Jan Hau LeeYoke Hwee ChanOi Fah LaiJanil Puthucheary

Vasopressin and copeptin levels in childrenwith sepsis and septic shock

Received: 21 February 2012Accepted: 31 December 2012Published online: 24 January 2013� Springer-Verlag Berlin Heidelberg andESICM 2013

J. H. Lee ()) � Y. H. Chan � J. PuthuchearyChildren’s Intensive Care Unit,Department of Paediatric Subspecialties,KK Women’s and Children’s Hospital,100 Bukit Timah Road,Singapore 229899, Singaporee-mail: leejanhau@gmail.comTel.: ?65-6394-2708Fax: ?65-6394-1700

J. H. Lee � Y. H. Chan � J. PuthuchearyDuke-NUS Graduate School of Medicine,8 College Road, Singapore 169857,Singapore

O. F. LaiDepartment of Clinical Research,Singapore General Hospital, Outram Road,Singapore 169608, Singapore

Abstract Purpose: Levels ofvasopressin and its precursor copeptinin pediatric sepsis and septic shockare not well defined. The main aim ofthis study is to compare the serumlevels of vasopressin and copeptin inchildren with septic shock or sepsisand in healthy children. We hypoth-esized that vasopressin and copeptinlevels are elevated in early and latestages of pediatric septic shock.Methods: Three groups wereincluded: healthy children, childrenwith clinical diagnosis of sepsis, andchildren admitted to the pediatricintensive care unit (PICU) withdiagnosis of sepsis shock. Bloodsamples were drawn from children inall groups within 24 h of admission.For the septic shock group, addi-tional samples at 24-h intervals weredrawn up to 120 h after PICUadmission. We used competitiveimmunoassays to determine vaso-pressin and copeptin levels.Results: There were 70 children inthe control group, 53 children in the

sepsis group, and 13 in the septicshock group. At baseline, there was adifference in median vasopressinlevels [60.9 (Interquartile range:32.3, 138.0) vs. 141.1 (45.2, 542) vs.326 (55.6, 399) pg/mL, p \ 0.05],but there was no difference in co-peptin levels [1.2 (0.8, 1.8) vs. 1.5(1.0, 2.2) vs. 0.9 (0.8, 1.2) ng/mL,p = 0.14] between the three groups.There was no difference in vaso-pressin and copeptin levels in earlyand late stages of pediatric septicshock. Conclusions: Baselinevasopressin levels were differentbetween the three groups. In pediat-ric septic shock, vasopressin andcopeptin levels are not robust mark-ers for severity and clinicaloutcomes.

Keywords Vasopressin � Copeptin �Sepsis � Septic shock � Pediatrics �Child

Introduction

Severe sepsis and septic shock are common admissiondiagnoses to the pediatric intensive care unit (PICU) [1, 2].There has been an improvement in the mortality rateof children with septic shock over the past decade, withcurrent mortality rates ranging between 10 and 18 % [3, 4].Aggressive fluid resuscitation immediately after hospi-tal admission, appropriate antibiotics, inotropes and

vasopressors form the cornerstones of treatment manage-ment [5]. In children with catecholamine-resistant shock,vasopressin can be considered as additional therapy [3, 6, 7].

Vasopressin is also an important hormone in the regu-lation of vascular tone [8]. In contrast to the relativedeficiency of vasopressin in adults with septic shock [9, 10],studies in children with septic shock have shown thatvasopressin levels were elevated on admission and remainedso over the first 72 h following admission [11, 12].

Intensive Care Med (2013) 39:747–753DOI 10.1007/s00134-013-2825-z PEDIATRIC ORIGINAL

The physiological significance of vasopressin makes itslevels in children with sepsis and septic shock of greatrelevance in the critical care management of these children.However, measurement of vasopressin has been problem-atic in the clinical setting mainly due to its short half-lifeand instability [13, 14].

Copeptin has recently been investigated as an alterna-tive surrogate marker [13, 14]. Copeptin is a stable peptidewhich is quantitatively cleaved from the vasopressin pre-cursor. Being more stable in plasma and serum, laboratorymeasurement of copeptin is more reliable [13, 14]. Thesecharacteristics make copeptin an attractive surrogatemarker for endogenous vasopressin levels. To the best ofour knowledge, there are no studies investigating thelevels of copeptin in children with sepsis and septic shock.

To address this gap in the medical literature, we con-ducted a prospective study to compare the levels ofvasopressin and copeptin in children with sepsis and septicshock with a control group. We planned to examine thedistribution of data a priori in order to determine the mostappropriate method to test the hypothesis that vasopressinand copeptin levels are elevated in early and late stages ofpediatric septic shock, and that their levels are correlatedwith severity of illness and vasopressor need in childrenwith septic shock.

Materials and methods

We conducted a single center prospective study in a ter-tiary hospital in Singapore (KK Women’s and Children’sHospital) between July 2008 and December 2011. Ourhospital is a tertiary pediatric hospital with 600 beds, 20high-dependency beds and 16 PICU beds. We recruitedchildren from three clinical work areas: general wards,high-dependency ward and PICU. Our main groups ofinterest were children with sepsis and septic shock.Informed consent was obtained from the parents of allchildren for this study. The study was approved by theInstitutional Review Board of our hospital.

Subjects

Children with sepsis admitted to the general ward and high-dependency units were approached and recruited in thesepsis group. We used the same sepsis definition proposedat the International Pediatric Sepsis Consensus (IPSC)conference [15]. Children with sepsis and features of car-diovascular organ dysfunction (as defined at the IPSCconference) from PICU were recruited in the septic shockgroup [15]. For the control group, we recruited previouslywell children admitted for elective gastrointestinal endos-copy, pre-operative children for circumcision, inguinalhernias and chronic orthopedic conditions.

Neonates weighing \2.5 kg, neonates \36 weeks ges-tation, children[16 years of age, children with a history ofchronic renal impairment, chronic liver impairment, activechemotherapy, chronic mineralocorticoid/glucocorticoidtherapy and central nervous system tumors were excludedfrom the study.

Study procedures

We collected demographic data from all children recruitedin the study. Duration of hospital stay and mortality wererecorded for all children in the sepsis and septic shockgroups. Additionally, in the septic shock group, data onintensive care support (e.g., number of mechanical venti-lation days, number and maximal doses of inotropes andvasopressors) and pertinent laboratory measurements(e.g., creatinine, white blood cell count, platelet count andliver enzymes) were also collected. We used these data togenerate quantitative descriptors of illness severity such asoxygenation index (OI), vasoactive-inotropic score (VIS),and pediatric logistic organ dysfunction score [16–18].

Blood samples for vasopressin and copeptin wereobtained from all recruited children within 24 h of presen-tation to the hospital by an indwelling arterial or venouscatheter (if available) or by venipuncture. Children withseptic shock also had blood drawn for measurement ofvasopressin and copeptin every 24 h up to 120 h afteradmission. Blood samples were drawn using tubes con-taining aprotinin (500 KIU/mL of blood). The samples werecentrifuged at 1,6009g for 15 min at 4 �C. Serum from thetubes were transferred to clean Eppendorf tubes and storedfrozen at -20 �C until the samples were analyzed.

Measurement of AVP and copeptin serumconcentration

Laboratory staff was blinded to the study group of thesamples. Vasopressin in sera was determined using an Arg8-Vasopressin competitive immunoassay kit (Enzo LifeSciences, Exeter, UK). The intra-assay and inter-assayvariability of the kit is \11 and \9 % respectively. Thestandard calibration curve ranged from 4.1 to 1,000 pg/ml.

Copeptin in the sera was determined using a kit pur-chased from Phoenix Pharmaceuticals Inc. (Karlsnuhe,Germany). The assay is designed to detect a specific co-peptin peptide based on the principle of competitiveenzyme immunoassay. The standard calibration curveranged from 0.01 to 100 ng/ml. Precision was stated asintra-assay variation of 5–10 % with inter-assay varia-tion \15 %. Minimum detectable range was 0.24 ng/ml.

Statistical analysis

Statistical analyses were performed using STATA 12(College Station, TX). We examined the distribution of

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continuous variables and described the appropriate sum-mary statistics for them. For continuous variables, we usedthe Wilcoxon rank-sum and Kruskal–Wallis tests to com-pare between two and three groups respectively. In thecontrol group, we examined the difference in vasopressinand copeptin levels between genders by the Wilcoxon rank-sum test. We used the Kruskal–Wallis test to compare themedian values of vasopressin and copeptin between thethree groups within the first 24 h of admission, and vaso-pressin and copeptin levels in the septic shock group acrossdifferent time points. For each time point in the septic shockgroup, we performed Spearman’s correlation analysisbetween vasopressin and copeptin with clinical severityscores. For all analyses, a p value\0.05 was considered toindicate statistical significance.

Results

A total of 136 children were enrolled in our study; medianage was 7 years and 6 months [Interquartile range (IQR):3 years 7 months, 11 years 6 months]. The number ofmales was slightly more than females (77 males vs. 59females). Group-wise distribution was 70 children in thecontrol group, 53 in the sepsis group and 13 in the septicshock group (Tables 1, 2).

Pneumonia was the predominant cause of septic shockin our cohort (Table 1). Of the 13 children with septicshock, 12 children were on two or more inotropes orvasopressors; four children were given stress doses of

hydrocortisone (compared to none in the sepsis group).Two patients were on vasopressin infusion prior to thefirst blood sampling. We made the assumption thatexogenous vasopressin infusion may interfere with mea-surement of vasopressin levels. Thus, we excluded thesetwo patients from analysis with regards to vasopressinlevels but kept them for copeptin levels to allow usmeasure the level of endogenous copeptin in thesepatients. The median Pediatric Logistic Organ Dysfunc-tion score of the septic shock cohort was 12 (IQR: 11, 23).Three children had evidence of acute kidney injury at thetime of baseline blood sampling. Three children in theseptic shock group died (23 %); there were no deaths inthe control and sepsis groups.

There was a significant difference between the threegroups in the baseline vasopressin levels (p \ 0.05)(Table 3). However, there was no difference between thegroups in the baseline copeptin levels (p = 0.14)(Table 3). Given the wide range of serum concentrationsfor vasopressin and copeptin levels in all three groups(Table 3), the percentage coefficient of variation (% CV)between duplicates were calculated in order to validatethe results obtained for both assays. The % CV for bothassays was found to be in the acceptable range of less than10 %. Among septic shock patients, vasopressin and co-peptin levels were not affected by time (Fig. 1a, b).

We compared vasopressin and copeptin levels withVIS and limited our analysis to 72 h (time points with themost number of paired observations). We did not find anycorrelation between vasopressin (R = 0.12, p = 0.57) orcopeptin (R = 0.17, p = 0.42), and VIS, within the first

Table 1 Demographics ofstudy population Control

(n = 70)Sepsis(n = 53)

Septic shock(n = 13)

Age (months)Mean (SD) 120.7 (42.1) 52.6 (42.6) 100 (58.4)Median (IQR) 119.5 (89, 153) 42 (20.5, 83.5) 119 (40, 152.5)

Gender, N (%)Males 44 (62.9) 27 (50.9) 6 (46.2)

Race, N (%)Chinese 34 (48.6) 22 (41.5) 6 (46.2)Malay 27 (38.6) 20 (37.7) 5 (38.5)Indian 4 (5.7) 8 (15.1) 0 (0)Others 5 (7.1) 3 (5.7) 2 (15.4)

Source of sepsis, N (%)Respiratory Not applicable 34 (64.2) 6 (46.2)Gastrointestinal 6 (11.3) 0 (0)Renal 6 (11.3) 2 (15.4)Central nervous system 2 (3.8) 0 (0)Others 5 (9.4) 5 (38.5)

PRISM score, median (IQR) Not applicable 4 (0, 4) 13 (10, 22)Mechanical ventilation, N Not applicable 0 5Worst oxygenation index within 24 h

of admission, median (IQR)Not applicable Not applicable 18.9 (5.1, 30)

Maximum vasoactive-inotrope score within24 h of admission, median (IQR)

Not applicable Not applicable 18.5 (13.4, 25)

PICU length of stay (days), median (IQR) Not applicable Not applicable 6 (3, 8)Hospital length of stay (days), median (IQR) Not applicable 3 (2, 5) 12 (9, 15)

IQR interquartile range, PICU pediatric intensive care unit, SD standard deviation

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72 h of septic shock. We did not find any correlation ofvasopressin or copeptin levels with length of stay in thePICU. We examined the clinical characteristics of thepatients with outlier values of vasopressin and copeptin inall three groups and did not find obvious abnormal clin-ical parameters or clinical course.

Discussion

Vasopressin plays an important role in cardiovascularhomeostasis [19]. Exerting its effect on V1-receptors, it isa potent vasoconstrictor; it promotes water retention viaV2-receptors at the collecting ducts and plays a role in thebody’s stress response by stimulating adrenocorticotro-phic hormone secretion. The role of copeptin in the bodyis less clear, but it seems to be involved in ensuring thecorrect folding of vasopressin with no systemic effects[20]. Upon appropriate hemodynamic or osmotic stimuli,both vasopressin and copeptin are secreted into the cir-culation [13]. The in vivo half-life of vasopressin is24 min; however, the in vivo half-life of copeptin isunknown [13].

There are limited studies on vasopressin in pediatricseptic shock; even the ones that are available are con-flicting to each other. In an abstract publication involving11 children with septic shock from the age of 1 week to15 years old, mean vasopressin levels (4.83 ± 4.23 pg/ml)were significantly lower compared to previously pub-lished normal values (p \ 0.01) [21]. It was not stated inthe abstract when this sample of vasopressin was taken.Leclerc et al. [12] studied children with meningococcemia

and showed that the median vasopressin level of 18children with meningococcal septic shock was signifi-cantly higher compared to the median value of 15children with meningococcal infection without shock[41.6 (range 1.4–498.9) vs. 3.3 pg/ml (range 1.6–63.8),p = 0.001]. However, Lodha et al. [11], who studied 18children with septic shock and 20 children with sepsis, didnot show any statistically significant difference betweenthe median admission values of vasopressin between thetwo groups (116 vs. 106 pg/ml, p = 0.88). Our studyresults are consistent with those from Leclerc et al. [12] inthat we did find a statistically significant difference invasopressin levels between children with sepsis and septicshock and the control group.

Unlike in children, vasopressin levels have beenshown to be inappropriately low for the degree of hypo-tension among adults with refractory septic shock. Landryet al. [22] demonstrated that vasopressin levels weresignificantly lower in patients with septic shock comparedto patients with cardiogenic shock. Sharshar et al. [9]showed that approximately one-third of septic shockpatients have vasopressin deficiency, and this oftenoccurred at the late phase of septic shock. Given theinconsistent values in vasopressin levels in children withseptic shock, we postulate that vasopressin levels may below in a small subset of children with septic shock.Indeed, two of our children with septic shock receivedvasopressin infusion as part of their management forseptic shock within the first 24 h as they remainedhypotensive despite being on four vasopressors/inotropes.These conflicting and inconclusive results in vasopressinmeasurements could be in part due to its instability insera, the short half-life, and the difficulties of vasopressinmeasurement in the laboratory. This has led to a shift tomeasuring copeptin as it has the advantage of a longerin vitro half-life, more stability in the collection processand lack protein binding [14, 23].

There are limited studies on copeptin in children withsepsis and septic shock. Schlapbach et al. [24] studiedinfants with early onset sepsis and found there was nostatistically significant difference in median values ofcopeptin between infants with early onset sepsis andhealthy controls [35 (IQR 8–212) vs. 21 pmol/L (IQR5–324), p = 0.56]. A note to keep in mind while inter-preting this result is that cord blood was taken at birth andthe diagnosis of early onset sepsis in neonates can bemade up to 72 h of life. A study measuring copeptin

Table 2 Laboratory values of study population

Sepsis Septic shock

CRP, mg/dLMean (SD) 108.3 (101.1) 207.9 (133.3)Median (IQR) 88 (23.9, 164.7) 184.9 (145.9, 294.7)

TW, 9109

Mean (SD) 16.1 (9.3) 14.3 (11.7)Median (IQR) 14.7 (8.4, 22.0) 9.8 (2.7, 24.4)

Na, mmol/LMean (SD) 135 (3) 133 (5.5)Median (IQR) 136 (134, 137.5) 133 (132, 135)

CRP C-reactive protein, IQR interquartile range, Na sodium, SDstandard deviation, TW total white cell count

Table 3 Baseline vasopressinand copeptin levels of studypopulation

Control Sepsis Septic shock p^

Vasopressin,pg/mL, median (IQR)

60.9 (32.3, 138.0) 141.1 (45.2, 542) 326 (55.6, 399) \0.05

Copeptin,ng/mL, median (IQR)

1.2 (0.8, 1.8) 1.5 (1.0, 2.2) 0.9 (0.8, 1.2) 0.14

IQR interquartile range^ Kruskal–Wallis test

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levels in children with severe dengue infection did notshow any difference in copeptin levels at baseline betweenhealthy children and children with dengue hemorrhagicfever; there was also no difference in copeptin levels at48 h compared to baseline[25]. Although there are sig-nificant differences in pathophysiology of denguehemorrhagic shock and septic shock, it is likely that most,if not all, children with dengue hemorrhagic fever anddengue shock syndrome will satisfy the definition of sepsisand septic shock proposed at the IPSC conference, whichwe used in our study. The findings of our study and currentevidence suggest that copeptin may not be a robust markerfor pediatric sepsis and septic shock.

Results from adult patients have been more conclusiveand supportive for the value of vasopressin and copeptinas a marker of severity of sepsis and septic shock. Joch-berger et al. [26] showed that there was a significantdifference between baseline vasopressin levels in criti-cally ill adults admitted to the intensive care unit (ICU)compared to normal healthy adults (11.9 ± 20.6 vs.0.92 ± 0.38 pg/mL; p \ 0.001). This same study showedthat patients with hemodynamic dysfunction had higher

serum vasopressin concentrations than patients withouthemodynamic dysfunction (14.1 ± 26 vs. 8.7 ± 10.8 pg/mL; p \ 0.005) [26]. This group was not exclusivelycomposed of patients with septic shock, but also includedpatients with other forms of shock, such as cardiogenicshock. Studies examining copeptin levels in adults withsepsis and septic shock were more consistent than thoseconducted in children. Preliminary studies did show sta-tistically significant higher copeptin levels among patientswith sepsis and septic shock compared to healthy controls[13, 27]; and this finding was further strengthened by asmall prospective cohort of adult patients with infectionand septic shock wherein copeptin levels on the first dayof admission were higher in adults with septic shockcompared to adults with infection [28]. However, thisstudy did not show any difference between vasopressinlevels between adults with septic shock and adults withsepsis. We postulate that the inconsistency of vasopressinand copeptin levels in pediatric studies may be in part dueto the disparity in pathophysiology of septic shockbetween adults and children. Children tend to preservetheir systematic vascular resistance (SVR) to a greaterdegree compared to adults in evolving septic shock. Thispreservation of vascular tone independent of circulatingvasopressin and copeptin may be the reason for theinconsistent vasopressin level trends and observed lack ofdifference in copeptin levels between children with sepsisand septic shock in our study. The inconsistency ofvasopressin and copeptin deficiency in septic shock mayalso explain the lack of mortality benefits in pediatricpatients with vasodilatory shock treated with low-dosevasopressin [29]. Unfortunately, we were not able tomeasure SVR in our patients with septic shock, as it wasnot routine clinical practice in our PICU. Measuring SVRin future studies will be helpful in understanding thedifferences in the role played by vasopressin and copeptinin the physiology of septic shock in children and adults.

In our study, in contrast to baseline vasopressin levels,there was no difference in copeptin levels between thethree groups. Previously reported studies did not alwaysshow consistent results between these two closely relatedsubstances. Within the first day of admission to the ICU,Jochberger et al. [28] demonstrated a difference in co-peptin levels, but not vasopressin levels, between adultpatients with sepsis and septic shock. In addition to theinherent challenges in vasopressin measurement, there areother possible explanations for this inconsistency. Thedegree of inflammation has been shown to affect the ratioof copeptin to vasopressin [30]. As C-reactive protein is asurrogate marker of the differences in degree of inflam-mation, the differences in the degree of inflammationbetween the sepsis and septic shock groups could be aplausible reason for differing results in baseline vaso-pressin and copeptin levels in our study (Table 2). Thereare, however, other clinical settings where copeptinmeasurements have been shown to be a reliable surrogate

Fig. 1 a Vasopressin across different time points in septic shockgroup, b copeptin across different time points in septic shock group

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for vasopressin measurement. One such clinical setting isamong adults who underwent noncardiac surgery withpostoperative systemic inflammatory response syndrome(SIRS). A prospective study of 41 adults with threecomparison groups (abdominal surgery without SIRS,postoperative SIRS, and SIRS with shock) that excludedpatients with sepsis showed that copeptin levels correlatedsignificantly with vasopressin levels (R = 0.76,p \ 0.001) [31]. This study also demonstrated that thiscorrelation is affected by renal replacement therapy.

There are a few limitations in our study. We have a muchsmaller number of children in the septic shock group com-pared to the sepsis and control groups. This was mainly dueto the exclusion criteria that we used for our study. Since ourstudy was exploratory, and we did not have any evidence onwhat effect underlying diagnoses and treatment such as braintumors or chemotherapy have on copeptin secretion, we feltthat it was reasonable to exclude these patients. Follow-upstudies examining copeptin levels in children with onco-logical diagnosis and chemotherapy may be valuable. Thesmall number of children in the septic shock group limitedour availability to control for other variables (e.g., cortico-steroids, use of norepinephrine, dopamine, intensity of painand anxiety) that potentially can affect vasopressin levels insepsis. Including all these potential ‘‘confounders’’ in amultivariable analysis in a small sample will not be mean-ingful. We acknowledge that these factors may have indeedcontributed to the lack differences between the groups. Also,we did not perform serial levels of vasopressin and copeptinin children with sepsis, as most studies have demonstrateddifferences at the onset of septic shock [28]. Hence, we feltthat it was not reasonable to subject children who were notcritically ill to multiple venipunctures.

Conclusion

In our study, a difference was found in median vaso-pressin levels at baseline between the three groups.However, there was no difference in baseline copeptinlevels. There was also no difference in serial values ofvasopressin and copeptin in children with septic shock.The heterogeneity of clinical sepsis remains a majorchallenge in clinical research of pediatric septic shock.Moving forward, we propose that pediatric critical carepractitioners focus research efforts within the first 24 h ofseptic shock and consider utilizing a strategy of investi-gating multiple markers simultaneously. Recenttechnologies such as multiplex immunoassays may beuseful because they are capable of measuring a panel ofmarkers simultaneously [32]. This multi-biomarkerapproach can potentially help to stratify children in whomdifferences in early vasopressin and copeptin levels aremost marked, and can aid in better clinical use of vaso-pressin in septic shock.

Acknowledgments This study was funded by the NationalResearch Medical Council, Singapore under the New InvestigatorGrant award. The authors would like to thank Ms. Liu Juan, Ms. YuBuDuo, Ms. Ng Poh Ling and Ms. Diana Teo from the hospital’sresearch center for their administrative assistance and recruitmentof patients; and Ms. Cecilia Chandra and Dianne Bautista for theirkind statistical advice. The authors also appreciate the support ofSingHealth/Duke-NUS Academic Medicine Research Institute,Singapore and medical editing assistance of Taara Madhavan(Associate in Clinical Sciences, Duke-NUS Graduate MedicalSchool, Singapore).

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