Statistics, not experts.
Explore the source record for details and available documents.
Expert Testimony↗
Biomedical subjects
W Meadow
Publications and source records attributed to W Meadow.
Hemodynamic homeostasis during acute hypoxia in septic and nonseptic piglets: differential role of prostaglandins and nitric oxide.
We studied the hemodynamic responses of 29 anesthetized and mechanically ventilated piglets to acute hypoxia [reduction of Pao2 from 130 to 38 mm Hg induced by inhalation of 7% fraction of inspired oxygen (Fio2) for 7.5 min] before and during group B beta-hemolytic streptococci (GBS) sepsis. During hypoxia, nonseptic piglets maintained stable systemic blood pressure [105+/-9 (SD) to 97+/-14 mm Hg] and cardiac output (CO) (667+/-72 to 685+/-113 mL/min). However, during GBS/hypoxia, systemic blood pressure fell from 94+/-17 to 49+/-25 mm Hg, CO fell from 397+/-146 to 223+/-142 mL/min (both p < 0.001 versus pre-GBS), and cardiac arrest often ensued. We tested three hypotheses that might underlie GBS-induced intolerance to systemic hypoxia: 1) GBS-induced reduction of systemic CO/systemic oxygen delivery (QO2) below a critical QO2 beyond which the superimposition of hypoxia becomes intolerable; this mechanism is unlikely as nonseptic piglets with comparable reductions in CO/QO2 (induced by inflation of a left atrial balloon) tolerated hypoxia well; 2) GBS-induced inhibition of nitric oxide (NO) synthesis that is vital to tolerance of hypoxia; this mechanism is unlikely as infusion of the NO substrate L-arginine did not restore tolerance to hypoxia during GBS infusion (as it did after inhibition of NO synthesis during infusion of N-nitro-L-arginine in nonseptic piglets); and 3) GBS-induced production of pathologic prostaglandins that impaired the piglet's capacity to tolerate hypoxia; this mechanism finds support in the observation that inhibition of prostaglandins with the cyclooxygenase inhibitor indomethacin completely restored the ability of septic piglets to tolerate hypoxia. Further evaluation of GBS-induced intolerance to systemic hypoxia may provide insight into the incompletely understood mechanisms by which sepsis induces circulatory collapse in experimental animals and in humans.
Animals↗
Correlation of flow probe determinations of common carotid artery blood flow and internal carotid artery blood flow with microsphere determinations of cerebral blood flow in piglets.
We investigated whether blood flow determined by a flow probe situated on one common carotid artery provided an accurate estimation of unilateral cerebral blood flow (CBF) in piglets. In eight anesthetized, mechanically ventilated piglets, blood flow determined by an ultrasonic flow probe placed on the right common carotid artery was correlated with CBF determined by microspheres under two experimental conditions: 1) before ligation of the right external carotid artery with both the right external and internal carotid circulations intact [common carotid artery blood flow (CCABF) condition], and 2) after ligation of the right external carotid artery (ipsilateral to the flow probe) with all residual right-sided carotid artery blood flow directed through the right internal carotid artery [internal carotid artery blood flow (ICABF) condition]. The left carotid artery was not manipulated in any way in either protocol. Independent correlations of unilateral CCABF and ICABF with microsphere-determined unilateral CBF were highly significant over a 5-fold range of CBF induced by hypercarbia or hypoxia (r = 0.94 and 0.92, respectively; both p < 0.001). The slope of the correlation of unilateral CCABF versus unilateral CBF was 1.68 +/- 0.19 (SEM), suggesting that CCABF overestimated CBF by 68%. The slope of the correlation of unilateral ICABF versus unilateral CBF did not differ significantly from unity (1.06 +/- 0.15), and the y intercept did not differ significantly from zero [-1.3 +/- 5.2 (SEM) mL]. Consequently, unilateral ICABF determined by flow probe accurately reflected unilateral CBF determined by microspheres under these conditions. Flow probe assessments of CCABF and ICABF in piglets may provide information about dynamic aspects of vascular control in the cerebral circulation that has heretofore been unavailable.
Animals↗
Effects of nebulized nitroprusside on pulmonary and systemic hemodynamics during pulmonary hypertension in piglets.
We tested the effects of nebulized nitroprusside (Neb-NP) on pulmonary and systemic hemodynamics during pulmonary hypertension induced by hypoxia or group B streptococci infusion in piglets. Twenty-three anesthetized and mechanically ventilated piglets received Neb-NP under four experimental conditions: 1) normoxia; 2) 15 and 60 min of pulmonary hypertension induced by hypoxia; 3) after pretreatment with dipyridamole; 4) pulmonary hypertension induced by infusion of group B streptococci. In addition, Neb-NP was contrasted to nebulization of tolazoline. During hypoxia-induced pulmonary hypertension, Neb-NP significantly reduced pulmonary artery pressure [PAP; -8.4+/-0.9 (SEM) mm Hg] and pulmonary vascular resistance (-25+/-2.1%) (both p < 0.001), whereas neither systemic arterial pressure nor cardiac output changed significantly. Selective pulmonary vasodilation began within 2 min of the onset of Neb-NP, and did not wane over 1 h. In contrast, within 5 min after Neb-NP was discontinued while hypoxia persisted, PAP rose significantly. Pretreatment with dipyridamole did not enhance the pulmonary vasodilation induced by Neb-NP, but did reduce systemic arterial pressure. Nebulized tolazoline did not reduce PAP significantly, but did lower systemic arterial pressure. Selective pulmonary vasodilation induced by Neb-NP was significantly smaller during group B streptococci-induced versus hypoxia-induced pulmonary hypertension. In sum, Neb-NP produced prompt, significant, selective reduction of PAP in piglets with pulmonary hypertension. Cautious extrapolation of these findings to selected clinical conditions in human infants may be warranted.
Administration, Inhalation↗
A proactive, data-based determination of the standard of medical care in pediatrics.
A 3-week-old infant awoke with a fever. He was taken to the doctor who noted that the child was irritable. The doctor took him to the hospital where a resident performed a spinal tap, started an intravenous (IV) line, and ordered antibiotics. The entire drama, from entering the doctor's office to infusion of ampicillin, took 2 hours. The doctor was sued for malpractice. Expert witnesses for the plaintiff testified that he had deviated from the standard of medical care by taking too long to administer antibiotics, which, in their view, ought to have been given within 30 minutes. Expert witnesses for the defense testified that 2 hours to administer antibiotics in this case was within the standard of care. What ought to be the response of the pediatric community to discrepant expert testimony such as this? One possible response is nothing. Lawyers from both sides will find expert medical witnesses who articulate positions favorable to their clients (as they did in this case), and the truth will emerge after vigorous cross-examination. This, we suggest, is inadequate. We believe that some expert opinions can be viewed as better than others. That is, some opinions describe the standard of medical care correctly while other expert opinions are (to put it charitably) idiosyncratic, failing to depict accurately the skill and care ordinarily administered in comparable situations. Currently, jurors are informed about the standard of care by expert witnesses, who rely on their own medical knowledge and experience. However, a huge body of literature demonstrates that recollections of individual experience are inevitably flawed, and flawed in a nonrandom direction (the Monday morning quarterback phenomenon). Consider the infant with meningitis. When experts in pediatric emergency medicine and pediatric infectious diseases (ID) were asked about the median time from emergency room (ER) presentation to administration of antibiotics in a child with suspected meningitis, their opinions were wrong and slanted toward the outcome known to be desired (namely, a shorter elapsed time). ER physicians (median estimated time to antibiotic administration [AB-TIME] = 46 minutes) and ID physicians (median estimated AB-TIME = 80 minutes) consistently underestimated the actual median value of AB-TIME determined by chart review (120 minutes). From the judicial perspective such potential flaws in expert testimony are assumed to be equally distributed among experts. All admissible evidence is a priori of equal weight until a jury decides otherwise. The standard of medical care is created anew by expert testimony in each individual case, disappearing, like Brigadoon, upon resolution of the dispute. However, to anyone but a lawyer, the standard of medical care must exist as something outside the courtroom testimony of experts, and if it does exist, it should be easily described so that expert testimony can be judged more (or less) accurate in depicting it. We contend that medical care is not a single behavior that conforms to or deviates from an idiosyncratic and retrospectively determined standard, but rather a distribution of behaviors in response to a variety of medical circumstances. For a given scenario, each of several possible responses can be ascribed a relative frequency based on empirical data, and the consequent normal curve depicts the totality of medical care. Substandard care then falls out neatly as behaviors lying outside the large majority of cases. Juries would be empowered (as they are currently) to determine exactly where on this curve substandard care lies, but at least the debate would share the same description of reality. Recent US Supreme Court guidelines regarding expert testimony provide an opportunity to expand the use of databases in medical negligence cases. The Court restricted expert testimony to "scientific knowledge ... based on generating hypotheses and testing them to see if they can be falsified ... (ABSTRACT TRUNCATED)
Databases as Topic↗
Resource allocation in neonatal and medical ICUs. Epidemiology and rationing at the extremes of life.
This study compared resource allocation to patients who eventually die in neonatal ICUs (NICUs) and adult medical ICUs (MICUs). It was performed via retrospective, chart review study at ICUs at the University of Chicago-an inner city, tertiary care, academic medical center. All patients were admitted to the neonatal, general medical, or coronary ICU during 1 calendar yr. Overall mortality in the NICU (66/827; 7.9%) was significantly lower than in the adult ICUs (219/1320; 16.5%) (p < 0.001). However, mortality for the smallest newborns (< 751 g; 51% mortality) was higher than for the oldest adults (> 54 yr; 30% mortality) (p = 0.05). Fifty-six percent (37/66) of all neonates who died in the NICU did so within the first 48 hr of life. In contrast, nearly two-thirds (134/219) of adult ICU deaths occurred after 48 hours in the ICU (p < 0.02). The percentage of ICU bed-days devoted to nonsurviving adults (28.8%) was significantly larger than the percentage of NICU bed-days devoted to nonsurviving babies (7.8%). Even among babies at greatest risk to die (birth weight < 751 g), the percentage of NICU bed-days allocated to nonsurviving infants was less than 20%. In contrast, for the oldest ICU patients (> 84 yr) this value exceeded 50%, for ICU patients > 84 yr old who required mechanical ventilation, the percentage of ICU bed-days allocated to nonsurvivors approached 90%. Care for the elderly in MICUs involves a far greater proportional expenditure of money toward those who will not survive than does care for newborns in NICUs. To the extent that allocation decisions are driven by concerns about distributive justice and the efficient use of scarce resources, it would be more justifiable to ration intensive care for the very old than the very young.
Adult↗
Physicians' experience with allegations of medical malpractice in the neonatal intensive care unit.
OBJECTIVE: To assess the personal experience of all practitioners of neonatal intensive care unit (NICU) medicine in the United States with the medical malpractice system; in particular, to assess the circumstances of malpractice allegations in which they themselves had personal experience, and to extrapolate from their individual experiences to the field of neonatology in general. DESIGN: Written survey of all MDs practicing NICU medicine in the US. PARTICIPANTS: Two thousand four hundred ninety-eight NICU physicians as determined from three sources: a) the American Board of Medical Specialists; b) the American Academy of Pediatrics Section of Neonatal/Perinatal Medicine; and c) a listing of neonatologists provided by Ross Laboratories. MAIN OUTCOME MEASURES: Responses to survey questions. RESULTS: We received 1813 responses, representing approximately 75% of all physicians practicing NICU medicine in the US. Overall, 43% of respondents had experienced at least one claim of malpractice against them. The probability of a malpractice allegation increased with years in practice, from approximately 20% for NICU physicians in practice </=5 years (65/337), to approximately 60% for NICU physicians in practice >15 years (276/469). Men and women were equally likely to have been sued, accounting for years in practice. Physicians practicing in community NICUs were more likely to be sued than those in university settings. On a scale of 1 to 4 (4 being most reasonable) the median assessment of the reasonableness of malpractice allegations was 1, mean 1.2. On a scale of 1 to 4 (4 being the highest) the median assessment of effectiveness of the current system in identifying true malpractice was 1, mean 1.4. The respondents believed that approximately 80% of malpractice allegations were inappropriate; conversely, they believed that approximately 80% of true medical malpractice escaped detection. On a scale of 1 to 4 (4 being the highest), the median assessment of the detrimental effect of the present malpractice system on health care was 4, mean 3.4. CONCLUSIONS: Most NICU physicians will be sued if they practice long enough. In this context, efforts to use malpractice claims to seek out evildoers (such as underlie the National Practitioners Data Bank) appear ill-conceived. Similarly, exhortations for physicians to become either more educated or more sensitive are unlikely to reduce malpractice claims. Our data suggest that malpractice in the NICU appears to function more like a lottery than like a mechanism for either quality assurance or just retribution.
Community Health Services↗
Obstetric management and group B streptococcal sepsis. Have we made progress? Has it made a difference?
Explore the source record for details and available documents.
Anti-Bacterial Agents↗
The relationship between physician behaviors and blood gas values in the first hours of life--implications for "standards" of medical care for infants with respiratory distress.
It is standard practice for physicians to use blood gas (BG) evaluations when evaluating neonates with respiratory distress. In this study we addressed two questions: (1) What is the distribution of BG values in a population of infants receiving BG evaluation in the first 4 hours of life; and (2) How does the behavior of physicians correlate with BG values in these infants? We discuss the implications of our findings for claims about "standards" of medical care for newborn infants with respiratory distress. We reviewed medical records for 226 infants with birthweight > 2000 grams who were not intubated at the time of first BG determination. For 199 arterial samples, mean values were pH = 7.31 +/- 0.9 (SD); PaCO2 = 38.5 +/- 11.9 torr; PaO2 = 104 +/- 52 torr; and base excess (BE) = -6.5 +/- 3.8 mEq/L. These values did not differ significantly from previously published data for normal term infants without respiratory distress. However, the a/A ratio (0.45 +/- 0.19) for patients in our distressed population was significantly lower than reported for normal infants (0.65 +/- 0.10). For 186 infants admitted directly to our Newborn Intensive Care Unit, the elapsed time from birth to BG 1 was 1.07 +/- 0.64 hours. This value did not vary significantly as a function of severity of illness, assessed by pH, PaCO2, PaO2, a/A ratio, or BE. No blood gas parameter was simultaneously sensitive and specific for predicting subsequent mechanical ventilation. PaCo2 1 > 80 torr was associated with subsequent mechanical ventilation in 4 of 4 infants; however, the positive predictive value of PaCO2 1 was < 50% for levels below 80 torr, and only 4 of 22 infants eventually intubated were identified by a value of PaCO2 1 > 80 torr. The power of "abnormal" values of PaO2, a/A ratio, pH, or BE to predict subsequent intubation was even lower than PaCO2. Jurors in medical malpractice cases are instructed to define negligence as a deviation from the "skill and care ordinarily used in similar cases," and to determine the existence or absence of negligence guided by the testimony of "expert" witnesses. Recognizing that anecdotal recall of experience, even by "experts," may be inaccurate and is often systematically biased (the "Monday morning quarterback" phenomenon), we propose that the testimony of expert witnesses ought to conform, whenever possible, to a data-based description of medical care that actually is "ordinary used in similar circumstances". Our current observations suggest that (1) expert opinions of the "standard" to evaluate neonatal respiratory distress with a BG sample should reflect that the time scale is 1 to 2 hours, not 10 to 20 minutes; and (2) expert opinions that "abnormal" BG values either "require" or "preclude" intubation for most newborn infants with respiratory distress find little support in data. Clinical observation, not BG values, appears to be the most powerful "standard" by which physicians determine whether to initiate mechanical ventilation for newborn infants with respiratory distress.
Blood Gas Analysis↗
Birth weight-specific mortality for extremely low birth weight infants vanishes by four days of life: epidemiology and ethics in the neonatal intensive care unit.
BACKGROUND: The persistent differences between those who question the appropriateness of aggressive resuscitative measures for many extremely low birth weight (ELBW) infants (birth weight < 1001 g) and those who generally initiate such treatment has been a source of ongoing tension for physicians, parents, judges, and policymakers. We believe that much of this tension may be a result of the way the issue is framed. We began this study with the intuition that although many ELBW infants die, most succumb quickly. Were this true, discussions that considered only survival rates might miss the point. A more relevant statistic might be the degree to which interventions prolong dying, extend suffering, or use resources for infants who will eventually die. METHODS: We determined the survival and nonsurvival for 429 ELBW infants admitted to our neonatal intensive care unit (NICU) for 3 years. We noted particularly the relationship between birth weight, illness severity (fraction of inspired oxygen [Fio2] requirement for infants requiring mechanical ventilation), and the time course of mortality for nonsurvivors. We next calculated a resource utilization index (NICU bed days occupied by survivors and nonsurvivors) for each patient and for the population as a whole. Finally, we determined how NICU resources were distributed among infants who eventually died and those who survived. RESULTS: Of the 429 ELBW infants alive on day of life (DOL) 1,202 (47%) survived to be discharged. on DOL 1, both birth weight and illness severity independently predicted likelihood of survival. Approximately 80% of ELBW deaths occurred in the first 3 days of life-- consequently, once an infant had survived to DOL 4, the likelihood of survival was dramatically enhanced (81% for the 249 patients alive on DOL 4). In addition, although survival for DOL 4 infants continued to depend on illness severity, survival no longer depended on birth weight. These observations on DOL 4 were confirmed in the subpopulation of 212 infants whose birth weight was < 750 g. Overall, although 53% of ELBW babies admitted died, only approximately 13% of all NICU bed-days (a proxy for resource allocation) were devoted to infants who did not survive. This figure did not vary as a function of birth weight. CONCLUSION: Generally, when we talk of survival rates to parents, ethics committees, or policy makers, we base our predictions largely on birth weight. The data presented here suggest that predictions should be corrected by including DOL and that, when this is done, the prognostic value of birth weight rapidly diminishes. In addition, birth weight-specific mortality and day of death for nonsurvivors correlated inversely; that is more of the smaller infants died, but the doomed ones died more quickly. Consequently, medical resources allocated to nonsurvivors remained low, and independent of birth weight. This formulation lends weight both to the reasonableness of physicians in offering NICU care to ELBW infants, with unlikely prospects for survival, and of parents and surrogate decision-makers in requesting/ assenting to it.
Bed Occupancy↗
Can and should level II nurseries care for newborns who require mechanical ventilation?
Perinatal regionalization was conceived roughly 25 years ago to provide centralized care for critically ill newborn infants. As for many 25-year-old concepts, the obligatory centripetal design of many regionalization policies may need to be modified. This article presents the outcomes of 408 surviving patients who required mechanical ventilation (136 born in one community hospital and 272 birthweight-matched infants born in our tertiary center), and were cared for in our perinatal network. Mechanical ventilation of a resident population of newborns at a community NICU appeared to be as effective as ventilatory care at a regionalized tertiary neonatal intensive care unit, when assessed by comparing birthweight-matched populations for length of hospital stay, days on ventilator, and the need for home O2. Some may still claim that every baby who requires mechanical ventilation must be transferred to a tertiary care center. In an era of heightened interest in health services, health outcomes, and cost-effectiveness analysis, however, the authors believe that such claims will be subjected to increasing scrutiny. Our study represents a first attempt at determining the shape such scrutiny might take, and the sort of data analyses that may be required to reformat a perinatal network.
Humans↗
Expert testimony, legal reasoning, and justice. The case for adopting a data-based standard of care in allegations of medical negligence in the NICU.
Sunstein has written, "First, and most obviously, judgments about specific cases must be made consistent with one another. A requirement of coherence, or principled consistency, is a hallmark of analogic reasoning (as it is of reasoning of almost all sorts)." In cases of alleged medical negligence, our current system of malpractice litigation supports the possibility that inaccurate anecdotal testimony by expert witnesses may be credited equally or even preferred to more accurate testimony based on empiric data. This condition lends itself to inconsistent outcomes that violate basic principles of justice. In our view, the standard of medical care ought not be described by the idiosyncratic postulation of single behavior (analogous to promulgating the equation of a single line on a Cartesian plane). Rather, the standard of medical care is best viewed as a distribution of behaviors (family of lines) that can be empirically determined to account for most practice decisions in comparable cases. The recent Daubert formulation of admissibility of expert testimony can be interpreted as providing judicial support for a hierarchy of expert testimony in cases of alleged medical negligence. On this view, testable comparisons of the behavior in question against reliably documented distributions of standard medical behavior in similar circumstances rank higher than untestable comparisons using unreliable anecdotal recollections of individual expert's undocumented experience. We believe that widespread adoption by the medical community of the principle that the value of expert testimony describing the standard of medical care increases in direct proportion to its congruence with a data-based determination of the distribution of skill and care ordinarily provided in similar circumstances would significantly reduce the potential for injustice visited on plaintiff and defendant alike.
Expert Testimony↗
Distributive justice across generations. Epidemiology of ICU care for the very young and the very old.
Babies of extremely low birthweight and elderly adults both require expensive and scarce resources, and both have a relatively poor prognosis for survival if they require intensive care. Thus, proposals for rationing often target one or both of these groups. We suspected that although mortality rates might be higher in the neonatal intensive care unit (NICU) than in the adult intensive care unit (ICU), NICU care might nevertheless be more cost effective, where cost efficiency is measured along the dimension of resources targeted to survivors. We examined mortality patterns in our NICU and for adults admitted to our medical intensive care units. We found that adult ICU patients who died consumed many times more ICU resources before their death than did their NICU confreres, independent of the severity of illness or likelihood of dying. Although there may be many legitimate concerns about justice and ethics in the NICU, undue expenditure of society's resources prolonging the dying of extremely low birthweight infants is not among them. To the extent that concerns about distributive justice drive allocation decisions in ICU care, it would seem more justifiable to ration intensive care for the very old, not the very young.
Age Factors↗
Effects of inhibition of endothelium-derived relaxation factor on hemodynamics and oxygen utilization during group B streptococcal sepsis in piglets.
OBJECTIVE: To determine the effects of the inhibition of endothelium-derived relaxation factor in an animal model of neonatal group B streptococcal sepsis. DESIGN: Comparison of three experimental protocols: a) N-nitro-L-arginine; b) group B streptococcal; and c) group B streptococcal/N-nitro-L-arginine. SUBJECTS: Piglets, 1 to 2 wks old. INTERVENTIONS: Endothelium-derived relaxation factor inhibition was produced in nonseptic piglets by the infusion of a competitive inhibitor of nitric oxide synthase, N-nitro-L-arginine, at 30 mg/kg (N-nitro-L-arginine protocol; n = 6). Human group B streptococcal sepsis was modeled in piglets by the continuous infusion of live group B streptococcal organisms at approximately 5 x 10(9) organisms/kg cumulative dose (group B streptococcal protocol; n = 8). Endothelium-derived relaxation factor inhibition during a group B streptococcal sepsis was produced by N-nitro-L-arginine infusion during continuing group B streptococcal infusion (group B streptococcal/N-nitro-L-arginine protocol; n = 7). MEASUREMENTS AND MAIN RESULTS: Both N-nitro-L-arginine and group B streptococcal infusion significantly increased systemic and pulmonary vascular resistance and decreased cardiac output and oxygen delivery. N-nitro-L-arginine differed from group B streptococcal infusions in its effects on systemic blood pressure (BP) (N-nitro-L-arginine increased BP while group B streptococcal infusions did not), and pulmonary/systemic vascular resistance ratio (group B streptococcal infusions increased pulmonary/systemic vascular resistance ratio more than N-nitro-L-arginine did). The group B streptococcal/N-nitro-L-arginine group differed significantly from piglets receiving continued group B streptococcal infusion without N-nitro-L-arginine in cardiac output (significantly lower in group B streptococcal/N-nitro-L-arginine), oxygen delivery (significantly lower in group B streptococcal/N-nitro-L-arginine), and pulmonary vascular resistance (significantly higher in group B streptococcal/N-nitro-L-arginine). CONCLUSIONS: Group B streptococcal sepsis in human newborns and in animal models of human newborns is characterized by a hemodynamic constellation of "cold shock"--increased vascular resistance and reduced systemic blood flow. Endothelium-derived relaxation factor inhibition during group B streptococcal sepsis in piglets exacerbated many of the adverse hemodynamic consequences of group B streptococcal infusion. We speculate that endothelium-derived relaxation factor inhibition has no foreseeable therapeutic role in neonatal septic shock.
Animals↗
Putting futility to use in the NICU: ethical implications of non-survival after CPR in very low-birth-weight infants.
Explore the source record for details and available documents.
Cardiopulmonary Resuscitation↗
Inflammatory mediators and neonatal sepsis. Rarely has so little been known by so many about so much.
Many questions remain unanswered (and probably many more remain unasked) about neonatal sepsis. In addition, many mediators of inflammation have been implicated in neonatal sepsis at one time or another. The goal of this article is to put together what the authors view as some of the more important outstanding questions with what is known about some of the more important mediators. We address four questions specifically: (1) Why is neonatal sepsis different from all other (adult) sepsis? (2) 41Is control of pulmonary hypertension the white whale or red herring in neonatal septic shock? (3) Is sepsis more like dominoes or like 52 pick-up? and (4) Is disruption of QO2/VO2 coupling a legitimate clinical concern or a laboratory anomaly?
Adult↗
The effects of intravenous L-arginine supplementation on systemic and pulmonary hemodynamics and oxygen utilization during group B streptococcal sepsis in piglets.
PURPOSE: In these investigations, three questions were addressed. First, to what extent did inhibition of endothelium-derived relaxation factor (EDRF) mimic the hemodynamic disturbances noted in a piglet model of neonatal group B streptococcal (GBS) sepsis? Second, to what extent would an attempt to augment EDRF production reverse the hemodynamic effects of continued GBS infusion in septic piglets? Third, to what extent would an attempt to augment EDRF production affect hemodynamics in piglets who were not septic. METHODS: Six experimental protocols were studied in a total of 25 piglets. The extent to which inhibition of EDRF resembled GBS sepsis was determined by comparing hemodynamic observations during (1) EDRF inhibition (using a competitive inhibitor of nitric oxide synthase, N-nitro-L-arginine [NNLA], 80 mg/kg) with (2) GBS infusion. Next, the extent to which an attempt to augment EDRF production would reverse hemodynamic effects of neonatal GBS sepsis was addressed by comparing hemodynamic observations during (3) administration of pharmacological doses (300 mg/kg) of the EDRF precursor L-arginine (L-ARG) in piglets receiving continuous GBS infusion with (4) continuous GBS infusion in piglets who did not receive L-ARG. Finally, to provide an additional comparison for the protocols described above, the effects of (5) L-ARG in piglets pretreated with NNLA were compared with (6) L-ARG infusion in normal piglets, who had received neither GBS nor NNLA. RESULTS: Both NNLA and GBS increased systemic and pulmonary vascular resistance and decreased systemic cardiac output. For equivalent reductions in cardiac output, GBS preferentially vasoconstricted the pulmonary versus systemic circulation, whereas NNLA produced equivalent vasoconstriction in both circulations. During continuous GBS infusion, L-ARG attenuated the progressive increase in systemic and pulmonary vascular resistance, pulmonary artery pressure, and pulmonary vascular resistance/systemic vascular resistance. L-ARG infusion in nonseptic, non-NNLA-treated piglets had no significant effect on any hemodynamic variable. L-ARG infusion in piglets pretreated with NNLA restored hemodynamic values towards those of piglets treated with L-ARG alone. CONCLUSIONS: EDRF inhibition with NNLA appeared to model GBS infusion partially but not completely. L-ARG appeared to produce desirable hemodynamic effects during GBS sepsis when compared with the consequences of ongoing GBS infusion without L-ARG. Given the constellation of increased pulmonary and systemic vascular resistance often observed during neonatal GBS sepsis in human infants, all these effects of L-ARG, if extrapolated from our piglets to the clinical arena, would appear to be beneficial. Particularly in the context of deleterious consequences resulting shunting or right ventricular decompensation from increased afterload), L-ARG administration might prove clinically useful.
Age Factors↗
The role of prostaglandins and endothelium-derived relaxation factor in the regulation of cerebral blood flow and cerebral oxygen utilization in the piglet: operationalizing the concept of an essential circulation.
The brain is considered an "essential" organ, defined as one whose blood supply is preferentially maintained vis-à-vis other less-essential circulations during periods of reduced systemic cardiac output (CO). We asked whether the actions of either prostaglandins or endothelium-derived relaxation factor might underlie the essential qualities of the cerebral circulation; that is, would the absence of one or the other impair the ability of the brain to preferentially redirect systemic blood flow during a period of reduced systemic CO. We compared hemodynamics in the cerebral and systemic circulations in 33 anesthetized piglets under three conditions that reduced systemic CO equivalently: endothelium-derived relaxation factor inhibition with the substituted L-arginine analog N-nitro-L-arginine (NNLA; 25 mg/kg), prostaglandin inhibition with indomethacin (INDO; 5 mg/kg), and inflation of a left atrial balloon (LAB) catheter. NNLA, INDO, and LAB each reduced CO to an equivalent value (approximately 30% from baseline). NNLA and INDO, but not LAB elevated systemic blood pressure, cerebral perfusion pressure (CPP), systemic vascular resistance (SVR), and cerebral vascular resistance (CVR). Cerebral blood flow (CBF) was preserved after NNLA and LAB but fell after INDO (-35%). Despite the equivalent reduction in CO noted during the three experimental protocols, the proportion of systemic blood flow directed toward the brain (CBF/CO) rose significantly during LAB and NNLA (+30%) but fell significantly during INDO (-12%). Similarly, relative cerebral vascular resistance (CVR/SVR) fell significantly during LAB and NNLA but rose during INDO.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗