Intraoperative Rapid PTH Protocols in Primary Hyperparathyroidism (PHPT)

Intraoperative rapid PTH does not itself define cure:
- It is an intraoperative predictor of adequacy of resection
Formal cure after parathyroidectomy:
- Is still biochemical eucalcemia lasting at least 6 months
Rapid PTH works:
- Because intact PTH has a short half-life:
  - Roughly 3 to 5 minutes:
    - So levels should fall quickly after all hyperfunctioning tissue is removed
The AAES guidelines:
- Recommend intraoperative PTH monitoring with a reliable protocol for minimally invasive parathyroidectomy:
  - They note cure rates of about 97% to 99% in selected patients when adjunctive IPM is used
Core concept:
- The practical question in the OR is:
  - “Has all hypersecreting parathyroid tissue been removed?”
    - Rapid PTH helps answer that in real time
Most protocols use a baseline sample before incision and / or immediately before excision:
- Then a post-excision level at 10 minutes, with an additional 20-minute sample when the decline is borderline or delayed
The most common reason the curve is misleading:
- Is a PTH spike from gland manipulation:
  - Which is why many surgeons rely on the highest pre-incision or pre-excision value rather than only the pre-incision sample
Main intraoperative PTH protocols
- The classic comparative study of 260 patients with concordant imaging:
  - Found overall accuracy of:
    - 97.3% for Miami, 92.3% for Vienna, 83.8% for Rome, and 65% for Halle criteria
  - In that same study:
    - Miami criteria was the best-balanced criterion for predicting cure:
      - Whereas Rome and Halle were somewhat better for detecting multigland disease but at the cost of more negative conversions to bilateral exploration
The Miami criterion:
- Is the most widely used:
  - A > 50% fall from the highest pre-incision or pre-excision PTH level, measured 10 minutes after excision of the abnormal gland
- In the major Miami experience and subsequent reviews:
  - This approach achieved about 97% to 98% sensitivity, 97% specificity, ~99% PPV, and ~97% to 98% overall accuracy for postoperative eucalcemia
- Long-term follow-up from the Miami group also showed durable outcomes with very low recurrence after focused surgery guided by intraoperative rapid PTH
- This is why, in everyday endocrine surgery practice, the Miami criterion is usually the most useful protocol:
  - It is easy to remember, fast, reproducible, and has the best overall balance between avoiding persistent disease and avoiding unnecessary wider exploration
- A 2024 network meta-analysis including 72 studies and 19,072 patients found that among conventional criteria:
  - The Miami criterion had the best diagnostic properties overall
Vienna criterion:
- The Vienna criterion also uses a > 50% drop at 10 minutes:
  - But the reference is the defined pre-incision baseline rather than the highest pre-excision value
- It was designed to standardize interpretation and improve identification of multigland disease
- In the comparative dataset above:
  - Vienna performed well, with 92.3% overall accuracy:
    - But still not as well as Miami for routine prediction of cure
  - In practical terms, Vienna is reasonable if your team insists on a strict, fixed baseline, but it is less forgiving when pre-excision manipulation creates a spike:
    - That is one reason many high-volume groups prefer Miami’s use of the highest available baseline
Halle criterion:
- Is much stricter:
  - Success is called only when PTH drops into the low-normal range:
    - Classically around 35 pg/mL:
      - Shortly after excision
- This gives excellent specificity, but it performs poorly as a routine stopping rule because many successfully treated patients still have PTH levels above that threshold intraoperatively:
  - Especially if starting levels are high or clearance is delayed
- In the Barczyński comparison, Halle had 100% specificity but only 65% overall accuracy:
  - Meaning it would trigger many unnecessary further explorations
- For that reason, Halle is usually not the best default criterion for standard sporadic PHPT with concordant imaging:
  - It is too strict for routine use
Rome criterion:
- Is a more complex, stricter protocol
- In one description, it requires a > 50% fall from the highest pre-excision level and / or a value within the normal range and / or an additional fall by 20 minutes
- The point of Rome is to improve detection of persistence and multigland disease:
  - Especially when the early curve is ambiguous
- A 2022 study evaluating the Rome approach found that the 20-minute / baseline ratio:
  - Had the highest diagnostic significance and suggested the 20-minute sample is particularly informative
- Rome can be useful when the 10-minute value is borderline, when preoperative localization is less reliable, or when multigland disease is a real concern:
  - But as a standard protocol for all focused cases, it adds complexity and tends to increase exploration without clearly outperforming Miami for overall cure prediction
What do meta-analyses say about using ioPTH at all?
- Beyond comparing criteria, the broader question is whether using ioPTH improves outcomes
- A 2021 systematic review / meta-analysis of 28 studies and 13,323 patients found operative failure rates of 3.2% with ioPTH versus 5.8% without ioPTH:
  - With a significant reduction in persistent / recurrent PHPT when ioPTH was used
- Another 2021 systematic review / meta-analysis focused on minimally invasive parathyroidectomy included 12 studies and 2,290 patients and found that ioPTH use was associated with higher cure rates (OR 3.88, 95% CI 2.12–7.10) and a lower need for reoperation:
  - It did increase conversion to bilateral exploration, but without higher morbidity
- So the evidence supports the value of ioPTH, especially when doing focused or minimally invasive surgery and when multigland disease is a concern
Are stricter cutoffs better?
- Usually, not enough to justify routine adoption
- Newer work continues to test stricter thresholds:
  - A 2025 ROC analysis found that a 60% drop gave the best balance of sensitivity and specificity in that cohort, outperforming 50% and 70% on AUC, but the authors also cautioned that stricter thresholds may cause overtreatment and unnecessary exploration
  - Similarly, a 2025 two-center study suggested that combining the Miami rule with normalization to the reference range may help in selected cases, but the overall literature still favors the Miami criterion as the best general-purpose rule, which is consistent with the large network meta-analysis
Practical interpretation in the OR
- A resident-friendly approach is:
  - Draw pre-incision and pre-excision PTH
  - Remove the suspected gland
  - Check 10-minute PTH
  - If > 50% drop from the highest baseline → likely cure, stop if anatomy and clinical context fit
  - If borderline or not adequate → wait for 20-minute level and continue exploration if still not satisfactory
  - That approach handles the common real-life issues:
    - Manipulation spikes, delayed clearance, and occult multigland disease
When rapid PTH is especially helpful:
- Rapid PTH is most helpful in:
  - Focused / minimally invasive parathyroidectomy
  - Discordant or equivocal localization
  - Suspicion for multigland disease
  - Reoperative surgery
  - Cases where confirmation of adequacy of excision will determine whether you stop or proceed to wider exploration
Bottom line: which protocol is most useful?
- For most sporadic PHPT cases, especially with focused surgery:
  - The Miami criterion is the most useful protocol:
    - It has the best combination of simplicity, speed, evidence base, and diagnostic performance, and it remains the most widely adopted and best-supported criterion in comparative studies and network meta-analysis
Key references:
- Wilhelm SM, et al. AAES Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016.
- Barczyński M, et al. Evaluation of Halle, Miami, Rome, and Vienna intraoperative iPTH assay criteria. Langenbecks Arch Surg. 2009.
- Khan ZF, et al. Intraoperative Parathyroid Hormone Monitoring in the Surgical Management of Sporadic PHPT. Endocrinol Metab. 2019.
- Quinn AJ, et al. Systematic review/meta-analysis of ioPTH in MIP. JAMA Otolaryngol Head Neck Surg. 2021.
- Medas F, et al. Systematic review/meta-analysis of rapid ioPTH. Int J Surg. 2021.
- Staibano P, et al. Network meta-analysis of diagnostic test accuracy. JAMA Otolaryngol Head Neck Surg. 2024/2025 indexing.