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Annals of Clinical & Laboratory Science 36:67-72 (2006)
© 2006 Association of Clinical Scientists

Severe Hypophosphatemia in Sepsis as a Mortality Predictor

Renana Shor1, Aaron Halabe1, Sofia Rishver1, Yulian Tilis1, Zipora Matas2, Asora Fux2, Mona Boaz3 and Julio Weinstein4
1 Departments of Internal Medicine and Metabolic Bone Diseases, 2 Biochemistry, 3 Statistics, and 4 Diabetes, Edith Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Address correspondence to Renana Shor, M.D., Edith Wolfson Medical Center, PO Box 5, Holon, Israel; fax 972 3 502 8382; e-mail: halabe{at}wolfson.health.gov.il.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Hypophosphatemia has long been reported to be associated with sepsis and has been correlated with sepsis severity. This retrospective study was undertaken at a university hospital to determine whether severe hypophosphatemia could serve as a mortality predictor in septic patients. Charts of 6,190 septic patients who were hospitalized during one year (2001–02) were examined. Fifty-five patients were selected and were divided into 2 groups: group 1 comprised 26 patients with severe hypophosphatemia (serum inorganic phosphate (Pi) <1 mg/dl); group 2 comprised 29 patients without severe hypophosphatemia (Pi >1 mg/dl. The patients’ charts were reviewed and information was collected regarding medical anamnesis, physical examination, hematological and biochemical analyses, chest x-ray, and cultures of blood and urine. The results demonstrated that 80.8% of the patients with severe hypophosphatemia died, vs 34.5% of the patients without severe hypophosphatemia (p = 0.001). Being in the severe hypophosphatemic group increased the risk of death by nearly 8-fold (odds ratio = 7.98; 95% CI = 2.3 to 27.6). These findings indicate that severe hypophosphatemia can serve as an independent mortality predictor in sepsis.

Keywords: hypophosphatemia, sepsis, mortality prognosis


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hypophosphatemia has long been reported to be associated with sepsis and gram-negative infections. Hypophosphatemia develops in the early stages of sepsis and is correlated with the severity of the patient’s clinical condition [1,2]. A high incidence of hypophosphatemia was observed in patients with sepsis during the initial 24 hr of hospitalization and serum inorganic phosphate (Pi) levels <2 mg/dl were especially suggestive of Gram negative sepsis [3,4].

The mechanism by which hypophosphatemia develops involves redistribution of Pi from the extracellular fluid into the cells [5]. The underlying mechanisms that explain the deleterious role of hypophosphatemia in sepsis involve phosphate participation in diverse metabolic pathways that relate to ventricular stroke work and arterial pressure [6,7]. Zazzo et al [8] reported that mortality rate was increased in surgical intensive care unit patients with hypophosphatemia, compared to patients with a normal serum Pi (30% vs 15.2%, respectively; p <0.05). Their study involved a heterogeneous group of patients that included subjects with sepsis, diabetes, alcohol withdrawal, or insulin infusion. In the present study we have tested the contribution of hypophosphatemia in predicting outcome in a homogeneous group of septic patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The charts of 6,190 patients with sepsis who were hospitalized at the Edith Wolfson Medical Center during one year (2001–2002) were reviewed. Sepsis was defined according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference [9] (see boxGo).


Definitions of SIRS and Sepsis (ACCP/SCCM Consensus Conference [9])

Systemic Inflammatory Response Syndrome (SIRS). The systemic inflammatory response to a wide variety of severe clinical insults, manifested by ≥ 2 of the following conditions:

  1. Temperature >38°C or <36°C,
  2. Heart rate >90 beats/min,
  3. Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
  4. White blood cell count >12,000/mm3, <4000/mm3, or >10% immature (band) forms.

Sepsis. The systemic inflammatory response to a documented infection. In association with infection, manifestations of sepsis are the same as those defined for SIRS. It should be determined whether they are a direct systemic response to the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities. The clinical manifestations would include ≥ 2 of the following conditions as a result of documented infection:

  1. Temperature >38°C or <36°C,
  2. Heart rate >90 beats/min,
  3. Respiratory rate >20 breaths/min or PaCO2 <32 mmHg,
  4. White blood cell count >12,000/mm3, <4000/mm3, or >10% immature (band) forms.

 

Septic patients were categorized into 2 matching groups: patients with serum phosphate levels >1.0 mg/dl and patients with severe hypophosphatemia (<1 mg/dl). Patients with alcoholic ketoacidosis, diabetes mellitus (type 1 or those treated with insulin), patients receiving hyperalimentation, antacids, vitamin D preparations, calcium carbonate, or acetazolamide were excluded from the study. The patients’ charts were reviewed and information was collected regarding age, gender, alcohol consumption, medications taken at home, and medical anamnesis. Results of the physical examination were recorded, including blood pressure, temperature, respiratory rate, and pulse. Also recorded were results of chest x-ray and routine laboratory analyses, including complete blood count, urea, creatinine, glucose, calcium, electrolytes, liver enzymes, total protein, albumin, INR, PTT, blood gases, urinalysis, and blood and urine cultures.

Serum inorganic phosphate concentrations (Pi) were measured with an Olympus AU 2700 analyzer using the manufacturer’s reagents. Serum Pi reacts with molybdate to form an intensely colored heteropolyacid complex. Absorbance at 340/380 nm is directly proportional to the Pi concentration. The reagent mixture contains a surfactant that eliminates the need to prepare a protein-free filtrate [10,11]. The reference population included hospitalized patients and those who came to the emergency room. Only 0.42% of the reference population had serum Pi levels <1 mg/dl. The reference values for serum Pi laboratory for adults <60 yr of age are 2.7 to 4.5 mg/dl, and 2.3 to 3.7 mg/dl for those ≥ 60 yr of age. The coefficient of variation of replicate analyses is 1.59%.

Data analyses were carried out using SPSS software (version 9.0, SPSS, Inc., Chicago, IL, USA). Serum Pi levels were dichotomized into Pi <1.0 mg/dl, which was considered as severely hypophosphatemic, and ≥ 1.0 mg/dl, which was considered as not severely hypophosphatemic. For continuous variables, such as age and laboratory parameters, descriptive statistics were calculated and reported as mean ± SD. Normalcy of distribution of continuous variables was assessed using the Kolmogorov-Smirnov test. Normally distributed continuous variables were compared between the severe and non-severe hypophosphatemic groups using the t-test for independent samples. Continuous variables with distributions that deviated significantly from normal were compared by Pi group using the Mann-Whitney U test. Categorical variables such as sex, comorbidities, and concomittant medications were described using frequency distributions. The Chi-square test with 99% Monte Carlo confidence intervals was used to detect differences in categorical variables by Pi group. Odds ratios with 95% confidence intervals (CI) were calculated for death using the Mantel-Haenszel test by Pi group. Logistic regression analysis was used to find odds ratios for death while simultaneously examining covariates. All tests were two-sided and differences were considered significant at p <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 55 patient charts was identified: 26 with severe hypophosphatemia (group 1) and 29 without severe hypophosphatemia (group 2). The patients’ ages ranged from 31 to 92 yr in the severe hypophophatemic group and from 33 to 92 yr in the non-severe hyophosphatemic group. The patients’ characteristics are shown in Tables 1Go and 2Go. As can be seen, fever (37.8 ± 1.0°C vs 37.1 ± 0.9°C. p = 0.014) and blood pH (7.44 ± 0.09 vs 7.34 ± 0.10, p = 0.009) were significantly higher, while serum creatinine (1.1 ± 0.6 mg/dl vs 2.4 ± 3.0 mg/dl, p = 0.035), serum calcium (7.6 ± 1.2 mg/dl vs 8.4 ± 0.9 mg/dl, p = 0.015), and serum Pi (0.8 ± 0.1 mg/dl vs 4.3 ± 2.0 mg/dl, p <0.001) were significantly lower in patients with severe hypophosphatemia (group 1) compared to patients in group 2. Hypertension was less frequent in the severely hypophosphatemic group (23.1% vs 62.1%, p = 0.006), as was the use of diuretics (15.4% vs 58.6%, p = 0.002).


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  		Table 1. Descriptive parameters of patients with sepsis, categorized by serum Pi concentrations.
 

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  		Table 2. Comparisons of continuous variables, categorized by serum Pi concentrations (data are mean ± SD).
 
Comparison of continuous variables by death (Table 3Go) showed that subjects who died (group A) had lower values of Hb (9.7 ± 1.6 g/dl vs 10.8 ± 1.8 g/dl, p = 0.026) pCO2 (32.4 ± 7.6 mmHg vs 55.9 ± 39.8 mmHg, p = 0.002), bicarbonate (19.9 ± 7.3 mmol/L vs 25.5 ± 6.6 mmol/L p = 0.035), and Ca (7.7 ± 1.2 mg/dl vs 8.5 ± 0.8 mg/dl, p = 0.011). Serum Pi was not significantly lower in patients who died compared to those who survived.


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  		Table 3. Comparison of continuous variables, categorized by death (group A) or survival (group B) (data are mean ± SD).
 
When using severe hypophosphatemia (Pi <1mg/dL) as a predictor of death, we found that death occurred more frequently in the severe hypophosphatemic group (group 1). Thus, 80.8% of patients in group 1 died compared to 34.5% in group 2 (p = 0.001). The Mantel Haenszel odds ratios (OR) for death were 7.98 (95% CI 2.3–27.6). In other words, being in the severely hypophosphatemic group increased the risk of death by nearly 8-fold (Table 4Go). Controlling for age, sex, Hb, and calcium strengthened the association of severe hypophosphatemia and death: OR = 11.2 (95% CI: 2.17–58.12). The other variables were not significantly associated with death.


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  		Table 4. Severe hypophosphatemia as a predictor of death in patients with sepsis.
 
Subjects with a positive blood culture showed marginally significant elevation of serum Pi values compared to subjects with negative cultures (3.36 ± 2.4 mg/dl vs 2.1 ± 2.2 mg/dl, p = 0.07). Subjects positive for Gram negative bacteria had significantly higher serum Pi values than subjects without existing Gram negative bacteria (3.8 ± 2.3 mg/dl vs 2.3 ± 2.3 mg/dl, p = 0.047). Only one patient was positive for Gram positive bacteria. Positive blood cultures were negatively associated with death. Specifically, among patients who died, 26.7% had positive blood cultures compared to 56.5% of subjects who survived (p = 0.041).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The association of hypophosphatemia and sepsis is well established and has even been proposed as a diagnostictool [1,12]. A highincidenceof hypophosphatemia was reported during the initial 24 hr of hospitalizations; phosphate levels <2 mg/dl were especially suggestive of Gram negative sepsis [3].

In this study, we demonstrated that death was more frequent in septic patients with severe hypophosphatemia compared to those without severe hypophosphatemia (80.8% vs 34.5%, p = 0.001). In a logistic regression model of death, including sex, age (universal confounders), severe hypophosphatemia (Pi <1.0 mg/dl), and positive blood culture, only severe hypophosphatemia was significantly associated with death (odds ratio 7.98, 95% CI 2.3 to 27.6). In other words, being in the low Pi group increased the risk of death 8-fold. Another important finding was that subjects positive for Gram negative bacteria had higher serum Pi levels compared to subjects with sterile blood cultures (3.8 ± 2.3 mg/dl vs 2.3 ± 2.3 mg/dl, p = 0.047). Further, a positive blood culture was negatively associated with death. Specifically, among patients who died, 26.7% had positive blood cultures compared to 56.5% of subjects who survived (p = 0.047). It seems possible that patients with positive blood cultures received antibiotic treatment that was better oriented towards the exact pathogen and therefore they faired better than those who were treated empirically. Moreover since the antibiotic treatment was prescribed according to culture results, more efficient bacterial cell death might be expected to occur, thus causing the release of lipopolysaccharides, which in turn increase the concentration of inflammatory cytokines [13].

Interestingly, significant inverse associations have been reported between inflammatory cytokines and serum Pi levels, especially in patients with positive blood cultures [14]. Since high levels of inflammatory cytokines are observed in the early stages of sepsis, elevated cytokine levels could provide an explanation for the association of early sepsis and hypophosphatemia [14].

The mechanism by which hypophosphatemia develops involves redistribution of phosphate from extracellular fluid into the cells. Acute respiratory alkalosis as occurs in sepsis causes a rise in intra-cellular pH, which stimulates phosphofructokinase activity and glycolysis [15]. The stimulated glycolysis increases the formation of phosphorylated carbohydrate compounds, which draw their phosphate from the extracellular fluid, causing decreased serum Pi levels [5,15].

Zazzo et al [8] reported that 28.8% of surgical intensive care patients had hypophosphatemia. They identified 3 risk factors for the development of hypophosphatemia: sepsis, diuretics, and total parenteral nutrition. Compared to normophosphatemic patients, their hypophosphatemic group had a higher mortality rate (30% vs 15.2%, p <0.05). Unlike our study, however, the patients evaluated by Zasso et al [8] were heterogenous. including subjects with alcohol withdrawal, total parenteral nutrition (TPN), cachexia, gastrointestinal wasting, multiple blood transfusions, and sepsis. Furthermore, the decrease in Pi levels was not uniform. Not surprisingly, the increased mortality in Zazzo et al’s study was attributed to higher incidence of sepsis and septic shock [8]. Other potential deleterious effects of hypophosphatemia that are of primary importance in sepsis and septic shock include decreased myocardial contraction, increased incidence of cardiac arrythmias, impaired response to vasopressive agents, and decreased oxygen delivery to tissues [2,6–8]. It is possible that the common underlying mechanisms that explain the deleterious role of hypophosphatemia in sepsis involve phosphate participation in diverse metabolic pathways that relate to venticular stroke work and arterial pressure [2,6–8]. It was reported that severe hypophosphatemia resulted in a 50% depression of chemotactic phagocytic and bactericidal activity of granulocytes.

Decreased granulocyte ATP levels have also been demonstrated, which could suggest diminished neutrophil survival as well [16]. These defects all occurred when serum Pi depletion was severe (<1 mg/dl) [2,5,6]. These findings may partially explain the association between hypophosphatemia and increased mortality.

We conclude that septic patients with severe hypophosphatemia have a higher mortality rate compared to a similar group with higher serum Pi levels. In septic patients, severe hypophosphatemia can serve as a meaningful and easily monitored prognostic marker, which is less costly and more convenient to measure than inflammatory markers (cytokines). Clinicians should be cognisant of the importance of severe hypophosphatemia in sepsis and should observe it carefully.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Von Landenerg P, Shoenfeld Y. New approaches in the diagnosis of sepsis. Israel Med Assn J 2001;3:439–442.
  2. Schwartz A, Gurman GM, Cohen G, Gilutz H, Brill S, Schily M, Gurevitch B, Shoenfeld Y. Association between hypophosphatemia and cardiac arrhytmias in the early stages of sepsis. Europ J Inter Med 2002;13:434–438.
  3. Riedler GF, Scheitlin WA. Hypophosphatemia in septicaemia: higher incidence in gram-negative than in gram-positive infections. Br Med J 1969;22:753–756.
  4. Lentz RD, Brown DM, Kjellstrand CM. Treatment of severe hypophosphatemia. AnnIntern Med 1978;89:941–944.
  5. Brautbar N, Leubovici H, Massry SG. On the mechanism of hypophosphatemia during acute hyperventilation: evidence for an increased muscle glycolysis. Mineral Electrolyte Met 1983; 9:45–50.
  6. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. NEJM 1977;297:183–187.
  7. Saglikes Y, Massry SG, Iseki K, Brautbar N, Brandt R, Brunton LL, Buxton IL, Vlachakis N, Campese VM. Effect of phosphate depletion on blood pressure and vascular reactivity to norepinephrine and angiotensin II in the rat. Am J Phisiol 1985;248:F93–99.
  8. Zazzo JF, Troche G, Ruel P, Maintenant J. High incidence of hypophosphatemia in surgical intensive care patients: efficacy of phosphorus therapy on myocardial function. Intensive Care Med 1995;21:826–831.[Medline]
  9. Bone RC, Balk RA, Carra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–1655.[Abstract/Free Full Text]
  10. Daly JA, Ertingshavsen G. Direct method for determining inorganic phosphate in serum with Centrifichem. Clin Chem 1972;18):263–265.[Abstract/Free Full Text]
  11. Gamst O, Try K. Determination of serum phosphate without deproteinization by ultraviolet spectrophotometry of the phosphomolybdic acid complex. Scand J Clin Lab Med 1980;40:483–486.
  12. Shoenfeld Y, Hager S, Berliner S, Gallant LA, Pinkhas J. Hypophosphatemia as a diagnostic aid in sepsis. NY State J Med 1982;82:163–165.[Medline]
  13. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis 1999;179:S294–304.
  14. Barak V, Schwartz A, Kalickman I, Nisman B, Gurman G, Shoenfeld Y. Prevalence of hypophosphatemia in sepsis and infection: The role of cytokines. Am J Med 1998;104:40–47.[Medline]
  15. Travis S, Sugerman HG, Ruberg RI, Dudrick SJ, Delivoria-Papadopoulos M, Miller LD, Oski FA. Alterations of red-cell glycolytic intermediates and oxygen transport as a consequence of hypophosphatemia in patients receiving intravenous alimentation. NEJM 1971;285:763–768.[Medline]
  16. Craddock R, Yawata Y, VanSanten L, Gilberstadt S, Silvis S, Jacob S. Acquired phagocyte dysfunction. A complication of the hypophosphatemia of parenteral hyperalimentation. NEJM 1974;290:1403–1407.[Medline]



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