Corrigendum: Direct vs. redirected admission of critically ill children to PICU after interfacility transfer: a retrospective cohort study.

[This corrects the article DOI: 10.3389/fped.2024.1307565.].

Direct vs. redirected admission of critically ill children to PICU after interfacility transfer: a retrospective cohort study.

Background: Critically ill children must often be transported long distances for access to critical care resources in Canada. This study aims to describe and compare characteristics and outcomes in patients presenting in the community and requiring inter-facility transport and admission to a Pediatric Intensive Care Unit (PICU). Methods: This is a retrospective cohort study of children admitted to the ICU at the Hospital for Sick Children from 2016 to 2019 after inter-facility transport. Characteristics and outcomes were compared between children admitted to the PICU within 24 h from their initial critical care transport request, and children admitted after initial redirection to a non-ICU care setting, 24-72 h from request. The primary outcome was severity of illness at PICU admission. Secondary outcomes included duration of mechanical ventilation, organ dysfunction, PICU length of stay and mortality. Results: A total of 2,730 patients were admitted after inter-facility transport to either the medical/surgical or cardiac ICU within 72 h of initial critical care transport request. Of these children, 2,559 (94%) were admitted within 24 h and 171 (6%) were admitted between 24 and 72 h. Children admitted after initial redirection were younger and residing in more rural centers. Children who were initially redirected had lower severity of illness (PRISM-IV median score 3 vs. 5, p = 0.047) and lower risk of mortality. Interpretation: Initial redirection to a non-ICU care setting rather than directly admitting to the PICU did not result in increased severity of illness or mortality. This study highlights the need to better understand which factors influence disposition decision-making at the time of initial transport request. Further research should focus on the impact of transport factors on clinical outcomes after PICU admission.

Extracorporeal life support: the precarious balance of hemostasis.

Extracorporeal life support is by far the most extraordinary and complex form of extracorporeal technology used in the practice of critical care medicine. It is used to support critically ill patient who suffer acute respiratory or cardiac failure unresponsive to conventional support. As extracorporeal technologies have refined the pathophysiologic reaction that occurs at the blood/biomaterial interface has not been conquered; a new set of physiologic responses/derangements occur with the patient's exposure to the artificial circuit. Without this support mortality is near certain and with support if management is not precise and judicious the complications can be catastrophic. The management of a patient on ECLS is the same as for any critically ill patient with the added need for anticoagulation to maintain patency of the extracorporeal circuit without causing bleeding within the patient and thrombosis within the circuitry or the patient. This is the precarious balance of hemostasis during ECLS.

Safety and efficacy of recombinant activated factor VII for refractory hemorrhage in pediatric patients on extracorporeal membrane oxygenation: a single center review.

BACKGROUND: Medically refractory hemorrhage in patients on ECMO (extracorporeal membrane oxygenation) support can have catastrophic complications. Recombinant-Activated Factor VII (rFVIIa; NovoSeven®) may provide lifesaving hemostasis; however, there are reports of catastrophic thrombosis related to its administration. OBJECTIVE: This review attempts to add safety and efficacy data to existing literature regarding the use of rFVIIa for refractory hemorrhage in pediatric patients on ECMO support. Design/ METHODS: A retrospective chart review was performed for all pediatric patients on ECMO who received rFVIIa for refractory hemorrhage from 2004 to 2009. Data was extracted for each refractory bleeding event, including patient blood loss and transfused blood products in the 6 hours before the first dose, between rFVIIa doses and in the 6 hours after the final dose. For purposes of data collection, a hemorrhagic event was defined as new onset hemorrhage or a hemorrhage occurring at least 12 hours after the most recent dose of rFVIIa. RESULTS: In total, seven patients aged 1 month to 15 years received rFVIIa for 14 different hemorrhagic events. There was no significant difference in blood loss or blood product transfusion associated with rFVIIa administration. There was one patient-related and one ECMO-related complication temporally associated with rFVIIa administration: decreased ECMO circuit oxygenator efficiency and the development of an intra-gastric clot requiring surgical evacuation. CONCLUSION: These data suggest limited efficacy for rFVIIa use for refractory hemorrhage in pediatric patients on ECMO support. There were two non-catastrophic complications temporally associated with its administration.

Extracorporeal life support for acute respiratory distress syndrome due to severe Legionella pneumonia.

PURPOSE: Legionella is a common cause of community-acquired pneumonia (CAP) and is second only to Pneumococcal pneumonia as a cause of severe CAP that requires treatment in an intensive care unit. We report a case series of patients with severe Legionella pneumonia who developed the acute respiratory distress syndrome (ARDS), failed to improve with mechanical ventilation alone and required extracorporeal life support (ECLS). METHODS: We performed a retrospective study of all patients treated with ECLS at our institution for severe ARDS as a result of Legionella pneumonia from 1994 to 2006. RESULTS: A total of twelve patients with a diagnosis of Legionella pneumonia were treated with veno-venous (VV) ECLS over this time period. Nine of these twelve (75%) were successfully treated and weaned off ECLS and 8 patients (67%) survived to hospital discharge. Two (13%) died of multisystem organ failure, one patient (8%) died from global hypoxic encephalopathy and one (8%) was weaned from ECLS, but ultimately died of liver failure. Renal failure requiring some form of continuous dialysis occurred in seven patients (58%) and the survival for this sub-set of patients was 43%. CONCLUSIONS: Extracorporeal life support for severe ARDS associated with Legionella pneumonia is an effective treatment option when mechanical ventilation fails, especially when introduced early in the course.

The use of extracorporeal membrane oxygenation in pediatric patients with sickle cell disease.

Previous reports have described the use of extracorporeal membrane oxygenation (ECMO) for acute chest syndrome of sickle cell disease (SCD). However, there have been no reports of venoarterial (VA) ECMO for cardiac dysfunction in patients with SCD. We describe a patient with SCD and life-threatening cardiogenic shock who was successfully treated with VA ECMO. Furthermore, SCD patients have unique comorbidities that warrant particular consideration when utilizing ECMO. We discuss these considerations and review the documented experience with ECMO for pediatric SCD patients from the Extracorporeal Life Support Organization (ELSO) registry. From 1990 until 2012, 52% of the 65 pediatric patients with SCD placed on ECMO survived, with 85% of those receiving venovenous (VV) ECMO surviving and 43% of those receiving VA ECMO surviving. However, significant complications, such as bleeding, neurological injury and kidney injury, also occurred with both VV and VA ECMO. Ten percent of SCD patients receiving VA ECMO experienced either a cerebral infarct or hemorrhage; our patient suffered a cerebrovascular accident while on ECMO, though she survived with good neurologic outcome. To our knowledge, this is the first report of a pediatric patient with SCD and cardiogenic shock successfully managed with VA ECMO. In conjunction with the ELSO registry review, this case report suggests that, while VA ECMO can be successfully used in patients with SCD and severe cardiovascular dysfunction, clinicians should also be aware of the potential for serious complications in this high-risk population.

In vitro clearance of dexmedetomidine in extracorporeal membrane oxygenation.

Dexmedetomidine (DMET) is a useful agent for sedation, both alone and in combination with other agents, in critically ill patients, including those on extracorporeal membrane oxygenation (ECMO) therapy. The drug is a clonidine-like derivative with an 8-fold greater specificity for the alpha 2-receptor while maintaining respiratory and cardiovascular stability. An in vitro ECMO circuit was used to study the effects of both "new" and "old" membrane oxygenators on the clearance of dexmedetomidine over the course of 24 hours. Once primed, the circuit was dosed with 840 µg of dexmedetomidine for a final concentration of 0.9 µg/ml. Serial samples, both pre- and post-oxygenator, were taken at 5, 60, 360, and 1440 minutes. Concentrations of the drug were expressed as a percentage of the original concentration remaining at each time point, both for new and old circuits. The new circuits were run at a standard flow for 24 hours, after which time the circuit was considered old and re-dosed with dexmedetomidine and the trial repeated. Results show that dexmedetomidine losses occur early in the circuits and then continue to decline. Initial losses in the first hour were 11+-65% and 59-73% pre- and post-oxygenator in the new circuit and 36-50% and 42-72% in the old circuit. The clearance of the drug through the membrane oxygenator exhibits no statistical difference between pre and post or new and old circuits. Dexmedetomidine can be expected to exhibit concentration changes during ECMO therapy. This effect appears to be more related to adsorption to the polyvinyl chloride (PVC) tubing rather than the membrane oxygenator. Dosage adjustments during dexmedetomidine administration during ECMO therapy may be warranted in order to maintain adequate serum concentrations and, hence, the desired degree of sedation.*(Lack of equilibrium).

In vitro clearance of intravenous acetaminophen in extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life support system used as a bridge to transplantation in critically ill patients who suffer from acute respiratory or cardiac failure with resultant hypoxemia and tissue hypoxia. This is not amendable to conventional support intervention. Previous studies have shown significant drug losses in the components of an ECMO circuit, leading to decreased plasma drug levels. An in vitro study was conducted to determine: (1) changes in intravenous acetaminophen levels over time and (2) changes in concentration observed between different sites of the ECMO circuit. A single bolus dose of intravenous (IV) acetaminophen was injected into a standard blood-primed ECMO circuit. Plasma drug concentrations in the circuit were then measured at specific time points at three different locations to determine concentrations of the drug at time 0, 15, 30, 60, 240 and 360 minutes. The three samples were drawn pre- and post-membrane oxygenator and the polyvinyl chloride (PVC) tubing. A second bolus dose was administered 24 hours after the first in order to compare "new" and "old" circuits. This entire process was repeated a total of three times. The results show that acetaminophen concentrations do not change significantly over time, with consistent levels seen in both new and old circuits (N=9). Average old circuit concentrations were approximately two times greater than the average new circuit concentrations after the circuit was re-dosed at 24 hours. Drug sequestration in the circuit was not significant in any of the three sites measured. It appears that, while acetaminophen levels remain relatively constant over a six hour period, dosing adjustments may be required for use in a circuit beyond the initial 24 hour period, depending on physiologic clearance of the drug. Assuming a six-hour dosing interval, levels should remain constant.

The dependency of expiratory airway collapse on pump system and flow rate in liquid ventilated rabbits.

PURPOSE: To evaluate the influence of pump system and flow pattern on expiratory airway collapse (EAC) in total perfluorocarbon ventilation. - METHODS: Prospective, controlled, randomized animal trial for determination of (1) post-mortem changes by repeated expiration procedures (EP) with a constant flow piston pump (PP) before and after sacrifice (n = 8 rabbits), (2) differences between pump systems by subjecting animals to both PP and roller pump (RP) circuits for expiration (n = 16 rabbits). EP were performed using a servo-controlled shut-off at airway pressures < 25 cm H subset 2O randomly with either pump at different flows. - RESULTS: Expired volumes before and after sacrifice were not significantly different. PP and RP revealed identical mean flows, while significantly more liquid was drained using PP (p<0.05). Increasing differences towards higher flow rates indicated profound flow pulsatility in RP. - CONCLUSIONS: (1) post-mortem changes in expired volumes are not significant, (2) EAC is related to flow rate and pump system; (3) relationship between expiratory flow rate and drainable liquid volume is linear inverse; (4) PP provides higher drainage than RP. - SUMMARY STATEMENT: Expiratory airway collapse is related to flow rate and pump system, post mortem changes in expirable volumes are not significant. Relationship between expiratory flow rate and drainable liquid volume is linear inverse, piston pump expiration provides higher drainage volumes than roller pump expiration.

Reduced platelet activation and thrombosis in extracorporeal circuits coated with nitric oxide release polymers.

OBJECTIVE: To determine whether the use of nitric oxide (NO)-releasing polymers coated onto the inner surface of extracorporeal circuits can reduce platelet consumption and activation in the absence of systemic heparinization using a rabbit model of venovenous extracorporeal circulation. DESIGN: Prospective, controlled trial. SETTING: Research laboratory at an academic medical institution. SUBJECTS: New Zealand White Rabbits. INTERVENTIONS: Anesthetized, tracheotomized, and ventilated New Zealand White rabbits were injected with freshly prepared, 111In(oxine)3 labeled single donor platelets through the external jugular vein. After baseline measurements, these animals were placed on venovenous extracorporeal circulation through a 1-m control circuit or NO test circuit for 4 hrs at a blood flow rate of 109-118 mL/min via roller pump. Four groups were studied: systemically heparinized control circuits, systemically heparinized NO test circuits, nonheparinized control circuits, and nonheparinized NO test circuits. Platelet counts, fibrinogen levels, and plasma free indium levels were measured hourly. Circuits were rinsed and retained for gamma counting after the 4-hr run or when the circuit clotted. Four animals, one from each group, did not receive radiolabeled platelets so that the circuits could be preserved for scanning electron microscopic examination after the 4-hr study. MEASUREMENTS AND MAIN RESULTS: Platelet consumption was significantly reduced in both the heparinized and nonheparinized NO test groups when compared with the controls (p < .0001 and p < .0004, respectively). Platelet adhesion to the extracorporeal circuits was significantly reduced in the nonheparinized test circuits when compared with the controls (p < .05). Scanning electron microscopic examination of the circuits revealed that in the absence of heparin and in the presence of a NO-releasing surface, platelets retained their spherical nonactivated shape. CONCLUSIONS: The incorporation of NO into the surface of extracorporeal circuits reduces platelet consumption and eliminates the need for systemic heparinization in a rabbit model of extracorporeal circulation.

Venovenous versus venoarterial extracorporeal life support for pediatric respiratory failure: are there differences in survival and acute complications?

OBJECTIVES: To examine the Extracorporeal Life Support Organization (ELSO) registry database of infants and children with acute respiratory failure to compare outcome and complications of venovenous (VV) vs. venoarterial (VA) Extracorporeal Life Support (ECLS). DESIGN: Retrospective cohort study. SETTING: ELSO registry for pediatric pulmonary support. PATIENTS: All nonneonatal pediatric pulmonary support ECLS cases treated at U.S. centers and reported to the ELSO registry as of July 1997. Patients were excluded if they had one or more of the following diagnoses: hematologic-oncologic, cardiac, abdominal surgical, burn, metabolic, airway, or immunodeficiency disorder. INTERVENTIONS: Venoarterial or venovenous extracorporeal life support for severe pulmonary failure. MEASUREMENTS AND MAIN RESULTS: From 1986 to June of 1997, 763 pediatric patients met the inclusion criteria. Overall, 595 were initially managed with VA bypass, and 168 with VV bypass. The VA group was younger (mean +/- SD, 26.1+/-42.2 months for VA vs. 63.5+/-68.7 months for VV) and smaller (11.8+/-15.1 kg vs. 22.9+/-23.8 kg) (p<.001). There were no differences between groups in number of days on mechanical ventilation before ECLS, number of hours on ECLS, or number of hours on mechanical ventilation post-ECLS in survivors. Mean pH and Paco2 values, positive end-expiratory pressure, and mean airway pressure just before placing the patient on ECLS were also similar. VA-treated patients had higher Fio2 requirements (p = .034), lower Pao2 (p = .047), and lower Pao2/Fio2 ratio (p = .014) just before cannulation. There was a trend of higher peak inspiratory pressure in VA-treated patients (p = .053). Overall, survival rate was not different for the two groups (55.8% for VA vs. 60.1% for VV; p = .33). Central nervous system complications were not different between the two groups. Examination of the same variables was then conducted after dividing the patients into four subgroups. There were no significant differences in survival or complications during bypass between VV and VA modes of ECLS in any subgroup. Stepwise logistic regression modeling was performed to control for variables associated with the outcome survival for VV and VA-treated groups, and variables measured before bypass were identified as being associated with improved survival. There was a trend of improved survival in the VV-treated patients (p = .12). CONCLUSIONS: Overall survival of pediatric patients with acute respiratory failure supported by VA or VV ECLS was comparable. A randomized clinical trial may be useful in clarifying these observations.

Recombinant Kunitz protease inhibitory domain of the amyloid beta-protein precursor as an anticoagulant in venovenous extracorporeal circulation in rabbits.

Investigations were performed to characterize a recombinant Kunitz protease inhibitory domain of the amyloid beta-protein precursor (rKPI) as anticoagulants. After a single intravenous infusion of wild type rKPI into dogs, its elimination fit a two compartment model with a t1/2alpha and t1/2beta of 5 and 77 min, respectively. Further investigations determined if a variant form of rKPI with 178-fold more potent anti-factor Xa activity (rKPI-DD135, Ki = 0.9 nM) could serve as an anticoagulant in a rabbit model of extracorporeal circulation using a venovenous shunt. A prospective investigation was initiated to compare standard heparin (n = 8) at 400 U/kg with different infusion concentrations of rKPI-DD135. After a single intravenous infusion of 1.89 mg/kg of rKPI-DD135 followed by a constant infusion at 0.003 (n = 3), 0.03 (n = 7), or 0.3 (n = 5) mg/kg/min, the anti-factor Xa activity of the animals' plasma rapidly reaches a steady state for the two lower infusion concentrations of the agent. All infusions of rKPI-DD135 prolong the activated clotting time with less variation than that seen with heparin administration. rKPI-DD135 anticoagulation does not prevent a drop in the platelet counts. Fibrinogen levels decrease only slightly when the circuit is anticoagulated with rKPI-DD135. rKPI-DD135 markedly prolongs the APTT, has little effect on the PT, and reduces plasma prekallikrein and plasminogen activation. The 0.3 mg/kg/min infusion concentration of rKPI-DD135 results in reduced deposition of 111Indium-labeled platelets on the circuit when compared to heparin. Last, after a steady state level is achieved, 60% of the plasma anti-factor Xa activity of rKPI-DD135 is eliminated within 60 min after stopping the infusion. These data show the rKPI-DD135 can provide single agent anticoagulation in a rabbit extracorporeal circuit. Development of short acting factor Xa inhibitors may be useful anticoagulants for cardiopulmonary bypass.

Extreme negative pressure does not cause erythrocyte damage in flowing blood.

In extracorporeal circulation, negative pressure is thought to be a source of hemolysis. This study was designed to investigate the effects of extreme negative pressure on flowing blood. The study model was pipe flow. The hemolysis generated by negative pressure driven flow was compared with that generated by positive pressure driven flow of equal magnitude to control for the hemolytic effect of shear stress. A series of pressures (720, 600, 500, -500, -600, and -720 mm Hg; n = 8) was tested for pipe diameters of 0.04 and 0.16 cm, with a length-to-diameter ratio of 500. The pressure difference across the pipe (deltaP) was equal to the magnitude of the applied pressure. The hemolysis was quantified by the modified index of hemolysis (MIH). For both pipe diameters, MIH was found to not depend on the deltaP or the blood collection day (multiple regression analysis, p = 0.50 and p = 0.63, respectively). There was no statistically significant difference between the MIH for equal deltaP generated by positive or negative pressure (p = 0.50) for both pipe diameters tested. MIH did depend upon the pipe diameter, with 0.04 cm having higher MIH at all pressures (p = 0.0003). Thus, negative pressure is not a significant hemolytic factor in flowing blood.

Effect of blood flow rate on thrombogenesis in a rabbit extracorporeal circulation model.

Blood flow is believed to affect the thrombogenicity of extracorporeal circulation (ECC). The purpose of this study was to look at the relationship between blood flow and thrombogenicity in a rabbit model of ECC. Rabbits were anesthetized and systematically heparinized. Bilateral jugular cannulation was performed, and the animals were placed on venovenous ECC. The circuits were composed of 1 m of 1/4 inch size surgical grade polyvinylchloride (PVC) tubing. ECC was maintained for 4 hours. Three experimental groups were studied: a high flow group (n=7; flow rate: 30 ml/min/Kg), low flow group (n=7; flow rate: 10 ml/mg/Kg), and no ECC group (n=7). Platelet count, fibrinogen concentration, PaO2/FiO2, and postmortem findings were evaluated. Platelet consumption was higher with high flow, and fibrinogen consumption was higher with low flow.

An approach to the treatment of severe adult respiratory failure.

OBJECTIVES: The purpose of this article is to evaluate outcome in adult patients with severe respiratory failure managed with an approach using (1) limitation of end inspiratory pressure, (2) inverse ratio ventilation, (3) titration of PEEP by SvO2, (4) intermittent prone positioning, (5) limitation of FiO2, (6) diuresis, (7) transfusion, and (8) extracorporeal life support (ECLS) if patients failed to respond. PATIENTS AND METHODS: This study was designed as a retrospective review in the intensive care unit of a tertiary referral hospital. One-hundred forty-one consecutive patients with hypoxic (n = 135) or hypercarbic (n = 6) respiratory failure referred for consideration of ECLS between 1990 and 1996. Overall, initial PaO2/FiO2 (P/F) ratio was 75+/-5 (median = 66). RESULTS: Lung recovery occurred in 67% of patients and 62% survived. Forty-one patients improved without ECLS (83% survived); 100 did not and were supported with ECLS (54% survived). Survival was greater in patients cannulated within 12 hours of arrival (59%) compared with those cannulated after 12 hours (40%, P < .05). Multiple logistic regression identified age, duration of mechanical ventilation before transfer, four or more dysfunctional organs, and the requirement for ECLS as independent predictors of mortality. CONCLUSIONS: An approach that emphasizes lung protection and early implementation of extracorporeal life support is associated with high rates of survival in patients with severe respiratory failure.

Effect of hyperventilation on regional cerebral blood flow in head-injured children.

OBJECTIVES: To study cerebral blood flow and cerebral oxygen consumption in severe head-injured children and also to assess the effect of hyperventilation on regional cerebral blood flow. DESIGN: Prospective cohort study. SETTING: Pediatric intensive care unit at a tertiary-level university children's hospital. PATIENTS: Twenty-three children with isolated severe brain injury, whose admission Glasgow Coma Scores were <8. INTERVENTIONS: PaCO2 was adjusted by altering minute ventilation. Cerebral metabolic measurements were made at three levels of PaCO2 (>35, 25 to 35, and <25 torr [>4.7, 3.3 to 4.7, and <3.3 kPa]) after allowing 15 mins for equilibrium. MEASUREMENTS AND MAIN RESULTS: Thirty-eight studies (each study consisting of three sets of measurements at different levels of PaCO2) were performed on 23 patients. At each level of PaCO2, the following measurements were made: xenon-enhanced computed tomography scans; cerebral blood flow; intracranial pressure; jugular venous bulb oxygen saturation; mean arterial pressure; and arterial oxygen saturation. Derived variables included: cerebral oxygen consumption; cerebral perfusion pressure; and oxygen extraction ratio. Cerebral blood flow decreased below normal after head injury (mean 49.6 +/- 14.6 mL/min/100 g). Cerebral oxygen consumption decreased out of proportion to the decrease in cerebral blood flow; cerebral oxygen consumption was only a third of the normal range (mean 1.02 +/- 0.59 mL/min/100 g). Neither cerebral blood flow nor cerebral oxygen consumption showed any relationship to time after injury, Glasgow Coma Score at the time of presentation, or intracranial pressure. The frequency of one or more regions of ischemia (defined as cerebral blood flow of <18 mL/min/100 g) was 28.9% during normocapnia. This value increased to 73.1% for PaCO2 at <25 torr. CONCLUSIONS: Severe head injury in children produced a modest decrease in cerebral blood flow but a much larger decrease in cerebral oxygen consumption. Absolute hyperemia was uncommon at any time, but measured cerebral blood flow rates were still above the metabolic requirements of most children. The clear relationship between the frequency of cerebral ischemia and hypocarbia, combined with the rarity of hyperemia, suggests that hyperventilation should be used with caution and monitored carefully in children with severe head injuries.

Chronic lung disease following neonatal ventilation. I. incidence in two geographically defined populations.

The objective of this study was to compare the incidence of chronic lung disease following neonatal ventilation in two geographically defined populations. Prospective data collection was carried out over a 1 year period from March 11, 1990 to February 28, 1991 in the Trent Health Region (England) and in British Columbia, Canada. All infants < or = 32 weeks gestation and/or < or = 1500 g birthweight born to mothers normally resident in either the Trent Health Region or British Columbia were included. The main outcome measures were mortality rate, presence of chronic lung disease, days of ventilation, and oxygen used by each infant. The proportion of shortened gestation, low birthweight babies was 1.5% in Trent and 1.2% in British Columbia (957 of 63,350 births in Trent and 526 of 45,333 births in British Columbia). There were no significant differences in mean birthweight or gestation between the two cohorts, but there was a trend towards lower mortality for infants 750-1500 g birthweight in British Columbia. The incidence of chronic lung disease (using either of two definitions) was significantly higher in British Columbia, with a corresponding greater amount of respiratory care required. This occurred despite higher use of antenatal steroids and surfactant therapy in the British Columbia group. We conclude that there are important clinical and resource implications resulting from the number of ventilator and oxygen days used by the preterm population in terms of planning of neonatal services. The role of individual treatment modalities in producing differences in the incidence of chronic lung disease warrants further study in the setting of a geographically defined population.