Gamble and Darrow: pathfinders in body fluid physiology and fluid therapy for children, 1914-1964.

The development of body fluid physiology and fluid therapy in pediatrics has special importance in the history of medicine because this development introduced physiology into clinical practice. James Gamble and Dan Darrow were leaders in this enterprise. Gamble was part of the group John Howland attracted to Johns Hopkins to establish the first organized program for clinical investigators in pediatrics. This group initiated fluid therapy as effective treatment for diarrheal dehydration and, led by Gamble, developed the discipline of body fluid physiology. Gamble was the first to describe the nature of extracellular fluid (ECF) to clinicians, using the new terminology for characterizing electrolytes in solution. In doing so, he became the teacher of body fluid physiology to a generation of medical students. Inexplicably, in his later years he failed to adopt yet newer terminology defining cations, anions, and acid-base status. This failure compromised his legacy. Dan Darrow extended our understanding of how body fluids react to hyper- and hyponatremia and to potassium deficiency. He was the first to add potassium to parenteral fluid therapy. In doing so, he broadened clinicians' understanding of body fluids but changed the emphasis of fluid therapy from rapid ECF restoration to replacement of estimated deficits. Unfortunately, this change in concept, taught by his successors as deficit therapy, slowed the adoption of oral rehydration therapy for treating diarrheal dehydration. The lapses noted for each of these men, now seen in hindsight, pale in comparison to their contributions. Pediatrics, medicine, and surgery are all indebted to the research of each, which emphasized the value of basic physiology in clinical practice.

Extracellular fluid and its proteins: dehydration, shock, and recovery.

This review highlights characteristics of extracellular fluid (ECF) that are often overlooked. ECF has, in addition to plasma and interstitial fluid (ISF) surrounding cells, a third large compartment, the ISF of skin and connective tissue. This acts as a reservoir that gives up ECF to plasma volume (PV) in order to sustain circulation in the event of either shock or dehydration. While Starling forces drive filtration, ECF is returned to PV more by lymph and less by Starling forces than previously appreciated. Lymph return to PV is dependent on physical activity and muscle contraction to overcome gravity. Regional change in metabolic rate alters the need for oxygen and nutrients that is met by a regional increase in capillary blood flow. Blood flow is controlled by vasoactive compounds released in response to a drop in PO(2); these relax capillary smooth muscle to increase blood flow and delivery of oxygen and nutrients. Plasma proteins, including albumin, are filtered into the interstitium through larger pores than those filtering ECF. The rate of protein filtration is set by size and charge of these larger endothelial pores and by size and charge of proteins. Charge of these pores, hence albumin permeability, is regulated by many of the same vasoactive compounds that control capillary flow. As a consequence, in response to gravitational stress and other forms of shock that reduce effective circulation, albumin as well as ECF is rapidly shifted from plasma and sequestered in ISF. When this has occurred, as in burn shock, restoration is better effected by generous expansion of ECF with Ringer's solution alone, rather than with Ringer's solution supplemented with human serum albumin or other colloid. Restoring both PV and ISF volume restores lymph circulation and returns sequestered albumin to PV.

Extracellular fluid restoration in dehydration: a critique of rapid versus slow.

We compared current recommendations for treatment of severe dehydration by World Health Organization physicians and by the American Academy of Pediatrics Committee on Pediatric Gastroenterology with those in general textbooks of pediatrics, written mostly by pediatric nephrologists. The former recommend rapid (1- to 2-h) and generous intravenous restoration of extracellular fluid (ECF) volume followed by oral rehydration therapy (ORT) to replace potassium, current maintenance, and diarrheal losses--the rapid rehydration regimen. Oral feedings usually are resumed in 8-24 h. General textbooks of pediatrics usually recommend giving 20 ml/kg saline "to restore circulation," followed by the deficit therapy regimen to correct serum electrolyte abnormalities and replace remaining deficits of water, sodium, chloride, and potassium over 1-2 days. Mortality for hospitalized patients with dehydration treated with rapid rehydration was <3 per 1,000; no recent results are reported for patients treated by deficit therapy. The rapid rehydration regimen improves patient well being and restores perfusion, so that oral feedings are readily tolerated and renal function corrects serum electrolyte abnormalities in 6 h. Amounts of saline given correspond to amounts given for treating various forms of shock. Deficit therapy regimens provide less ECF restoration and are slower at restoring perfusion; tolerance for oral feedings is delayed. Two hundred pediatric nephrologists were surveyed, asking how they would treat a patient with severe dehydration and a patient with 40% burns. Only 30 of 200 responded; 29 used a deficit therapy regimen, with 20-40 ml/kg ECF replacement, while a majority rapidly and generously restored ECF volume in burn shock. We recommend that fluid therapy chapters should stop teaching deficit therapy for treating severe dehydration and instead teach the rapid rehydration regimen.

Dorsal penile nerve block vs topical placebo for circumcision in low-birth-weight neonates.

OBJECTIVE: To investigate the efficacy and safety of dorsal penile nerve block (DPNB) and eutectic mixture of lidocaine (EMLA) for palliation of pain associated with circumcision in low-birth-weight infants. DESIGN: Randomized, blinded, controlled trial. SETTING: Intensive care nursery (step down unit) at Georgetown University Medical Center, Washington, DC. PARTICIPANTS: Fifty neonates with weights of 1600 to 2500 g at the time of circumcision who were discharged from the hospital between May 1994 and June 1995 were randomly assigned to the DPNB, EMLA, or control group. Twenty-five infants who were otherwise eligible were excluded because of parental refusal of consent to participate. INTERVENTIONS: Infants in the DPNB and EMLA groups received anesthesia with subcutaneous injection of 1% lidocaine hydrochloride or topical EMLA, respectively. The control group received sham anesthesia with topical placebo (acid mantle cream). MAIN OUTCOME MEASURES: Changes in physiologic variables (heart rate, blood pressure, oxygen saturation, and respiratory rate) and behavioral score 20 minutes before, during, and 5 and 20 minutes after circumcision between DPNB and control groups. Surgical complications and adverse effects were also monitored. RESULTS: Fifty infants were enrolled in the study: 19 randomized to the DPNB group, 19 to the control group, and 12 to the EMLA group. Enrollment into the EMLA group was suspended early because of redness and blistering of the foreskin in 2 infants, and this entire group was excluded from further analysis. The clinical course was similar in all groups of infants. All circumcisions were performed without complication or technical difficulty. Statistically significant differences were noted in heart rate, respiratory rate, and behavioral score when comparing the DPNB group with controls during and after circumcision. CONCLUSION: Dorsal penile nerve block is safe and effective in controlling pain associated with circumcision in low-birth-weight infants.

Sodium or chloride deficiency lowers muscle intracellular pH in growing rats.

Sodium deficiency and chloride deficiency are associated with a contracted extracellular (ECF) volume and impaired growth in young children and growing rats. In cell culture, lowering sodium in the medium reduces growth factor-stimulated Na+/H+ exchange activity, intracellular pH (pHi), and DNA synthesis. We studied the effect of chronic sodium deficiency and chloride deficiency upon growth, extracellular acid base status, and muscle pHi in young rats. We fed growing rats for 21 days either a control diet, or one deficient in sodium (0.005%), chloride (0.005%), or calories. Muscle pHi was measured using 31phosphorus nuclear magnetic resonance spectroscopy. Rats fed either the sodium-deficient or chloride-deficient diet developed ECF volume contraction and hyponatremia; growth in length and weight was impaired. Muscle pHi was decreased (pHi = 7.074 +/- 0.006, 7.078 +/- 0.006 vs. control 7.100 +/- 0.002; P < 0.02). In calorie-restricted rats, growth was impaired but pHi was not affected (pHi 7.103 +/- 0.008). Metabolic alkalosis developed in the chloride-deficient group; acid base status was not affected in the sodium-deficient group. Despite differences in ECF acid base status, both groups had a low muscle pHi. We speculate that the low muscle pHi was a result of the ECF volume contraction and hyponatremia; low muscle pHi may contribute to retarded cell growth.

Is blood pressure in later life affected by events in infancy?

This article reviews experimental and clinical evidence of whether primary hypertension (HTN) later in life is influenced by events early in life. The experimental evidence is drawn from studies in inbred strains of HTN-prone rats; the clinical evidence is drawn from studies in children and adults of the influence of genetics, nutrition, and stress on adult blood pressure (BP). Adult BP in HTN-prone rats is significantly influenced in the preweaning period by salt intake and genetic factors regulating extra-cellular fluid volume, and by maternal-infant interactions. BPs of children track with BPs of their parents. Children of parents with primary HTN are insulin resistant and have lower average cation flux values across cell membranes as do their parents; children and their parents with secondary HTN do not. Children with low birth weight have a higher prevalence of HTN as adults than better-nourished peers. Salt intake in children affects BP response to stress. Average salt consumption among different cultures correlates with the prevalence of HTN in those cultures. Varying salt intake of infants and children has little influence on BP later in childhood. The evidence suggests simple measures that might lower the risk for HTN in HTN-prone children in general. However, at present we lack reliable means for identifying children at risk for HTN specific means to lower that risk.

Dietary protein and growth in infants with chronic renal insufficiency: a report from the Southwest Pediatric Nephrology Study Group and the University of California, San Francisco.

This report describes growth and nutrition data from the feasibility phase of a clinical trial that was designed to evaluate the effect of diet protein modification in infants with chronic renal insufficiency (CRI). The purpose of the proposed trial was to compare the safety (effect on growth in length) and efficacy [effect on glomerular filtration rate (GFR)] of a diet with a low protein: energy (P:E) ratio versus a control diet in such patients. Twenty-four infants with GFRs less than 55 ml/min per 1.73 m2 were randomly assigned at 8 months of age to receive either a low-protein (P:E ratio 5.6%) or control protein (P:E ratio 10.4%) formula, which resulted in average protein intakes of 1.4 and 2.4 g/kg per day in the low and control groups, respectively. Overall energy intakes over a 10-month period of study averaged 92% +/- 12% recommended dietary allowance (RDA) for length in the low-protein group and 92 +/- 15% RDA in the control group. Weight for age standard deviation scores (SDS) were comparably low in both groups at the time of randomization (low-protein--2.0 +/- 1.3, control -1.9 +/- 1.1) and at the end of the study (low -1.9 +/- 1.2, control -1.7 +/- 0.9). Length for age SDS at entry tended to be lower in the low-protein group but were not significantly different in the two groups (low -2.2 +/- 1.4 vs. control -1.7 +/- 1.4). However, at 18 months the low-protein group had a significantly lower SDS for length (-2.6 +/- 1.2 vs. -1.7 +/- 1.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Serial measurements of GFR in infants using the continuous iothalamate infusion technique. Southwest Pediatric Nephrology Study Group (SPNSG).

We undertook a preliminary study to determine if a clinical trial was feasible that would compare the effect of a low protein vs a control formula on GFR and growth in infants with congenital renal insufficiency (CIo < 55 ml/min/1.73 m2). In this report from the Infant Diet Protein Study, we describe validation of a method using the plasma clearance of iothalamate (CIo) as an estimate of glomerular filtration rate (GFR) and results of the preliminary study relating to renal function. The plasma CIo method was validated as an accurate estimate of GFR by showing it to be the same as the plasma clearance of inulin (CIn). In the preliminary study infants who qualified for the study were randomly assigned to a low protein or control formula and were followed from 8 to 18 months of age. CIo was measured at 8, 14 and 18 months of age in 21 of the infants and at 8 and 18 months of age in all twenty four infants that entered the study. Average absolute GFR in the 24 infants increased in the 10 month period from 5.3 +/- 2.7 to 7.6 +/- 4.5 ml/min. The percent increase in GFR was no different in infants whose GFR at 8 months of age was severely reduced from those whose GFR was only moderately reduced. When adjusted for age and body size, GFR did not change. Change in mean CIo or serum creatinine (SCr) from 8 to 18 months of age between the infants in each diet groups was not different. We conclude that a clinical trial enrolling more infants and extending the study period is necessary to evaluate dietary protein effect.

Plasma renin activity as a marker for growth failure due to sodium deficiency in young rats.

We evaluated the effect of feeding diets of varying sodium content on growth and plasma renin activity (PRA) in young rats. In the first study, four groups of rats were offered 10 g/100 g body weight per day of diets containing either 0.005%, 0.015%, 0.03%, or 0.3% sodium; weight gain per day of each rat was followed for 10-14 days and PRA was then measured. A control group was fed a sodium-replete tryptophan-deficient diet which caused protein calorie malnutrition and inhibited growth. Weight gain (g/day) among the rats on the sodium-deficient diets varied directly (r = 0.81, P < 0.001) and PRA inversely (r = -0.82, P < 0.001) with dietary sodium content. PRA varied inversely with weight gain (r = -0.84, P < 0.001). Insulin-like growth factor-1 (IGF-1), which is depressed in calorie-deficient growth failure, was depressed in all the rats on the low-sodium intakes relative to ad libitum-fed controls, but did not vary in relation to dietary sodium or weight gain within those groups. In rats fed the tryptophan-deficient diet, both IGF-1 and weight gain were severely depressed; PRA was normal. In the second study, rats in each of two groups were pair fed, the diet containing either 0.03% or 0.3% sodium matched to rats fed the 0.005% sodium diet; weight gain was followed for 28 days. Both length and weight gain were retarded; PRA again varied inversely with dietary sodium content and with weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term results of renal transplantation in children.

The results of renal transplantation in 37 children, 3 through 16 years of age, who received transplants prior to June, 1970 in our center, were examined. Twenty-three received kidneys from living-related donors and 14 received kidneys from cadaver donors. Patient survival rates were 78% at 10 years and 68% at 20 to 26 years. Graft survival rates were 56% at 10 years, 31% at 20 years, and 23% at 22 to 26 years. Twenty children received on or more retransplants. At follow-up, 23 (62%) of the patients had functioning grafts and two (5%) were undergoing dialysis. Cataracts, hypertension, and aseptic necrosis of bone were the most common medical complications and most of the patients were more than two standard deviations below average height. Most enjoyed good rehabilitation, however: more than 70% were employed or performing full time housework, more than 50% were married, 24% had children, and all had normal activity at least part of the time. These results, achieved with immunosuppressive methods now considered obsolete, indicate that renal transplantation is a satisfactory long-term treatment for children with renal failure.

Effects of reduced renal function and dietary protein on muscle protein synthesis.

We describe a rat model of renal failure that separates catabolic and anabolic states from each other. Muscle protein synthesis was compared during the anabolic period between sham (S) operated and renal failure (RF) rats that were fed different levels of dietary protein. Male rats weighing between 60 and 80 g first had a partial left nephrectomy and then were given a tryptophan deficient diet from four to six days to induce weight loss. On the second day of the diet either a renal decapsulation (S rats) or a simple right nephrectomy (RF rats) was done to enhance the catabolic response in both and to induce renal failure in the RF rats. Following the period of feeding the deficient diet, both groups were fed a nutritionally complete 14, 17, 20 or 30% protein diet for three to five days. This induced a brisk anabolic response as measured by weight gain. Differences in body weight between the S and RF rats after three to five days on the repletion diet generally was less than 10%. The rats then were fasted overnight, fed a standard meal and muscle protein synthesis (Sm%) was measured two hours post-feeding. Sm% was estimated from the incorporation of 3H phenylalanine (PHE) into muscle 10 minutes following the i.v. injection of 3HPHE (25 muCi/100 g body wt) with carrier PHE to flood all the precursor amino acid pools. Weight loss in the catabolic phase was greater and the net weight gain for the two phases was less in the RF group. Overall, renal failure resulted in a significant reduction in Sm% (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Expressing glomerular filtration rate in children.

We have reviewed the studies that provide the current standards of reference for glomerular filtration rate (GFR) in normal children from 14 days to 12 years of postnatal age. These standards currently are presented as ml/min per 1.73 m2, i.e., adjusted to average adult body surface area. Children from birth to 1 year of age have adjusted values below the adult range, making comparisons of observed to reference values difficult. Currently, there is no accepted way of obtaining reference values that vary smoothly with age. An analysis of the absolute GFR values in normal children taken from published studies led to an equation that estimates average GFR in relation to weight and term-adjusted age from -2 months (7 months gestational age) to 12 years in children at least 14 days post delivery. When these data are transformed to percentage of normal (% nl) for age and weight (i.e., percentage of the estimated average), it is possible to describe approximate apparent lower limits of normal GFR as is now done for adults and older children. For children with loss of renal mass, GFR expressed as % nl for age and weight provides a convenient standardization which has several useful applications. First, results expressed as % nl for children of different ages, particularly under 1 year of age, can be combined with those of older children for summary purposes. Second, the course of GFR measured serially in children is more appropriately described using this method for expressing GFR. Reporting GFR in absolute values is also useful, particularly in patients whose body mass is significantly distorted or whose absolute GFR is low.

Monitoring renal function in children with urological abnormalities.

In clinical practice glomerular filtration rate routinely is estimated by measuring serum creatinine and using the Schwartz formula for calculating an estimate of creatinine clearance or using the Gates formula for calculating the clearance of diethylenetriaminepentaacetic acid based on the uptake during radionuclide imaging. We compared these methods to the plasma clearance of iothalamate during extended constant infusion. All 3 tests were performed in 14 boys and 5 girls 9 months to 16 years old with urological abnormalities and moderate renal insufficiency. Using iothalamate as the reference, calculated creatinine clearance overestimated glomerular filtration rate by more than 20% in 12 of the 19 patients (63%). Diethylenetriaminepentaacetic acid uptake grossly overestimated glomerular filtration rate; in only 3 instances was the estimate within 20%. The accuracy of both formulas was better in older patients and in those with more normal renal function. We conclude that the Gates formula for measuring glomerular filtration rate is grossly inaccurate in children with diminished renal function and the Schwartz formula, although better, has a poor level of predictability.

Growth rate in infants with impaired renal function.

We report changes in renal function and growth rate in children with reduced renal function who were kept on a low normal phosphorus formula until 18 months of age. The relationship between serum creatinine values and derived creatinine clearance and residual renal function is reviewed regarding the risk of progressive loss of function. Expressing growth as growth velocity standard deviation scores over 6-month intervals gave a more accurate description of growth performance than did change in height standard deviation scores. A relationship between residual clearance and growth velocity was inferred. However, the growth of children with a less severe reduction in function was affected intermittently by intercurrent infections and inadequately treated acidosis and salt wasting. Children with a more severe reduction in function, despite maintenance on the low-phosphorus formula, had elevated serum parathormone levels. We conclude that following growth (as serial growth velocity standard deviation scores) in relation to other variables gives more insight into factors affecting growth in these children; the level of residual function affects growth potential but other complicating factors also have an effect.

Nutritional management of children with chronic renal failure. Summary of the task force on nutritional management of children with chronic renal failure.

Current information on the adaptations to progressive loss of renal function is presented. The assessment of renal function in infants and children using serum creatinine concentration and its derivatives is considered as are various methods for assessment of growth. Children with creatinine clearances less than 50% of normal, who do not have uremic symptoms (and who are not on dialysis), should be ingesting diets providing close to 100% of the RDA for calories with 8% of the calories as protein. Recommendations for nutritional management of children on chronic peritoneal dialysis are also presented.