Non-invasive haemodynamic monitoring to individualise fluid resuscitation in adult diabetic ketoacidosis: A randomized controlled pilot trial

Table 1 Schedule of enrollment, interventions, and outcome assessments

Outcome	Admission	First fluid resuscitation	Day 1	Day 2	Day 3	Last fluid resuscitation	Day 4	…	Day 13	Day 14	Discharge
Fluid replacement	-	-	1, 2	1, 2	1, 2	-	1	1	1	1	-
Days of hospitalisation	-	-	-	-	-	-	-	-	-	-	1, 2
Complications	-	1	1	1	1	1	1	1	1	1	1, 2
Time to urine ketone conversion	-	-	1	1	1	-	1	1	1	1	1, 2
Blood glucose	1, 2	-	1, 2	1	1, 2	-	1	1	1	1	1
USCOM technical parameters	-	1, 2	1	1	1	1, 2	-	-	-	-	-

¹Indicates that the outcome was measured at the corresponding time point.

²Indicates that data from that time point are reported in the results section.

Timing of measurements for prespecified trial outcomes from admission through day 14 and hospital discharge, including fluid replacement, length of hospitalisation, complications, time to urinary ketone clearance, blood glucose and ultrasonic cardiac output monitor-derived haemodynamic parameters. USCOM: Ultrasonic cardiac output monitor.

Table 2 Baseline demographic and clinical characteristics of the study population, mean ± SD

Parameter	USCOM group (n = 25)	Control group (n = 25)	Statistical effect size	P value
Age (years)1	51.8 ± 13.5	44.1 ± 18.1	1.70	0.093
BMI (kg/m2)1	24.1 ± 2.5	24.8 ± 4.3	-0.74	0.464
SBP (mmHg)1	127.1 ± 16.1	132.5 ± 23.1	-0.95	0.346
DBP (mmHg)1	77.8 ± 10.6	76.0 ± 15.5	0.47	0.641
MAP (mmHg)1	94.2 ± 11.5	94.8 ± 16.8	-0.15	0.881
Heart rate (bpm)1	102.2 ± 19.4	104.1 ± 18.1	-0.35	0.731
Respiratory rate (breaths/minute)1	24.7 ± 6.1	22.5 ± 5.1	1.35	0.180
SpO2 (%)1	96.6 ± 2.1	96.2 ± 1.4	0.80	0.431
Sex (male/female)2	11/14	10/15	0.04	0.396

¹Independent-samples t-tests.

²Pearson’s χ² or Fisher’s exact tests.

Baseline demographic, vital sign, and clinical characteristics of participants randomized to ultrasonic cardiac output monitor-guided vs control management. Data are presented as mean ± SD unless otherwise stated. P values compare groups using appropriate parametric or non-parametric tests (for instance, independent-samples t-tests for continuous variables and χ² or Fisher’s exact tests for categorical variables), as indicated by superscripts in the table. BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MAP: Mean arterial pressure.

Table 3 Fluid intake, net fluid balance, and urine output in ultrasonic cardiac output monitor-guided vs control groups, mean ± SD

Time point	USCOM group (n = 25)	Control group (n = 25)	t-value	Cohen’s d	Mean difference	95%CI	P value
Fluid replenishment (mL)
24 hours	6514.04 ± 1925.03	6230.80 ± 1433.69	0.590	0.167	283.24	-681.97 to 1248.45	0.558
48 hours	3052.68 ± 933.51	3010.96 ± 1386.33	0.125	0.035	41.72	-630.37 to 713.81	0.901
72 hours	1751.04 ± 544.65	2328.88 ± 733.72	-3.162	-0.894	-577.84	-945.29 to -210.39	0.003a
Total 72 hours	11317.76 ± 2436.41	11570.64 ± 2726.75	0.35	0.10	-252.88	-1217.82 to 1723.58	0.730
Net fluid replenishment (mL)
24 hours	2681.68 ± 1833.34	3351.00 ± 1232.93	-1.515	-0.428	-669.32	-1557.76 to 219.12	0.136
48 hours	2934.12 ± 1529.80	4180.96 ± 1833.98	-2.610	-0.738	-1246.84	-2207.22 to -286.46	0.012a
72 hours	2916.36 ± 1542.48	4675.84 ± 2021.83	-3.459	-0.978	-1759.48	-2782.10 to -736.86	0.001a
Urine output (mL)
24 hours	3832.36 ± 1015.11	2879.80 ± 1148.91	3.107	0.879	952.56	336.05-1569.07	0.003a
48 hours	2800.24 ± 1411.51	2181.00 ± 1112.64	1.723	0.487	619.24	-103.51 to 1341.99	0.091
72 hours	1768.80 ± 839.23	1834.00 ± 978.60	-0.253	-0.072	-65.20	-583.61 to 453.21	0.801

^aP < 0.05.

Overall, compared with the control group, the ultrasonic cardiac output monitor (USCOM) group demonstrated significantly lower net fluid replenishment at 48 hours and 72 hours, significantly lower fluid replenishment at 72 hours, and significantly higher urine output at 24 hours. Values are presented as mean ± SD. Independent-samples t-tests were used to compare USCOM and control groups at each time point. The mean difference was calculated as the USCOM group minus the control group; therefore, negative values indicate lower values in the USCOM group. The 95% confidence interval represents the confidence interval around the mean difference. Effect sizes were estimated using Cohen’s d, calculated from the pooled SD. P values are two-sided and were not adjusted for multiple comparisons. USCOM: Ultrasonic cardiac output monitor; CI: Confidence interval.

Table 4 Blood glucose trajectories, urinary ketone clearance, and length of hospital stay, mean ± SD

Time point	USCOM group (n = 25)	Control group (n = 25)	t-value	Cohen’s d	Mean difference	95%CI	P value
Blood glucose (mmol/L)
24 hours	16.07 ± 3.62	15.99 ± 4.51	0.07	0.02	0.08	-2.25 to 2.41	0.944
48 hours	15.81 ± 3.54	14.84 ± 4.15	0.89	0.25	0.97	-1.23 to 3.17	0.377
72 hours	13.85 ± 4.09	13.32 ± 3.23	0.51	0.14	0.53	-1.56 to 2.62	0.612
Time for urinary ketone bodies to turn negative (day)
Discharge	6.04 ± 2.29	6.28 ± 2.59	0.35	0.10	-0.24	-1.15 to 1.63	0.730
Length of hospitalisation (day)
Discharge	7.8 ± 2.77	9.72 ± 3.38	2.18	0.62	-1.92	0.15-3.69	0.034a

^aP < 0.05.

Blood glucose concentrations at 24 hours, 48 hours, and 72 hours after admission, time to urinary ketone clearance, and total length of hospitalisation in ultrasonic cardiac output monitor-guided and control groups. Data are presented as mean ± SD, with mean differences and 95% confidence interval. P values are from two-sided independent-samples t-tests. “Discharge” denotes the time point at which the participant left the hospital. Time to urinary ketone clearance is defined as the cumulative number of hospital days from admission until the last recorded urinary ketone test is negative. USCOM: Ultrasonic cardiac output monitor; CI: Confidence interval.

Table 5 Haemodynamic effects of ultrasonic cardiac output monitor-guided fluid resuscitation in the intervention group, mean ± SD

Parameters	Baseline	Post-resuscitation	t-value	Cohen’s d	Mean difference	95%CI	P value
SV (mL)	29.8 ± 4.5	68.6 ± 9.7	14.82	2.96	38.8	33.2-44.4	< 0.001
CO (L/minute)	3.0 ± 0.7	5.4 ± 1.0	12.00	2.40	2.4	1.9-2.9	< 0.001

Stroke volume and cardiac output were measured by ultrasonic cardiac output monitor at baseline (before the first rehydration therapy) and after completion of protocolised fluid resuscitation in the ultrasonic cardiac output monitor group. Data are paired means ± SD, with within-patient mean differences and 95% confidence interval. P values are from two-sided paired t-tests, chosen to minimise inter-individual variability when comparing the same patient before and after treatment. Baseline indicates measurements before the first rehydration therapy; post-resuscitation indicates measurements obtained before the last rehydration treatment. SV: Stroke volume; CO: Cardiac output; CI: Confidence interval.

Table 6 Incidence of complications in ultrasonic cardiac output monitor-guided vs control groups, n (%)

Complication	USCOM group (n = 25)	Control group (n = 25)	χ2	Cohen’s d	Absolute risk difference	95%CI	P value
Hypoglycemia1	6 (24)	5 (20)	0.12	0.086	+0.04	-0.19 to 0.27	0.733
Hypokalemia1	6 (24)	5 (20)	0.12	0.086	+0.04	-0.19 to 0.27	0.733
Pulmonary oedema2	0 (0)	1 (4)	-	0.252	-0.04	-0.12 to 0.04	0.313
Acute kidney injury2	2 (8)	3 (12)	-	0.134	-0.04	-0.21 to 0.09	0.640
Arrhythmia2	5 (20)	3 (12)	-	0.274	+0.08	-0.12 to 0.28	0.440

¹Pearson’s χ² tests.

²Fisher’s exact tests as indicated.

Incidence of prespecified complications - including hypoglycaemia, hypokalaemia, pulmonary oedema, acute kidney injury and arrhythmia - from the initiation of fluid resuscitation until hospital discharge. Values are the number of patients (%) in each group, together with absolute risk differences and corresponding 95% confidence interval. USCOM: Ultrasonic cardiac output monitor; CI: Confidence interval.

Table 7 Fluid intake, net fluid balance, and urine output in participants younger than 60 years, mean ± SD

Time point	USCOM group (n = 17)	Control group (n = 21)	t-value	Cohen’s d	Mean difference	95%CI	P value
Fluid replenishment (mL)
24 hours	6637.35 ± 2220.25	6232.43 ± 1402.32	0.69	0.22	404.92	-794.0 to 1603.8	0.497
48 hours	3035.59 ± 921.23	3141.10 ± 1403.68	-0.27	0.09	-105.51	-907.6 to 696.6	0.787
72 hours	1727.76 ± 456.78	2300 ± 699.01	-2.91	0.95	-572.24	-973.1 to -171.3	0.006a
Total 72 hours	11400.71 ± 2677.67	11669.24 ± 2840.30	-0.30	0.10	-268.53	-2079.5 to 1542.5	0.773
Net fluid replenishment (mL)
24 hours	2759.12 ± 2007.14	3200.76 ± 1081.40	-0.82	0.27	-441.64	-1555.0 to 671.7	0.424
48 hours	2748.94 ± 1400.17	4036.62 ± 1816.50	-2.40	0.78	-1287.68	-2376.0 to -199.4	0.021a
72 hours	2796.71 ± 1579.76	4442.81 ± 2007.73	-2.76	0.89	-1646.10	-2855.7 to -436.5	0.009
Urine output (mL)
24 hours	3878.24 ± 1083.97	3031.67 ± 1144.61	2.32	0.76	846.57	108.7-1584.4	0.026a
48 hours	3045.76 ± 1584.61	2305.24 ± 1134.93	1.68	0.54	740.52	-153.2 to 1634.2	0.102
72 hours	1680 ± 635.42	1899.05 ± 1016.13	-0.81	0.25	-219.05	-768.5 to 330.4	0.423

^aP < 0.05.

Subgroup analysis of cumulative fluid intake, net fluid balance, and urine output at 24 hours, 48 hours, and 72 hours and over the first 72 hours among participants aged < 60 years in ultrasonic cardiac output monitor-guided and control groups. Data presentation, definitions of time intervals, and statistical methods are as described for Table 3. USCOM: Ultrasonic cardiac output monitor; CI: Confidence interval.

Table 8 Fluid intake, net fluid balance, and urine output in participants aged 60 years or older, mean ± SD

Time point	USCOM group (n = 8)	Control group (n = 4)	t-value	Cohen’s d	Mean difference	95%CI	P value
Fluid replenishment (mL)
24 hours	6252 ± 734.71	6222.25 ± 1417.23	0.05	0.03	29.75	-1274.9 to 1334.4	0.961
48 hours	3089 ± 899.41	2327.75 ± 791.66	1.43	0.87	761.25	-372.2 to 1894.7	0.184
72 hours	1800.5 ± 665.55	2503 ± 793.00	-1.63	1.00	-702.5	-1623.8 to 218.8	0.135
Total 72 hours	11141.5 ± 1807.49	11053 ± 1952.32	0.08	0.05	88.5	-2342.9 to 2520.0	0.939
Net fluid replenishment (mL)
24 hours	2517.125 ± 1217.20	4139.75 ± 1496.80	-2.04	1.24	-1622.625	-3286.0 to 39.7	0.069
48 hours	3327.625 ± 1620.86	4938.75 ± 1473.68	-1.67	1.02	-1611.125	-3686.8 to 464.5	0.127
72 hours	3170.625 ± 1318.32	5899.25 ± 1246.86	-3.44	2.10	-2728.625	-4385.3 to -1071.9	0.005a
Urine output (mL)
24 hours	3734.875 ± 761.75	2082.5 ± 517.27	3.87	2.37	1652.375	701.1-2603.7	0.002a
48 hours	2278.5 ± 491.07	1528.75 ± 395.61	2.64	1.61	749.75	116.4-1383.2	0.024a
72 hours	1957.5 ± 1096.61	1542.5 ± 474.26	0.71	0.43	415	-884.3 to 1714.3	0.495

^aP < 0.05.

Subgroup analysis of cumulative fluid intake, net fluid balance and urine output at 24 hours, 48 hours and 72 hours and over the first 72 hours among participants aged ≥ 60 years in ultrasonic cardiac output monitor-guided and control groups. Data presentation, definitions of time intervals, and statistical methods are as described for Table 3. USCOM: Ultrasonic cardiac output monitor; CI: Confidence interval.

Table 9 Evidence landscape for fluid resuscitation in diabetic ketoacidosis

Evidence domain	Direction	Certainty	Clinical maturity	Core interpretation
Guideline-based fluid resuscitation	↑	Moderate	Established care	Fluid resuscitation remains foundational, but most protocols rely on fixed formulas and static clinical assessment
Fluid composition: Balanced crystalloids vs normal saline	↗	Low-moderate	Selective clinical use	Balanced fluids may improve acid-base or chloride profiles, but evidence remains heterogeneous
Fluid rate and volume strategies	?/↗	Low-moderate	Contextual evidence	Paediatric evidence predominates; optimal adult-specific rates and volumes remain uncertain
Rehydration timing and complications	?	Low	Contextual/risk evidence	Excessive or poorly tailored fluid strategies are associated with neurological complications, AKI, or prolonged hospitalisation, but causal inference is limited
Protocol/order-set implementation	↗	Low-moderate	Implementation evidence	Standardised protocols may improve adherence and DKA resolution but may introduce trade-offs such as hypoglycaemia
Adult DKA evidence-based	?	Low	Evidence gap	Adults remain underrepresented despite high clinical burden and comorbidity-related fluid-overload risk
Dynamic haemodynamic monitoring	↗	Low	Experimental clinical approach	No previous included study used non-invasive haemodynamic or stroke-volume-guided protocols; the present pilot trial provides proof-of-concept evidence
High-risk adults, older patients, and those with cardiac/renal comorbidity	?	Very low	Hypothesis-generating	These populations may benefit most from individualised monitoring, but direct evidence is sparse
Resource-limited emergency settings	↗	Low	Translational promise	Portable, non-invasive monitoring may be scalable when invasive monitoring is unavailable, but evidence of its implementation is needed

This table summarises the direction, certainty, and clinical maturity of evidence across primary domains identified in the embedded narrative synthesis of studies on diabetic ketoacidosis (DKA) rehydration. Evidence was organised into domains concerning rehydration timing and complications, fluid type, fluid volume and rate, protocol implementation, adult evidence gaps, and dynamic haemodynamic monitoring. Direction symbols indicate whether the available evidence supports established or clinically relevant practice, suggests promising but preliminary findings, or remains uncertain or indirect. The clinical translation continuum distinguishes established guideline-based care, selective clinical use, contextual or implementation evidence, experimental clinical approaches, and evidence gaps requiring future trials. Overall, the evidence supports the central role of fluid resuscitation in DKA, but most existing studies rely on fixed protocols, fluid-composition comparisons, or retrospective data on implementation. Adult DKA populations are underrepresented, and no previous study in the included evidence base used non-invasive haemodynamic monitoring or stroke-volume-guided fluid resuscitation. The present ultrasonic cardiac output monitor-guided pilot trial therefore occupies the experimental clinical approach stage and provides proof-of-concept evidence for a physiology-guided strategy. Certainty categories are narrative and reflect study design, population relevance, consistency, and directness. “↑”: Established or clinically relevant evidence; “↗”: Promising but preliminary evidence; “?”: Uncertain, indirect, or heterogeneous evidence; AKI: Acute kidney injury; DKA: Diabetic ketoacidosis.