E.CCM. Bauer TT. The ﬁnding of NO being good and bad in differing amounts or circumstances has posed a dilemma for investigators. 16: 59 – 63 Amantéa SL. Chest 2002. 10: 172–174 Potts RG. Leathley MJ: Increased incidence of nosocomial pneumonia in mechanically ventilated patients with subclinical aspiration. Lancet 1999. Piva JP. Stewart BJ. none can fully explain the phenomenon seen. during reperfusion only. Most of the studies examining INO effects on pulmonary pathophysiology were performed in isolated lung models (1–5) and in situ lung models. intragastric-placed small bore nasoenteric feeding tubes: A randomized. et al: Equal aspiration rates from postpyloric and 7. et al: Comparison of cuffed and uncuffed endotracheal tubes in young children during general anesthesia. In fact. et al: Comparison of blue dye visualization and glucose oxidase test strip methods for detecting pulmonary aspiration of enteral feedings in intubated adults. Another explanation was the upregulation of endothelin with a concomitant down-regulation of intrinPediatr Crit Care Med 2004 Vol. J Pediatr 1994. They found that administering INO during the ischemic period of CPB worsens post-CPB hemodynamic status. Graves SA: Incidence of aspiration with endotracheal tubes in children. Dr. Metheny NA: Risk factors for aspiration. neutrophil number.0000113927. Similarly. An explanation of the detrimental effect of INO during CPB is elusive. Pediatr Crit Care Med 2004. are detrimental. Winterbauer RH. The seemingly good and bad effects on a single organ are amply demonstrated in the lung. INO during both ischemia and reperfusion yielded intermediate beneﬁts. prospective study. Phang PT. Khine HH. Durning RB. and histologic evaluation because of the short time frame or because the histologic evaluation is crude and subjective (hemorrhage. myeloperoxidase. 161: 589 –592 6. Anesthesiology 1997. Reynolds G. the beneﬁcial effects of steroids used in asthma may be partly due to decreased NO production.
Proc Natl Acad Sci U S A 1995. Craig DM. Nitric oxide is produced by many cells within the lung (albeit in small amounts—parts per billion) and appears to play a critical role in the pathophysiology of the pulmonary vascular bed and airways (10 –12). Mouchawar A. Output of NO via NO synthase II. 76: 1324 –1329 6. CPE Division of Pediatric Critical Care Medicine University of Florida HSC/Jacksonville Jacksonville. produces larger quantities of NO (13. 91:12086 –12090 13. Pinsky DJ. which both lead to its consumption. Pediatr Crit Care Med 2004. hypoxia and ischemia might alter NO concentrations and bioactivity by multiple and sometimes opposing mechanisms. 156:454 – 458 3. 60:1169 –1176 5. 27:389 –393 11. Gaston B. Therefore. Kavanagh BP. 80:782–788 2. although important. Based on these iterations. J Appl Physiol 1996. Chowdhury NC. et al: Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Experiments in both cell culture in animal and human lungs have shown that enzymatic NO production exhibits a characteristic oxygen dependence and thus hypoxia reduces enzyme activity to synthesize NO (15–18). An appreciation of the complexity of NO physiology in lung injury. Hybertson BM. Thromb Haemost 1995. Chee CB. In fact. Wise RM. Mazmanian M. 14). Am J Respir Crit Care Med 1997. Foster AG. in view of the complex relationships in NO production during ischemic reperfusion injury. et al: Inhaled nitric oxide results in deteriorating hemodynamics when administered during cardiopulmonary bypass in neonatal swine. how relevant are these ﬁndings to the clinician? Does the piglet’s physiology approximate the human neonate in whom CPB may be used? It is possible that the basal NO production and response to INO during CPB seen in healthy piglets would be different from that seen in neonates with congenital heart disease in whom hypoxia. The ﬁ ndings of the study. need to be veriﬁed under conditions more likely to be seen in the neonate undergoing CPB. et al: Prevention of ischemic-reperfusion lung injury by inhaled nitric oxide in neonatal piglets. Pediatr Crit Care Med 2004 Vol. NO production measured by exhaled NO is reduced postoperatively and is thought to be due to lung epithelial or pulmonary vascular endothelial injury (24). Murakami S. 2 Mechanical forces imposed on cells by dynamically changing blood (pulsatile vs. During ischemia and reperfusion. 92:7809 –7813 14. 114:1061–1069 8. Hubble CL. 20). Barbotin-Larrieu F. et al: Nitric oxide mediates ﬂuid accumulation during cardiopulmonary bypass. Mazmanian GM. Rice TW. regulation. et al: Constitutive and inducible nitric oxide synthase gene expression. J Appl Physiol 1994. oxygen radical-dependent leak in isolated rat lungs. 112:168 –174 7. which could be further induced by inﬂammatory mediators. De Raeve HR. ischemia. Guidot DM. and consumption. et al: Alteration of the neonatal pulmonary physiology after total cardiopulmonary bypass.sic NO synthesis resulting in the elevation of pulmonary vascular resistance and pulmonary hypertension. increased or decreased pulmonary blood ﬂow. 74:58 – 65 12. Hypoxia. This is likely to explain the hemodynamic values seen in the INO during CPB only group and also may explain the blunted response to INO in the group receiving INO both during and after CPB. and activity in human 197 . et al: Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. Eppinger MJ. J Thorac Cardiovasc Surg 1996. et al: Disparate effects of nitric oxide on lung ischemia-reperfusion injury. These complex interactions are likely to alter NO production. it also has been suggested that pH changes associated with ischemia can trigger this chemistry in the heart and aorta (22. Pinsky DJ: The vascular biology of heart and lung preservation for transplantation. et al: Inhaled nitric oxide prevents neutrophilmediated. Cheifetz IM. and altered pulmonary mechanics may be present before CPB. However. NO can serve both as an antioxidant (by inhibiting lipid free radicals) and as an oxidant (by contributing to peroxynitrite formation). Proc Natl Acad Sci U S A 1994. generation. J Thorac Cardiovasc Surg 1997. Guo FH. 5:157–162 9. Moreover. Asano K. Serraf A. does not enable us to fully explain the study ﬁndings. Bacha EA. MD. one can predict that ischemic reperfusion injury would be associated with a complicated picture of NOS expression. a reaction that takes place predominantly during acidic/reducing conditions as may be seen during ischemic reperfusion injury (19. INO should be used with caution if at all during CPB. et al: The nitric oxide/cyclic GMP pathway in organ transplantation: Critical role in successful lung preservation. control for the multitude of factors involved will be needed to unravel their relative contribution — a daunting task indeed. FL REFERENCES 1. Barnes PJ: NO or no NO in asthma? Thorasc 1996. however. Several authors have reported that preoperative pulmonary hypertension and left to right shunts seem to be related to postoperative pulmonary vascular reactivity (25 – 27). Endogenous NO production and bioactivity are subject to great alterations due to hypoxia. No. Regardless of the explanation. Repine MJ. both theories go adrift because worse hemodynamics than the control group (no INO) would be expected but did not occur in the group that received INO only during CPB. During ischemia. and airway epithelial cells normally produce NO via the NO synthase III pathway. these mechanical stimuli are reduced with the potential effect of decoupling NO synthesis from shear stresses. nonpulsatile ﬂow) and air ﬂow (including positive end-expiratory pressure) are also important contributors to both microvascular and airway NO production. Naka Y. Jones ML. 5. Goldsmith J. therefore. Endothelial cells constitutively express a relatively low output of NO via NO synthase I enzymatic pathway. Robotin M. 269: L2–L5 4. Am J Physiol 1995. An examination of endogenous NO generation in lung ischemic reperfusion injuries may provide the physiologic underpinning of the seemingly contradictory ﬁndings. might increase NO generation from nonenzymatic sources involved in the reduction of inorganic nitrate to NO. It is also possible that dosing of INO during CPB altered the response to post-CPB INO without upregulation of endothelin. acidosis. Ann Thorac Surg 1995. The tantalizing data remind us that too much of a good thing may be good for nothing. et al: Effects of various timings and concentrations of inhaled nitric oxide in lung ischemia-reperfusion. Ward PA. Although the potential relevance of this phenomenon to lung pathology has been demonstrated by showing alteration of acid-base balance and increase in NO production from nitrate and acidic pH in asthma (21). 23). In the meantime. Bonnet N. 51:218 –220 10. and reperfusion. Wehberg KE. Ann Med 1995. Barnes PJ: Nitric oxide and airway disease. Niranjan Kissoon. however. Baudet B. The relative contribution of each of these complex interactions will need to be unraveled to fully explain the observed phenomenon.
Laskowski D.15. Caramori M. A great deal of excitement has been generated by recent studies that suggest that hypoxic-ischemic brain injury can be reversed or ameliorated by the use of therapeutic postresuscitative hypothermia. In 1973. Implications for asthma pathophysiology. Circulation 1987. and “deﬁbrination syndrome” was ﬁrst described in the 1960s. Abu-Soud HM. et al: Changes in pericardial surface pressure during pulmonary hypertensive crises after cardiac surgery. 271: H8 –H146 Ziesche R. J Clin Invest 1998. (5) demonstrate that neonatal asphyxia is associated with systemic thrombosis and depletion of two important anticoagulant proteins: antithrombin III and protein C. Samouilov A. et al: Decreased exhaled nitric oxide may be a marker of cardiopulmonary bypass-induced injury. et al: Regulation of human endothelial nitric oxide synthase by hypoxia and inﬂammation in human pulmonary arteries — implications for the therapy of pulmonary hypertension in COPD patients. Herulf M.5 hrs after birth. Compagnoni and colleagues (4) simultaneously reported. lung epithelial cells. that postresuscitative cooling led to a signiﬁcant improvement in neurologic outcome in adults who. 5. randomized. 20. 91:10089 –10093 Dweik RA. et al: Endogenous airway acidiﬁcation. El Beshlawy et al. Am J Pathol 1980. The child had a remarkable recovery and was considered neurologically normal at 1 yr of life.PCC. Acta Physiol Scand 2001. 2 198 . heparinized whole blood exchange transfusion was “well established” as an effective therapy for asphyxia with deﬁbrination syndrome in the term newborn (9). Samouilov A. Herulf M. Proc Natl Acad Sci U S A 1994. Am J Physiol 1996. If therapeutic hypothermia becomes a mainstay. controlled trial format. Acta 19. 25. then the next clinical question is which approach can act synergistically with this therapy to further improve both survival and neurologic outcome from asphyxia neonatorum? In this issue of Pediatric Critical Care Medicine. Acta Physiol Scand 2001. 167:469 – 476 Nelin LD. 16. Rudolph AM. had ventricular ﬁbrillation-induced cardiac arrest (2. Williams WG. he was in shock with deep blue skin. 28:533–547 Del Nido PJ. His temperature was 35. Skyberg and Jacobsen (7) reported the ﬁrst successful treatment of this syndrome in an asphyxic term newborn infant who presented with severe spasticity and opisthotonus 5. of whom one million die and one million have serious neurologic impairment (1). 66: 532–534 Hoffman JIE. Bjorne J. Faller DV: Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. Kuppusamy P: Nonenzymatic nitric oxide synthesis in biological systems. for the most part. 1411: 250 –262 Modin A. Petkov V. 171:9 –16 Hunt JF. No. that newborns with asphyxia who were subjected to whole-body cooling within 6 hrs of birth to a temperature between 32°C and 34°C for 72 hrs had a signiﬁcant reduction in major neurologic abnormalities and abnormal magnetic *See also p. The link between perinatal asphyxia. Biochim Biophys Acta 1999. In Pediatr Crit Care Med 2004 Vol. in a randomized. et al: Nitritederived nitric oxide: A possible mediator of 24. Mosgoller W. Dawson CA: Effect of hypoxia on nitric oxide production in neonatal pig lung.62216. controlled trial of postresuscitative hypothermia for perinatal asphyxia are expected to be discussed at a “Hot Topics” conference in neonatology. Malik R. et al: Nitritederived nitric oxide: A possible mediator of “acidic-metabolic” vasodilation. J Cell Physiol 1996. 27. The child had vasoocclusive ﬁbrin thrombi (consistent with disseminated intravascular coagulation pathophysiology) and hyaline thrombi (platelet thrombi consistent with thrombotic thrombocytopenic pur- pura pathophysiology) occluding vessels. the results of a multicenter. Villamater J. et al: Nitric oxide synthesis in the lung. 161:694 – 699 Zweier JL. Bjorne J. and several subsequent reports refer to treatment with heparinized whole blood exchange transfusion as the established therapy for asphyxia neonatorum. 76(Suppl III): III-93–III-96 Meyrick B. Independent groups in Austria and Australia demonstrated. 26. Reid L: Ultrastructural ﬁndings in lung biopsy material from children with congenital heart defects. Am J Respir Crit Care Med 2000. Biochim Biophys Acta 1999. 17. Anaesthesiol Scand Suppl 1996. Regulation by oxygen through a kinetic mechanism. At the time of the writing of this editorial. 101:660 – 666 Phelan MW. Fang K. 18. and his cerebrospinal ﬂuid contained visible blood. in a sequential series trial format from 1997 to 1999. 23. 171:9 –16 Beghetti M. Thomas CJ. Heymann MA: Pulmonary vascular disease with congenital heart lesions: Pathologic features and causes. Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. 22. 163.0000121302. Circulation 1958. Ann Thorac Surg 1998.D6 resonance imaging ﬁndings.8°C. The neonatal community was favorably impressed by this report. The authors speculate that the use of antithrombin III concentrate and protein C concentrate should be investigated in asphyxia neonatorum. Kuppusamy P: Nonenzymatic nitric oxide synthesis in biological systems. 1411: 250 –262 Modin A. Hambleton and Appleyard (8) performed a controlled trial of fresh frozen plasma infusion alone in asphyxiated low birthweight infants (Ͻ2. 109: 97–98 Zweier JL. Silkoff PE. They and others concluded that although fresh frozen plasma infusion was not effective.5 kg) and found no reduction in intraventricular hemorrhages with this treatment. Leissring and Vorlecky (6) reported autopsy ﬁndings of a term newborn with asphyxia after breech delivery for severe preeclampsia. 21. He was treated as deﬁbrination syndrome with one exchange transfusion of 500 mL of heparinized whole blood (containing 2500 international units of heparin) plus an 8-day course of corticosteroid therapy. 101: 527–542 Is it time to revisit a role for antithrombotic therapy in asphyxia neonatorum?* I t has been estimated that approximately 130 million births occur worldwide each year with four million newborns suffering birth asphyxia. thrombosis. 3).1097/01. “acidic-metabolic” vasodilation.
El Beshlawy A. 346:549 –556 4. Roman J. Monatsschr Kinderheilkd 1977. we agree that it is time to investigate whether antithrombin III concentrate and protein C concentrate have a therapeutic role in newborns with asphyxia and acquired antithrombin III and protein C deﬁciency. 346:557–563 3. et al: Coagulation. 115:105–111 7. 42:372–375 13. leaving the newborn with severe anticoagulant protein deﬁciency and a proclivity to systemic thrombosis (5. Preparatory studies will likely be needed. and von Willebrand factor-cleaving protease. Blood Coagul Fibrinolysis 1996. 126(Pt 5):1224 –1230 2. Canciani MT. Pogliani L. Wenzel E: Diagnostic therapeutic problems of deﬁbrination syndrome in shock. preventing uncontrolled platelet thrombosis (hyaline thrombi). antithrombin III. et al: Treatment of comatose survivors of cardiac arrest with induced hypothermia N Engl J Med 2002. N Engl J Med 2002. and ADAM TS 13 compared with adults (14. Newborns have markedly reduced levels of antithrombin III. 82:222–227 5. Hall M. ﬁ brinolytic and kallikrein systems in neonates with uncomplicated sepsis and septic shock. The rationale given is that heparin “activates” antithrombin III. 19:467– 473 15. Hambleton G. Vorlicky LN: Disseminated intravascular coagulation in a neonate. In the past. Patients with activated protein C resistance can be successfully anticoagulated with warfarin or heparin therapy. Buonocore G. Hunter J. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma. Unlike antithrombin III and protein C. patients with consumptive coagulopathy may require anticoagulant therapy as well as procoagulant replacement. namely. Instead. Lista G. Dubbers A. Jacobsen CD: Deﬁbrination syndrome in a newborn and its treatment with exchange transfusion. Pediatr Crit Care Med 2004. Carcillo Children’s Hospital of Pittsburgh Pittsburgh. little thought was given to treating or reversing the associated thrombotic microangiopathy. Much has changed since the 1970s. Abou-Elew HH. 7:684 – 688 14. PA REFERENCES 1. preventing ongoing coagulation while the procoagulant factors prevent bleeding from consumptive coagulopathy. coagulation is not decreased at 35°C. et al: Study of protein C.agreement with the ﬁndings of Hambleton and colleagues. 155:580 –588 11. Their ﬁndings support severe depletion of the anticoagulant proteins antithrombin III and protein C in the setting of systemic thrombosis. For example. Kirsch W. 15). 2:187–186 12. It is common practice in veterinary medicine today to treat deﬁbrination syndrome by infusing heparin-treated fresh frozen plasma. However. Kavakli K. These therapies have little to no risk for causing bleeding when administered in the absence of heparin. et al: Hypothermia reduces neurologic damage in asphyxiated newborn infants. Three clinically important circulating anticoagulant proteins have been identi ﬁ ed. 23:142–148 199 . 58:83– 86 8. No. (5). Indeed. a 1996 randomized. 48: 31–38 9. The collective memory for the use of heparinized whole blood exchange has been lost. in this issue of Pediatric Critical Care Medicine. Ryan S. El Beshlawy et al. there has been a great improvement in knowledge about anticoagulant and procoagulant proteins and their role in thrombotic microangiopathic syndromes. Strater R. The Northern Neonatal Nursing Initiative (NNNI) Trial Group Eur J Pediatr 1996. Thorarensen O. Acta Paediatr Scand 1969. 5. whereas patients without “deﬁbrination” may only require anticoagulant therapies. consume antithrombin III and protein C. Antithrombin III and protein C can be more efﬁciently given as commercially puriﬁed concentrates. Mannucci PM: Plasma levels of the von Willebrand Factor Cleaving Protease in physiological and pathophysiological conditions in children. 5:163–166 6. or ADAM TS 13 (11). Replacement of Pediatr Crit Care Med 2004 Vol. because temperature itself has effects on coagulation. First. Brain 2003. Velasco F. and placental thrombosis Ann Neurol 1997. 125:621– 627 10. because some patients with perinatal asphyxia have deﬁbrination syndrome whereas others do not. neonatal stroke. protein C. 2 these anticoagulant factors can be achieved with plasma infusion or with concentrates. Coagulation is decreased at 32°C. Nguyen T. et al: Microvascular thrombosis in pediatric multiple organ failure: Is it a therapeutic target? Pediatr Crit Care Med 2001. 15). it is time to think about the potential role of anticoagulant therapies to further improve outcome and neurologic function after perinatal asphyxia. Bernard SA. it is not thought to have any effect on ﬁbrin. (5) provide a modern day evaluation of the coagulopathy associated with Asphyxia Neonatorum. and antithrombin III in hypoxic newborns. Antithrombin III is an active anticoagulant only when it is complexed with heparin. the effects of hypothermia on thrombosis and ﬁbrinolysis will need to be considered. Second. Leissring JC. In summary. 13). Mild hypothermia to improve neurologic outcome after cardiac arrest. Pathophysiologic processes that cause endotheliopathy. Activated protein C resistance (also known as factor V Leiden deﬁciency) has been reported as a cause of ischemic stroke in neonates and infants (12. Each 10 mL/kg of plasma given replaces approximately 10% of normal activity. Appleyard WJ: Controlled trial of fresh frozen plasma in asphyxiated low birthweight infants. et al: Non protein bound iron as early predictive marker of neonatal brain damage. Nowak-Gottl U. and neonatal hypoxia. Gray TW. et al: Factor V Leidien mutation: An unrecognized cause of hemiplegic cerebral palsy. whole blood is no longer available in much of the Western world where blood is presently banked as components. sepsis. controlled trial similarly showed that prophylactic treatment of preterm babies with fresh frozen plasma had no effect on outcomes (10). Arch Dis Child 1973. Buttner M. The von Willebrand factorcleaving protease ADAM TS 13 is always active. Buist MD. including sepsis (15) and perinatal asphyxia (5). Longini M. Hussein HA. Compagnoni G. protein C. Perrone S. Based on the ﬁndings of El Beshlawy et al. However. Biol Neonate 2002. Absence or inhibition of ADAM TS 13 is considered to be the cause of thrombotic thrombocytopenic purpuramediated thrombotic microangiopathy (11). now that brain injury appears to be at least partly reversible with therapeutic hypothermia. Han Y. Am J Dis Child 1968. Haemostasis 1993. protein S. Fernandez F. The Hypothermia After Cardiac Arrest Study Group. Protein C is an active anticoagulant when it is complexed with endothelial thrombomodulin. et al: Ischaemic stroke in infancy and childhood: Role of the Arg506 to Gln mutation in the factor V gene. Pediatr Hematol Oncol 2002. gelatin or glucose on early mortality and morbidity in preterm babies. Skyberg D. this enzyme cleaves thrombogenic large and ultralarge von Willebrand factor multimers. Antithrombin III concentrate and protein C concentrate are recommended therapies for newborns with congenital antithrombin III and protein C deﬁciency. Robert Clark Joseph A. when neurologic outcome was considered immutable after perinatal asphyxia. patient selection will be important to any study design.
have widespread use. But at what interface does perﬂubron reduce surface tension? Gas/perﬂubron interfaces have modest surface tension (18 dyne/cm). But what of the interface between perﬂubron and immiscible alveolar tissue surface material? If that interface had a surface tension of 40 dyne/cm. Spitale P. We know little of the relation of these properties to the lung dysfunction of meconium aspiration.1097/01. The picture that emerges may help to elucidate the pathophysiology of the meconium aspiration syndrome. Surfactant dysfunction is a widely recognized component of other lung diseases. The greater the concentration of meconium. although meconium reduces the surface tension of saline. and C) are more resistant to inactivation (10). Using a third technique. This ability to wet a perﬂubron ﬁlm is not directly correlated to the disease process.D5 I So which of these properties of meconium are relevant to clinical meconium aspiration syndrome? Clearly meconium aspiration makes the lungs stiff. et al: Improved oxygenation with exogenous surfactant administration in experimental meconium aspiration syndrome. Polymers such as dextran and polyethylene glycol can be added to surfactant to make it more resistant to this inhibition (8. Al-Mateen KB. which itself spreads readily over saline or Teﬂon. et al: Inhibition of pulmonary surfactant function by meconium. Dr. Brandt ML. Curstedt T. distraction (de Nouy ring). Does the “wetting” property of perﬂubron offer an opportunity here? Rubin et al. Bradley P. 167. However. No.0000115958. perﬂubron. Key Words: saline-suspended meconium. suggesting the potential for “ designer surfactants ” of greater resistance. the alveolar tissue is covered by a surface of complex composition. dryness. lift. It is probably simplistic to think of meconium aspiration syndrome as just another surfactant dysfunction state. Dailey K. Am J Obstet Gynecol 1991. 5. Designer surfactants might. wetting surfaces to spread. Wu Y. Pediatr Crit Care Med 2004. 17:75– 80 5. Pediatr Pulmonol 1994. The interface truly at issue during partial or tidal liquid ventilation for meconium aspiration is that of perﬂubron to a mixture (in one phase) of surfactant and meconium. including acute respiratory distress syndrome. Could per ﬂ uorocarbons like perﬂubron be used to reduce surface tension in meconium aspiration syndrome? Dr. 2 . ciliary transportability. a saline-perﬂubron interface has surface tension near 40 dyne/cm. Grimes MM. cough transportability. but at least that aspect of it is tangible. This interaction has been studied in vitro (2) and in intact animals (3–5) and has generated interest in surfactant therapy as a treatment of meconium aspiration (6. Robertson B: Exogenous 200 Pediatr Crit Care Med 2004 Vol. Might mucociliary clearance of meconium be enhanced by perﬂubron lavage.” and non-Newtonian interfacial adhesion tension. J Appl Physiol 1994. Laboratory and clinical experience argues that perﬂubron might prove useful. Fuloria and colleagues (1) have shown that the surface properties of perﬂubron are not altered by exposure to meconium. B. a saline/meconium-perﬂubron interface has a surface tension near that of perﬂubron and gas. roughly halfway between the surface tensions of perﬂubron (at air) and water (at air). Herting E. 77:1961–1971 4. and perﬂubron. the authors show that the interfacial tension between a perﬂubron layer and a meconium/saline suspension is variable and is inversely related to the logarithm of the meconium concentration. Sun B. even in the lung exposed to meconium. calf lung surfactant. (13) discussed various properties of meconium. may enhance the clearance of sticky meconium from airways by making it more slippery. 164:477– 481 3.Surface properties and the meconium aspiration syndrome* n this issue of Pediatric Critical Care Medicine. Dr. calf lung surfactant. But let’s come back to that. and mobilize droplets of meconium? Meconium is “sticky” and relatively “dry. Fuloria and colleagues (1) explore the physical properties and interactions of saline-suspended meconium. 7). Sun B. MD State University of New York at Buffalo Women’s and Children’s Hospital of Buffalo REFERENCES 1.23002. It also illustrates the weakness of the link between the behavior of meconium and the disease it produces. perﬂuorocarbons could not be helpful. Holm BA. 9). We are comfortably familiar with this. What of the other properties of meconium? Meconium suspension does not spread over Teﬂon. Of great interest here is the ﬁnding that at very low meconium concentration. Fuloria and colleagues (1) have shown that at high meconium concentration.PCC. meconium aspiration Copyright © 2004 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10. This would appear to correlate with loss of surfactant function. it interferes with the surface tension lowering effect of surfactant in proportion to the concentration of the suspension. describing it as characterized by cohesiveness (“spinability”). but the implication is that perﬂubron. Fuloria M. Moses D. therefore. 5:167–171 2. and surfactants having higher concentrations of surfactant proteins (A. slip. Curstedt T. Fuhrman. The authors show that. Dr. The rationale for highdose surfactant instillation in meconium aspiration syndrome is that giving more surfactant may reverse or overwhelm this interference.” Perhaps meconium particles obstruct airways and are hard to dislodge by “cough (air ﬂow) transport. like that of saline to perﬂubron.” Can such particles be washed away? There is recent interest in lavage using dilute surfactant as a means to mobilize and remove meconium (11. the lower is the interfacial surface tension. Fuloria and colleagues (1) further show that meconium suspension spreads poorly over Teﬂon but readily over perﬂubron. et al: Exogenous surfactant improves lung compliance and oxygenation in adult rats with meconium aspiration. “wetability. et al: Effect of meconium on the surface properties of perﬂ ubron. *See also p. 12). Perhaps this impairs mucociliary clearance of meconium.
Goerke J. Pediatr Pathol Molecular Med 2001. Bulas DI. 132:40 – 47 8. 40: 834 – 838 Pediatr Crit Care Med 2004 Vol. Lotze A. Robertson B: Dextran reduces surfactant inhibition by meconium. Knight GR. et al: Nonionic polymers reverse inactivation of surfactant by meconium and other substances. 159: 1391–1395 9. Pediatr Res 1996. Pediatrics 1999. Lu KW. Taeusch W. Martin GR. J Pediatr 1993. Acta Paediatrica 2000. Am J Respir Crit Care Med 1996. Kobayashi T. J Pediatr 1998. Lam BC. Yeung CY: Surfactant lavage for meconium aspiration syndrome: A pilot study. et al: The surface and transport properties of meconium and reconstituted meconium solutions. Lam BC. Patrinos ME. Fu KH.surfactant improves ventilation efﬁciency and alveolar expansion in rats with meconium aspiration. 103:1014 –1018 13. Keough KM: Inactivation of pulmonary surfactant and the treatment of acute lung injuries. Yeung CY. et al: Surfactant tracheobronchial lavage for the management of a rabbit model of meconium aspiration syndrome. 154:764 –770 6. 122:261–268 7. Lotze A. Rubin BK. 5. 2 201 . Tashiro K. Biol Neonate 2000. 20:519 –536 11. Mitchell B. Tomkiewicz RP. et al: Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. No. Am J Respir Crit Care Med 1999. et al: Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Taeusch HW. 89: 1439 –1445 10. 78:129 –138 12.
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